[Senate Hearing 110-]
[From the U.S. Government Publishing Office]



 
DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES, EDUCATION, AND RELATED 
              AGENCIES APPROPRIATIONS FOR FISCAL YEAR 2008

                              ----------                              


                         MONDAY, MARCH 26, 2007

                                       U.S. Senate,
           Subcommittee of the Committee on Appropriations,
                                                    Washington, DC.
    The subcommittee met at 3:30 p.m., in room SD-116, Dirksen 
Senate Office Building, Hon. Tom Harkin (chairman) presiding.
    Present: Senators Harkin and Specter.

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

                     National Institutes of Health

STATEMENT OF HON. THOMAS R. INSEL, M.D., DIRECTOR, 
            NATIONAL INSTITUTE OF MENTAL HEALTH

                OPENING STATEMENT OF SENATOR TOM HARKIN

    Senator Harkin. The Appropriations Subcommittee on Labor, 
Health and Human Services, and Education and Related Agencies 
will come to order. This is the subcommittee's second hearing 
on the National Institutes of Health this year. Last week we 
heard from NIH Director Elias Zerhouni and several top 
extramural scientists as we discussed the need for more NIH 
funding. Starting today and over the course of the 
subcommittee's next five NIH hearings, we will hear from each 
of the Institute and center Directors, usually in groups of 
four or five.
    We had actually done this before. I like this room, I like 
the setting, I like the way that we are at a table here, which 
makes it more conversational, rather than just sitting at a 
podium, that type of thing. So I like this much better. This is 
one of our Appropriations rooms. In fact, our predecessor on 
this when I first came to this committee used this room and we 
had those hearings at that time. I like the idea. I like the 
setting of it, so I am going to try to use this room as often 
as possible for these kinds of hearings. It is not as formal, 
it is more relaxed, and we can have a conversation.
    I will ask each of the Directors to speak for about 5 
minutes. We have your statements. We will make them a part of 
the record in their entirety. So I am just going to ask you for 
about 5 minutes to talk about some of the most important 
functions that you see in what you are doing, and then we will 
have a discussion with you, and we will do each Director's 
time. So I am thinking about 15 minutes per person, and we will 
do it that way. Then at the end, maybe if there are some wrap-
up things, then we will just kind of open it for a general 
thing at that time.
    So the five Institutes that are here today--NIMH, Mental 
Health; National Institute on Drug Abuse, NIDA; the National 
Institute on Alcohol Abuse and Alcoholism, otherwise known as 
NIAAA; National Institute on Deafness and Communication 
Disorders; and the National Institute of Neurological Disorders 
and Stroke, Dr. Landis. We grouped these together because all 
of these have to do with mind-brain behavior, and I am going to 
try to continue this kind of lumping together of different 
Institutes as we have these hearings.
    However, I just say that if you have other things you want 
to bring up, please do. Anything happening in your Institutes 
is fair game for us to discuss.
    With that, I turn to Senator Specter if you have anything 
in opening.

               OPENING STATEMENT OF SENATOR ARLEN SPECTER

    Senator Specter. Thank you, Mr. Chairman.
    We continue our hearings on the National Institutes of 
Health, and I consider this to be a matter of priority second 
to none in our budget. Health is our principal capital asset 
and the work which has been done by NIH has been truly 
spectacular. Senator Harkin and I have taken the lead, as is 
fairly well known, in increasing the funding for NIH from $12 
billion to almost $30 billion, and we have done that by taking 
a very sharp pencil and establishing priorities and eliminating 
items from a very important budget in deference to the greater 
importance of health care.
    We have three major Departments that we are responsible for 
funding: Health and Human Services, Education, and Labor. So 
that we have had to evaluate education priorities and worker 
safety priorities and health care priorities. But NIH has the 
potential to be a fountain of youth, in my opinion, and to 
really find ways to fund cures for many, many ailments.
    I say with some frequency, but not often enough, that when 
President Nixon declared war on cancer in 1970--had that war 
been pursued with the same intensity as other wars--my chief of 
staff, a beautiful young woman named Carie Lackman, at 48 would 
not have died of breast cancer, and last year one of my best 
friends, the Chief Judge of the Third Circuit emeritus, would 
not have died of prostate cancer; and I would not have gotten 
Hodgkins.
    When we talk about containing costs, the best way to 
contain costs is to prevent disease and to prevent illness. 
Senator Harkin and I are leading the fight for embryonic stem 
cells. It is scandalous when you have the major responsibility 
for funding health programs in the Federal Government but are 
not able to use any funds for stem cell research. Now, if these 
embryos would produce children we would be the last to suggest 
they be used. But we have taken the lead in putting up $2 
million to have adoptions, but only about 100 of some 400,000 
have been adopted. So it is a matter of useing them to save 
lives or having them ultimately discarded.
    Senator Harkin and I added an amendment to the budget 
resolution last week for $2.2 billion and that is only to stay 
afloat and tread water from the cost of living adjustments. But 
do not draw too much encouragement from it because the budget 
resolution is only Confederate money. The money does not 
materialize until there is an allocation. Then it does not 
materialize until there is an appropriation, and to call it 
Confederate money may be giving it too much credit. It may be 
more accurately called Monopoly money.
    But we are determined to fight this through. You can help 
us. As we said to Dr. Zerhouni last week, we need to have the 
best estimates you can make as to what this research means in 
terms of saving lives and quantifying--I know it is hard to 
do--how long it will take to find a cure for a given malady and 
how much it will save. For example--if you delay the onset of 
Alzheimer's--I have seen some statistics that shows health care 
cost savings into the billions of dollars. But that is what 
motivates the other 535 Members of Congress, if you can be 
specific and show them some savings.
    So thank you for what you are doing and I look forward to 
your testimony.
    Thank you, Mr. Chairman.
    Senator Harkin. Thank you, Senator Specter.
    So we will start with Dr. Insel, then Dr. Volkow, Dr. 
Battey, and then Dr. Landis.
    Dr. Thomas Insel has been the Director of the National 
Institute of Mental Health since September 2002, received his 
B.A. and M.D. degrees both from Boston University. So Dr. 
Insel, welcome. As I said, your statement is part of the 
record. Tell us what you are doing, what is important, and what 
we ought to know about.

                SUMMARY STATEMENT OF DR. THOMAS R. INSEL

    Dr. Insel. Thank you. First of all, Mr. Chairman, let me 
say how much we all appreciate being here. I have been in my 
job now for about 4\1/2\ years. I think this is the first time 
I have had a chance to talk with this subcommittee and update 
you with the kinds of things we are interested in.
    At the beginning, I would like to just very quickly run 
through where we see the biggest needs and then tell you a 
little bit about what we hope to do about them. There is no 
question that the needs across all of these Institutes in terms 
of the public health burden is very great. You will be hearing 
from all five of these NIH Institutes that focus on 
neuroscience and behavior. Together we cover about 1,000 
disorders of the nervous system affecting about 70 million 
Americans. These result in more hospitalizations than any other 
class of illnesses, including cancer and heart disease. You 
will hear about some of the costs, which in aggregate are about 
$800 billion per year. For my Institute, the mental health 
piece of this alone, represents for all health care about 6.2 
percent of the overall cost, and some parts of that are going 
up, such as medications, at a rate of about 20 percent per 
year.

                           PREPARED STATEMENT

    I think you know that the health care costs have now become 
about 16 percent of the GDP, predicted to go up to 20 percent 
by 2016. So these are very significant costs in the entire 
economy.
    [The statement follows:]
               Prepared Statement of Dr. Thomas R. Insel
    Mr. Chairman, and members of the Committee: I am pleased to present 
the fiscal year 2008 President's budget request for the National 
Institute of Mental Health (NIMH). The fiscal year 2008 budget includes 
$1,405,421,000. In my statement, I will call to your attention our 
Nation's most prevalent mental and behavioral disorders and include a 
brief review of our research activities and accomplishments.
              mental disorders are chronic brain disorders
    The NIMH mission is to reduce the burden of mental and behavioral 
disorders, such as depression, schizophrenia, autism, and bipolar 
disorder, through research on mind, brain, and behavior. Research is 
demonstrating that these illnesses are brain disorders, accessible by 
the tools of modern neuroscience. These disorders frequently begin in 
childhood and are chronic,\1\ affecting people of all races and 
ethnicities, in both rural and urban settings. To prevent a lifetime of 
disability for millions of Americans, NIMH research is identifying the 
biological basis of mental disorders, and pinpointing targets for 
diagnosis, prevention, and treatment.
---------------------------------------------------------------------------
    \1\ Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters 
EE. Lifetime prevalence and age-of-onset distributions of DSM-IV 
disorders in the National Comorbidity Survey Replication. Archives of 
General Psychiatry. 2005 Jun;62(6):593-602.
---------------------------------------------------------------------------
                 public health burden of mental illness
    In the most recent national household survey, as many as 44 million 
Americans met criteria for some mental disorder, with roughly 12 
million reporting symptoms so severe as to cause significant disability 
in the past year.\2\ According to the World Health Organization, mental 
disorders are also the leading cause of medical disability in the 
United States and Canada for people ages 15-44. The annual economic 
cost of mental illness in the U.S. is estimated at well over $150 
billion, with most due to the indirect costs of social services.\3\ The 
direct costs of mental health care represent 6.2 percent of the overall 
health care costs,\4\ which totaled 14.5 percent of the gross domestic 
product in 2001 according to the Centers for Medicare and Medicaid 
Services (CMS).
---------------------------------------------------------------------------
    \2\ Kessler, RC, Chiu, WT, Demler, O, Merikangas, KR, Walters, EE. 
Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in 
the National Comorbidity Survey Replication. Archives of General 
Psychiatry. 2005 Jun: 62, 617-627.
    \3\ New Freedom Commission on Mental Health, Achieving the Promise: 
Transforming Mental Health Care in America. Final Report. DHHS Pub. No. 
SMA-03-3832. Rockville, MD: 2003.
    \4\ Mark TL, Coffey RM, Vandivort-Warren R, Harwood HJ, King EC; 
MHSA Spending Estimates Team. United States spending for mental health 
and substance abuse treatment, 1991-2001. Health Affairs (Millwood). 
2005 Jan-Jun;Suppl Web Exclusives:W5-133-W5-142.
---------------------------------------------------------------------------
              advancing clinical research in mental health
    New tools in genomics, imaging, and behavioral science have given 
us traction for progress towards reducing this tremendous public health 
burden. NIMH has adopted the NIH clinical research vision, which 
focuses on the four P's of medical research: increasing the capacity to 
Predict who is at risk for developing disease; developing interventions 
that Pre-empt the disease process; using knowledge about individual 
biological, environmental, and social factors to Personalize 
interventions; and, ensuring that clinical research involves 
Participation from the diversity of people and settings affected.
    The Institute's focus on practical, or ``effectiveness,'' clinical 
trials embodies this research vision. Although traditional clinical 
trials are useful in determining if groups of patients respond to a 
treatment, NIMH's practical clinical trials, conducted with 10,000 
patients at 200 sites across the nation, have helped us to understand 
individual responses to treatment. DNA collected from participants in 
one such trial, the Sequenced Treatment Alternatives to Relieve 
Depression (STAR*D), led to the discovery of genetic variations 
associated with response to antidepressants. Through the inclusion of a 
diverse population, this research also found that the genetic variation 
that predicted a favorable response was less commonly found in African-
Americans. This pharmacogenomic approach can transform the treatment of 
mental disorders, allowing clinicians to personalize therapy choices 
based on a patient's unique biology.
    Results from these practical trials and related studies have taught 
us that current medications are helpful but not sufficient for most 
people with schizophrenia, depression, and bipolar disorder. While 
research on non-drug therapies is showing impressive results in 
treating a variety of mental illnesses, we clearly need a new 
generation of medications that are more effective and better tolerated. 
NIMH research during the past year reported on new classes of 
antidepressants that work within hours rather than weeks. These 
findings suggest that we can expect new medications that will transform 
the treatment of mental illnesses by influencing recently discovered 
targets in the brain.
    New treatments like these antidepressants are based on the emerging 
science of pathophysiology, the study of how brain structure and 
functioning are involved in mental disorders. For instance, research on 
fear has revealed a class of brain receptors and specific brain 
circuits involved in traumatic memories. Clinical trials with 
medications that specifically target those receptors and circuits have 
shown positive effects in reducing stress in response to reminders of 
trauma and, thereby, offer a new treatment for PTSD. Working with the 
Department of Defense and the Department of Veterans Affairs, NIMH is 
supporting research that will treat PTSD and may also prevent the 
persistence of fearful memories, thus pre-empting the development of 
PTSD altogether. With 13 percent of returning soldiers diagnosed with 
PTSD,\5\ we recognize the urgent need for safe and effective pre-
emptive interventions.
---------------------------------------------------------------------------
    \5\ Seal KH, Bertenthal D, Miner CR, Sen S, Marmar C. Bringing the 
War Back Home: Mental Health Disorders Among 103,788 U.S. Veterans 
Returning From Iraq and Afghanistan Seen at Department of Veterans 
Affairs Facilities. Archives of Internal Medicine. 2007 Mar 
12;167(5):476-482.
---------------------------------------------------------------------------
                   partnerships for research progress
    NIMH also aims to accelerate research discoveries through 
collaborative partnerships. Fifteen NIH Institutes invested in research 
on the nervous system have pooled resources to create the NIH Blueprint 
for Neuroscience Research, a framework to enhance collaboration in the 
development of research tools, resources, and training, all of which 
will be made available to the neuroscience research community. 
Initiatives will focus on neurodegeneration in 2007, neural development 
in 2008, and neural plasticity in 2009.
    Through public-private partnerships and additional grants 
coordinated by the Foundation for the National Institutes of Health 
(FNIH), the Genetic Association Information Network (GAIN) program will 
investigate the genetic roots of several common diseases and to provide 
the immediate, broad release of scientific information through a 
publicly accessible database. Four of the six current GAIN initiatives 
are related to brain disorders: attention deficit/hyperactivity 
disorder, schizophrenia, bipolar disorder, and major depressive 
disorder.
    The Biomarkers Consortium is a public-private research partnership 
of the FNIH that includes NIH, CMS, the Food and Drug Administration, 
and industry and advocacy organizations to help identify new and valid 
biomarkers that will advance the creation of innovative technologies 
and therapies for early detection, diagnosis, and treatment of disease. 
Some of the first research findings from the Biomarkers consortium and 
GAIN are expected later in 2007.
    These joint initiatives offer translational opportunities for 
further developing interventions and treatment options that can deliver 
more effective, personalized care across diverse populations and 
settings.
    In summary, this is a time of unprecedented excitement in mental 
health research. Neuroscience and genomics are yielding new insights 
and new treatments, providing great hope for the future. Large-scale, 
practical trials are helping us optimize the treatments available 
today. I appreciate this opportunity to tell you about those exciting 
breakthroughs in the science of mental illness. I look forward to your 
questions.

                   INDIRECT COSTS OF MENTAL ILLNESSES

    Senator Harkin. You are saying that mental health is 6.2 
percent overall? It is not--
    Dr. Insel. It is 6.2 percent of the overall costs of health 
care.
    Senator Harkin. Of the 16 percent.
    Dr. Insel. Of the 16 percent, right, of the GDP.
    Now, you have to recognize that when I talk about the costs 
of health care for mental illness, that is telling you a very 
small part of the story. Many of the costs here are not in the 
health care system per se, but in the social services, what we 
call the indirect costs of these disorders. According to the 
President's New Freedom Commission, which was a report issued 
in 2003, people with mental illness are the largest single 
group of patients in our public assistance programs, like SSI 
and SSDI. They are a large part of our homeless population and, 
according to the Department of Justice program on statistics 
there, our prisons and jails have increasingly become really 
the institutions for those with chronic mental illness, at 
least half of the people incarcerated having a serious mental 
illness, which is just extraordinary.
    Now, how you capture those costs is quite difficult. None 
of them are captured when we talk about the costs of health 
care. At the very least, I think it is fair to say that these 
indirect costs of mental health care swamp whatever it is that 
we are paying in the direct costs of providing medical care to 
those with mental illnesses. As you will hear, this is also 
true for addiction and alcoholism.

                            CHRONIC DISEASE

    It is probably equally important for you to realize that 
the real costs are not just in dollars, but in lives lost. As 
Senator Specter was saying, this is really a question of saving 
lives. You probably heard from Dr. Zerhouni that we are now 
thinking of the 21st century as the era of chronic disease, and 
that is undoubtedly true. Diabetes, hypertension, and heart 
disease are all chronic diseases which will become the big 
challenge of this century.
    But as you will hear from Dr. Volkow and others, mental and 
addictive disorders, are also chronic diseases. What sets them 
apart is they begin early in life. In a recent study, 50 
percent of adults with mental illness reported onset by age 14, 
75 percent by age 24.
    What that really means is that these are in fact the 
chronic disorders of young people in this country, mental 
illness and addictive disorders. They start early. Many are 
chronically disabling. This is why the World Health 
Organization, when it was looking at the largest sources of 
medical disability, ranked these disorders--mental illness and 
addiction--the number one cause of disability for Americans 
between 15 and 44. So it is an extraordinary saga that is 
largely untold. We often say that the costs in dollars and in 
lives are unacceptably large and largely unrecognized.
    Finally, let me just say before I turn this over is that 
one of the aspects of this, of these disorders being recognized 
as brain disorders, is that the group of people who are here at 
the table are now very much all of one mind. We can work 
together and collaborate in a way that was not as obvious a 
decade ago. You can see that in a number of ways. Not only do 
we recognize that there is a lot of comorbidity--Parkinson's 
and depression, certainly PTSD and addiction, bipolar illness 
and alcohol abuse--but it is also in the tools that we need.

                         NEUROSCIENCE BLUEPRINT

    So we have come together to form the Neuroscience 
Blueprint, which I believe Dr. Zerhouni may have mentioned. It 
is an attempt to collaborate and to develop resources and tools 
that will serve all these Institutes and will make a difference 
for people with brain disorders. We have also got the 
embodiment of this collaborative effort in a new facility, the 
Porter Neuroscience Building, under the NIH intramural program, 
which is a very exciting effort that I hope I can tell you more 
about during the question period.
    So I am going to stop here so we have more time, but I do 
want to say how much we appreciate the opportunity to be here.

                        DRUGS AND MENTAL HEALTH

    Senator Harkin. Dr. Insel, thank you very much.
    Let me just lead this off. First of all, just a general 
question. On mental health, are we putting too many eggs in the 
basket of finding a drug that masks, that perhaps gets someone 
through a tough time to respond to the immediacy of a mental 
illness? Are we putting too much in just finding these kind of 
drugs rather than getting to the underlying cause and taking 
the time and research to understand what led to that point?
    I say that because it just seems to me that more and more 
people with mental illness are just taking more and more drugs. 
I will tell you of a case I know vaguely, someone I happen to 
know. I do not want to get too specific because I want to 
protect privacy. Someone who is on a drug that was--I wish I 
could remember the name. I came here equipped to ask you about 
it. But it was a powerful anti-depressant type drug. When that 
person decided to get off that drug, it was like getting off of 
heroin or something. The bodily reactions and the mental 
reactions of that person getting off that drug was just awful. 
I wondered, why would a doctor prescribe this in the first 
place?
    So again, general question: Are we putting too much into 
just going after drugs or should we be looking at some of the 
underlying causes?
    Dr. Insel. The quick answer is yes. Let me explain that. 
This field in some ways has been cursed by having medications 
that are pretty good. These were not designed rationally. They 
were all discovered by serendipity. But surprisingly, some of 
them actually helped quite a few people. The down side is that 
much of the field of research has really focused on trying to 
improve the existing drugs instead of trying to understand the 
basic pathophysiology of the disorders. Understanding that 
would allow us to know how to design medications that really go 
after the core lesion, the core problem here. It also gives us 
some hints about how to get into preemptive care, how to get 
there before the psychotic part of schizophrenia emerges. We 
know schizophrenia is an illness that has many phases, just 
like heart disease. But we tend to intervene with heart disease 
before a myocardial infarction. We do not wait for someone to 
have a heart attack.
    In this field, we are waiting for someone to have a 
psychotic break before we really intervene. We do not need to 
do that.

                            EATING DISORDERS

    Senator Harkin. You and I discussed this once before, but I 
was told--I am going to repeat this without knowing whether it 
is factual or not, but I was told on more than one time or 
occasion that what I am about to say is true: that the single 
largest cause of young women dropping out of college is eating 
disorders. A lot of this has to do with mental health problems.
    So what is happening here? What is the Institute doing on 
this? Are you looking into eating disorders and the underlying 
mental health problems that either lead to it or exacerbate it?
    Dr. Insel. This is one of the places where, in contrast to 
what I just said about having pretty good medications that work 
for most people, we actually do not have medications that work 
for most people with eating disorders, nor do we have very 
rapid effective targeted psychotherapies or psychosocial 
therapies. This is one of the areas where we have the greatest 
difficulty with treatment.
    Dr. Volkow and I have talked a lot about this and in some 
ways eating disorders resemble an addictive disorder, where a 
lot of women diet, only a few get hooked and start dieting to 
the point where they actually become--it becomes a life-
threatening problem. We do not know how to treat that in a 
quickly targeted way, effectively, as well as we do many other 
disorders.
    We also do not know how to predict who is at risk, and that 
is one of the biggest questions for us. What we would like to 
do is not come up with necessarily the optimal treatment after 
somebody is already down to 65 or 70 percent of their normal 
body weight. We would like to be able to find out how do you 
keep them from getting to that point by intervening very early 
in the process, perhaps before this kind of addictive component 
gets started.

                              EPIGENETICS

    Senator Harkin. The last question before I turn it over to 
Senator Specter. You are expanding a program called Human 
Genetics, Epigenetics, and Genomics Underlying Mental 
Disorders. I know what genetics means, I think I know what 
genomics means, but I do not know what epigenetics is. What is 
that?
    Dr. Insel. It is a new and exciting area which several 
people at this table care a lot about. In a word or in a 
sentence, genetics and genomics have to do with the sequence of 
the genome, so what is the text. Epigenetics are those things 
that modify the text. Think of it as a highlighting pen that 
causes certain parts of the genome to be expressed in a certain 
cell. In any given cell, only about 20 percent of your genes 
get expressed. Now, why is that?
    Now, we partially know there are things that lay on top of 
the sequence. In some cases they reduce expression, in some 
cases they enhance it. That is the epigenetic tag or those are 
the modifiers to gene expression. We want to understand much 
more about how they work.
    Senator Harkin. Have you done much in that area in the 
past?
    Dr. Insel. Well, we have done quite a bit because we are 
interested in those parts--and we know that early experience 
does have something to do with whether you become addicted 
later, whether you develop depression or some of these 
illnesses. But we do not have the tools yet to do this at the 
kind of high throughput, high resolution stage of what we can 
do with genomic sequence. So right in that area we are a little 
bit inhibited from being able to make the kind of progress we 
like. So the next step is going to be tool development.
    Senator Harkin. Senator Specter.
    Senator Specter. Well, thank you, Mr. Chairman. If I may 
say so, I would prefer to hear what the witnesses have to say. 
I am going to have to excuse myself at about 4:30, and my 
preference, if it is acceptable to the chair, would be to hear 
them and then ask a question or two.
    Senator Harkin. Well, the only reason I wanted to do it 
this way is because then it is fresh on our minds. When he says 
something, I can interact with him. I thought we would go down 
each one. I would rather, if you do not mind, do it this way. 
But if you have to leave--and believe me, I understand 
everybody has got different schedules--if you have something 
for one of the directors, if you want to direct it, that would 
be fine.
    Senator Specter. Okay. When it is more pressing than 
hearing them, I will do so. If that arises, I shall.
    Senator Harkin. No, but if you had something you wanted to 
ask someone now, if you have got to go, if you want to ask 
someone now, that would be fine.
    Senator Specter. Well, let me hear Dr. Volkow. I do have 
one question which is very much on my mind, and there may be 
others. But let me defer to Dr. Volkow.
    Senator Harkin. Well, then next we will turn to Dr. Volkow, 
Director of the National Institute on Drug Abuse. Dr. Volkow 
received her B.A. from the Modern American School in Mexico 
City, Mexico, her M.D. from the National University of Mexico, 
Mexico City. Dr. Volkow, welcome. Please take 5 minutes and let 
us know what you are doing out there.
STATEMENT OF NORA D. VOLKOW, M.D., DIRECTOR, NATIONAL 
            INSTITUTE ON DRUG ABUSE
    Dr. Volkow. Mr. Chairman, it is a privilege for me to be 
here with my colleagues to share some of our initiatives at the 
National Institute on Drug Abuse. As you know, the social and 
individual costs of substance abuse and addiction to the 
society are nothing less than staggering and utterly 
unacceptable. On economic costs alone, the Institute of 
Medicine estimated that substance abuse, legal and illegal, 
including nicotine and alcohol, costs this country over half a 
trillion dollars annually, which includes not only medical 
costs but costs associated with the criminal system.
    NIDA's strategy to alter the course of this epidemic is 
based on a multi-pronged approach designed to understand how 
genes shape our brain, how environmental factors affect this 
process, and how brain function links to behavior, including 
that which characterizes addiction, which is the compulsive 
intake of the drug despite its catastrophic consequences.
    From the science we have learned that repeated drug use 
affects the function of multiple systems in the brain, 
including those involved with reward and pleasure, which 
motivate our behaviors on a daily basis, systems involved with 
learning and memory, which change our behavior as a function of 
experience, and systems involved with inhibitory control, which 
allow us to exert volitional control of our behaviors and 
emotions.
    Today I will stress and highlight how stress, one of the 
key environmental factors influencing the vulnerability for 
addiction, affects brain development and how in turn that 
affects the propensity for taking drugs. We have learned that 
addiction is not just a result of chronic drug use, but that 
genetics and, as I say, environmental factors play an 
extraordinarily important role. However, because we can 
currently not change our genes, which actually account for 50 
percent of the vulnerability to become addicted, a better 
understanding about how environment affects how our genes and 
brain develop offers an extraordinary opportunity for 
prevention.
    It is particularly relevant because drug addiction is fully 
preventable even in those that have a genetic predisposition to 
become addicted, provided they do not get exposed to drugs. 
However, the challenge is how you interfere with young people's 
taking drugs. I say young people, and that is because drug 
experimentation basically starts in adolescence and the earlier 
you start taking drugs the greater the vulnerability to become 
addicted. Why is that so? Multiple factors.
    One of them is that the brain when you are an adolescent is 
still in full development and many of the connections that link 
it with one another are not there. For example, the connections 
that associate your limbic brain, that is responsible for 
emotions and desires, with the thinking part of your brain, the 
prefrontal cortex, will not be fully formed until you are in 
your early 20s. As a result of that, adolescents are much more 
prone to engage in risky behaviors such as substance abuse.
    Unfortunately, the consequences of environmental stressors 
that influence the vulnerability for drug abuse start as early 
as in utero. Now we know, for example, from studies in 
laboratory animals that early exposure during pregnancy of 
animals to marijuana leads to a dysfunction of the newborn that 
continues to adulthood.
    Also, some very simple social stressors, such as we now 
know that if there is no physical contact between the newborn 
and the mother, physical contact, that will lead to silencing 
of a gene, what you were speaking about, epigenetics. That lack 
of physical contact silences a gene that is important in 
regulating our response to stress. These newborns then grow up 
to be very, very sensitive to stress, which is one of the 
factors that makes them vulnerable to addiction.
    Unfortunately, we know too well that childhood exposure to 
social and environmental stressors are extremely deleterious. 
Indeed, our studies, for example, show that children that were 
exposed to five or more social stressors that include a parent 
in jail, a parent that takes drugs, physical sexual abuse, 
neglect, are 10 times, 10 times more likely to become addicted 
than those that are not.
    Unfortunately, social stressors occur throughout all of our 
lives and at any age can lead to substance abuse, to the 
transition between substance abuse and addiction, and to 
relapse to those in recovery. Why? Because the systems that 
project stress have tremendous overlap with the systems in the 
brain that project these drugs.

                           PREPARED STATEMENT

    So in summary, we know, we recognize that drug addiction is 
a chronic disease that changes the brain in long-lasting ways, 
that profoundly affect behavior. We know that it is fully 
preventable, even in those that have a genetic vulnerability. 
Inasmuch as predisposition does not equate with 
predetermination, that knowledge about how environment affects 
our genes and our brain biology provides an extraordinary 
opportunity to tailor preventions to those that are at high 
risk because of their genetics or because of their 
environmental factors.
    So thank you for your attention. I will be happy to answer 
any questions you may have.
    [The statement follows:]
                Prepared Statement of Dr. Nora D. Volkow
    Mr. Chairman and Members of the Committee: I am pleased to present 
the fiscal year 2008 President's budget request for the National 
Institute on Drug Abuse (NIDA). The fiscal year 2008 budget included 
$1,000,365,000. Today, I will discuss NIDA's multifaceted strategy to 
help reduce the enormous toll that drug abuse and addiction take on 
this Country, highlighting recent scientific accomplishments, novel 
approaches to prevention and treatment, as well as our strong 
collaborations with other NIH institutes and with the Substance Abuse 
and Mental Health Services Administration (SAMHSA).
                              introduction
    Drug abuse and addiction are a major burden to society; economic 
costs alone are estimated to exceed half a trillion dollars annually in 
the United States--including health, crime-related costs, and losses in 
productivity.\1\ However, as staggering as these numbers are, they 
provide a limited perspective of the devastating consequences of this 
disease.
---------------------------------------------------------------------------
    \1\ Office of National Drug Policy (2004). The Economic Costs of 
Drug Abuse in the United States: 1992-2002. Washington, DC: Executive 
Office of the President (Publication No. 207303). 2004. Centers for 
Disease Control and Prevention. Annual Smoking--Attributable Mortality, 
Years of Potential Life Lost, and Productivity Losses--United States, 
1997-2001 Morbidity and Mortality Weekly Report 54(25):625-628, July 1, 
2005. Harwood, H. Updating Estimates of the Economic Costs of Alcohol 
Abuse in the United States: Estimates, Update Methods, and Data Report 
prepared by the Lewin Group for the National Institute on Alcohol Abuse 
and Alcoholism, 2000. 2000.
---------------------------------------------------------------------------
    The National Institute on Drug Abuse, within the National 
Institutes of Health, is pleased to again report continuing declines in 
both licit and illicit drug use, particularly among our Nation's youth. 
In fact, NIDA's latest Monitoring the Future (MTF) survey results show 
a 23 percent decline over the last five years in any past-month illicit 
drug use by students in the 8th, 10th, and 12th grades combined. 
Declines in teen cigarette smoking, now at its lowest rate since the 
survey began in 1975, signal particularly good news since this will 
translate not only into decreases in cancer-related mortality but also 
decreases in deaths associated with the myriad medical consequences of 
smoking (i.e., chronic obstructive pulmonary disease, asthma, premature 
birth, sudden infant death syndrome, and more). 



    Although abuse of most licit or illicit substances has decreased, 
such is not the case for prescription medications, particularly for 
opiate analgesics, which have produced steep increases in abuse-related 
emergency room admissions. The abuse of prescription medications occurs 
at all ages. However, it is particularly problematic in adolescents 
since this is the time when individuals are most vulnerable to 
addiction. The MTF revealed that in 2006, prescription medications, 
along with over-the-counter drugs (cough medicine), accounted for five 
of the top six drug abuse categories reported by 12th graders, 
marijuana still the most frequently abused illegal drug. Second in 
frequency of abuse was the prescription painkiller Vicodin, with 
roughly 1 in 10 seniors reporting abuse during the past year. 
Amphetamines ranked next, followed by over-the-counter cough medicines, 
with roughly 8 and 7 percent of 12th graders, respectively, reporting 
past-year abuse in 2006.
        prevention efforts--genes, environment, and development
    Because adolescence is typically when drug abuse and addiction take 
hold, NIDA continues to focus research on this vulnerable period of 
development. Given that the brains of adolescents have not fully 
developed, including the connections between brain areas involved with 
emotions and areas involved with judgment and decision-making, 
adolescents are less able to exert inhibitory control over emotions and 
desires and are hence more likely to engage in risky behaviors, 
including drug experimentation. However, the brain at this stage is 
also inherently more plastic, which offers opportunities for prevention 
interventions that could lead to greater resilience.
    Addiction results from the complex interaction of drugs, genes, and 
environmental and developmental factors. Thus NIDA has made the study 
of these interactions a priority, joining with other Institutes and 
organizations to support relevant research. Particularly relevant to 
substance abuse is the social environment, as genetic and imaging 
studies continue to reveal how the interplay of biological (i.e., 
genes, developmental stage) and social influences (i.e., family, peers, 
culture) affect individual choices and decisions about drugs. This 
knowledge is crucial to our future ability to tailor prevention 
interventions to address the risk areas of a given individual.
    NIDA also encourages and supports the development of next 
generation technologies to identify and catalogue the multiple 
functional changes to the DNA (i.e., ``epigenetic'' modifications) that 
can result from environmental variables, such as quality of parenting, 
stress, and exposure to drugs. This avenue of approach requires support 
of research to develop standardized and comprehensive ``phenotypes'' of 
social environments (including family, peers, school, neighborhood, 
community, and culture) that can be monitored at various stages of a 
person's life. A better understanding of the neurobiology of social 
behaviors is relevant both for the treatment of drug addiction as well 
as mental illness, which also involves social aspects of human behavior 
and frequently co-occurs with substance abuse.
                      treatments--novel approaches
    Historically, addiction therapies have targeted the brain's reward 
system to try and interfere with the pleasurable effects of drugs of 
abuse. Now, however, scientists have also identified the broader brain 
circuits that underlie fundamental aspects of drug abuse and addiction, 
such as craving, euphoria, motivation, learning, memory, interoception 
(i.e., sensitivity to internal stimuli such as hunger, pain), and 
inhibitory control--key contributors to addiction. These discoveries 
open wide the range of novel targets for different treatment 
approaches.
    The recent discovery that stroke victims who suffered damage to 
their right insula (a brain area involved in emotional experience and 
interoception) dramatically reduced their smoking behavior points to 
new directions in addiction treatment. Specifically, findings suggest 
that strategies to noninvasively affect activity in the insula may be 
beneficial for addiction. These include use of technologies such as 
rTMS (repetitive transcranial magnetic stimulation), a noninvasive 
method to influence brain activity in specific regions, or 
``neurofeedback,'' where patients learn to regulate specific regions in 
their brains by getting feedback from real-time brain images. Though 
not yet demonstrated for addiction, these techniques have shown 
promising results in depression and in the management of pain. They 
also open up a completely new way to develop psychotherapeutic 
interventions to target specific brain regions or circuits.


    New knowledge of how proteins interact with one another in circuits 
implicated in addiction has prompted the development of novel addiction 
medications. For example, the cannabinoid receptor system, which 
regulates the activity of the dopamine system--the common target for 
the reinforcing effects of all drugs of abuse--holds promise for 
treating various drug addictions and, interestingly, for obesity as 
well.
    Immunotherapeutic strategies offer another unique approach to 
relapse prevention. Such strategies are based on the development of 
vaccines to generate antibodies to the drug that block its entry into 
the brain and thereby interfere with its effects. Cocaine and nicotine 
vaccines are already in clinical trials, and NIDA has requested 
proposals to develop a methamphetamine vaccine.
                     putting research into practice
    A major NIDA objective is to translate findings from basic and 
clinical research to guide and inform the design of prevention and 
treatment interventions that can be successfully implemented in real-
world settings. People involved with the criminal justice system (6.9 
million adult Americans) represent one such group. Approximately half 
of prison inmates meet criteria for alcohol/drug abuse or dependence, 
and yet the vast majority return to the community with no treatment.\2\ 
In addition to the resulting high rate of recidivism for drug abuse and 
re-arrest, a recent study of inmates reported that untreated offenders 
were 12.7 times more likely to die within 2 weeks post-release than 
other state residents and that drug overdose accounted for 70 percent 
of those deaths.\3\ Because research has shown that treatment in the 
criminal justice system works, one of NIDA's initiatives is to support 
services research to help develop interventions that will be acceptable 
and sustained in the criminal justice system.
---------------------------------------------------------------------------
    \2\ Mumola CJ and Karberg JC (2006) Drug use and dependence, state 
and federal prisoners, 2004 (NCJ 213530). Washington, D.C.:Bureau of 
Justice Statistics, U.S. Department of Justice.
    \3\ Binswanger IA, Stern MF, Deyo RA, Heagerty PJ, Cheadle A, 
Elmore JG, Koepsell TD (2007) Release from prison--A high risk of death 
for former inmates. New Engl J Med 356:157-65.
---------------------------------------------------------------------------
    To this end, NIDA created and supports the Criminal Justice Drug 
Abuse Treatment Studies (CJ-DATS) initiative, an inter-agency 
collaboration aimed at bringing new treatment models into the criminal 
justice system to improve outcomes for drug-abusing offenders. To 
facilitate the translation of treatments to the criminal justice 
setting NIDA released a landmark publication entitled Principles of 
Drug Abuse Treatment for Criminal Justice Populations, designed to 
advance the concept of addiction as a brain disease and to summarize 
evidence-based principles for treating addiction in criminal justice 
settings.
    NIDA's Drug Abuse Treatment Clinical Trials Network (CTN) also 
plays a key role in bringing evidence-based treatments to community 
settings by testing the effectiveness of new interventions and by 
training providers in the implementation of research based practices in 
order to promote their acceptance and adoption in the community. To 
further enhance the dissemination and utilization of research findings 
and to expand the involvement of the medical community in the screening 
and treatment of drug abuse, NIDA has launched a new ``NIDA Goes to the 
Doctor'' initiative. As part of this initiative, NIDA recently 
established four Centers of Excellence for Drug Abuse Information, in 
collaboration with the American Medical Association, with the aim of 
advancing addiction awareness, prevention, and treatment in primary 
care practices.
                                hiv/aids
    Drug abuse plays a significant role in the spread of HIV, not only 
via injection drug use but also by increasing risky sexual behaviors. 
The addictive and intoxicating effects of many drugs can alter judgment 
and inhibition and lead people to engage in impulsive and unsafe 
behaviors. Drug abuse and addiction can also worsen the progression of 
HIV and its consequences, especially in the brain. Thus NIDA is 
supporting preclinical and clinical studies that examine the 
interactions between: drugs of abuse and HIV medication, HIV and 
plasticity (relative to changes that lead to addiction), and HIV and 
neurotoxicity (with regard to the adverse drug effects that result in 
neurodegenerative conditions such as dementia and parkinsonian 
symptoms).
    While all groups are affected by HIV/AIDS, not all are affected 
equally. African Americans bear a disproportionate burden of HIV/AIDS 
in the United States, which may in part reflect data showing that 
African Americans are predominant among those who become aware of their 
infection at later stages in the disease process, and who therefore 
represent lost opportunities for treatment. Because early HIV detection 
helps prevent its transmission and increase health and longevity--and 
is as cost-effective as screening for other conditions such as breast 
cancer and high blood pressure--NIDA is supporting research to make 
testing more acceptable in communities nationwide. To this end, NIDA 
recently held a meeting aimed at improving the rates of HIV screening, 
and is now incorporating the resulting recommendations, which include 
addressing associated stigma and optimizing early diagnosis and follow-
up linkages to care.
                               conclusion
    NIDA's comprehensive research portfolio is strategically positioned 
to capitalize on new scientific opportunities. Groundbreaking 
developments in the field of genomics signify an exciting era of 
research whereby we will be able to identify genes that make a person 
more vulnerable to drug abuse and addiction and devise counter 
strategies. We work toward a future in which early recognition of risk 
for addiction is no different than early recognition of other chronic 
medical diseases. Innovative use of imaging techniques allow scientists 
to design better treatments and more precisely judge their 
effectiveness, even predicting who would be most likely to benefit from 
selected therapies and who might be expected to relapse, so that 
preemptive interventions can be applied. Finally, advances in 
proteomics will help in designing much more sensitive tools to detect 
drug exposures and their consequences for individuals, heralding a 
future where diagnostic kits may be used to screen for drug abuse in 
the medical setting.
    Thank you, Mr. Chairman. I will be pleased to answer any questions 
the Committee may have.

                           DRUG ABUSE FACTORS

    Senator Harkin. You were talking about adolesents who are 
exposed to a parent who is on drugs. What were the other 
factors that can increase the likelihood of addition?
    Dr. Volkow. A parent that is not there because he or she is 
incarcerated, physically abused, sexually abused, neglected, 
mental health problems in the family, low socioeconomic status, 
or poor access to education. These social stressors are 
increasing the risk of substance abuse.
    Senator Harkin. So a factor of 10 is pretty important.
    Dr. Volkow. It is, dramatically.
    Senator Harkin. That is dramatic. So again it seems that 
drug abuse leads a lot of times I think to mental illness--am I 
correct in assuming that?
    Dr. Volkow. Certainly there is unequivocal evidence that 
early exposure, for example, to nicotine can trigger anxiety 
disorders, even with those that do not have the genetic 
predisposition. There is also evidence that it increases the 
risk of depression. There is an enormous amount of discussion 
about the involvement of marijuana smoke on triggering 
psychosis or schizophrenia.
    The thing is that it is happening, but probably depends 
upon having genetic vulnerability. What we do not know is can 
it trigger a schizophrenia-like disorder in someone that does 
not have the genetics.
    So your answer is yes.

                      ADDICTION IN OTHER COUNTRIES

    Senator Harkin. Well, it seems to me that we ought to be 
paying more attention to this other area also.
    Have you looked at addiction in the United States versus 
other countries?
    Dr. Volkow. Yes, I have looked at this and the data are 
disturbing. The United States is at or near the top of most 
international prevalence comparisons across several types of 
illegal drugs.
    Now, with respect to----
    Senator Harkin. That is illicit drug abuse?
    Dr. Volkow. Illicit drug abuse. For nicotine, for example, 
the United States does much better than other countries in 
Europe and in Latin America. With alcohol there is tremendous 
variability. There the United States is not so high-ranking. 
There are certain countries where the rate of abuse of alcohol 
is higher. It is in illicit substances that we are very, very 
high.

                   DRUG ABUSE BEING A CHRONIC DISEASE

    Senator Harkin. The only other point, just a very basic 
question. You talked about drug abuse being a chronic disease. 
How do we know it is really a disease?
    Dr. Volkow. Well, there have been studies both in 
laboratory animals and in humans. In laboratory animals, for 
example, if you do repeated administration of drugs you can 
lead to compulsive administration of drugs in those animals. In 
animals you can actually sacrifice them and look at the 
biochemical changes linked with drug use and they have been 
shown to persist months after the animal has been discontinued 
from the drug intervention.
    In humans now, with imaging technologies we can 
characterize the changes, both functional and biochemical, in 
the brain of people that are addicted. We followed--I used to 
do that before I became Director--these changes after the 
patients go through rehabilitation, and unfortunately many of 
them persist actually years after the person has stopped taking 
the drugs.
    This is consonant with the phenomenology where we see 
individuals that have been able to stop taking drugs for years 
after rehabilitation, where something happens, usually a 
stressor--social stressors are one of the most powerful--and 
they relapse, even though they had not touched a drug in years, 
accentuating the notion that changes are still there, and so 
you become vulnerable. As long as you can manage the situation 
in your environment, you are okay, but if there is the stressor 
that puts you at very high risk.
    Senator Harkin. Senator Specter.
    Senator Specter. No questions at this time.
    Senator Harkin. Now we move to Dr. T.K. Li. Appointed 
Director of the National Institute on Alcohol Abuse and 
Alcoholism in November 2002, Dr. Li got his undergraduate 
degree from Northwestern University, his M.D. from Harvard. Dr. 
Li, welcome. Please take about 5 minutes.
STATEMENT OF TING-KAI LI, M.D., DIRECTOR, NATIONAL 
            INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
    Dr. Li. Thank you, Senator Harkin, Senator Specter. I am 
pleased to be here with my colleagues to tell you about what 
NIAAA does and to update you on some of the new findings.
    Let me first quantify the burden of illness attributed to 
alcohol. I think you have heard about the burden of illness due 
to mental health disorders and drug abuse. In terms of alcohol, 
let me just tell you that the HHS Centers for Disease Control 
and Prevention rank alcohol as the third highest actual cause 
of death, meaning that it is the third most preventable cause 
of death over this country, the first being tobacco and the 
second being poor diet and inactivity. See figure 1.




    Alcoholism also is worldwide and is ranked as the third 
leading cause of disease in developed countries. It is a common 
disease. In this country, actually 1 out of 4 children are 
exposed in a family that has either alcohol abuse or alcohol 
dependence. Eighteen million people over the age of 18 have 
alcoholism and alcohol abuse. The cost estimated is $185 
billion.
    Now, what I will show is a recent realization. See figure 
2.



    That is the variety and the kinds of alcohol problems 
people have is actually different depending on the stage of 
life. So we have crafted our research mission for alcohol 
across the lifespan, from fetus all the way to seniors. Again, 
as indicated, when ill health or diseases appear early in life, 
the burden of illness is high because of the long duration of 
the illness. That is a very important factor.
    Therefore our mission is really to prevent and reduce harm 
as early in life as possible. This is preventing abnormal or 
high level patterns of drinking in pregnant mothers to those 
harmful patterns of use in children and adolescents, and then 
being able to predict the vulnerability factors as both you and 
Dr. Volkow have talked about and then target intervention for 
those who are at high risk for alcohol use disorders. Finally, 
we also want to personalize treatment in the afflicted 
individuals.
    I will give you three examples of what it has been and what 
it is now and what we have for the future. First is that we 
have always thought--that is what I was taught and I think all 
of us at the table probably were--that alcoholism is a disease 
of mid-life, in other words people in their 40s and in their 
50s. We now know that is not so. The highest prevalence of 
alcoholism is actually in our young people from age 18 to 24.
    So in order to be able to be effective in treating and 
preventing the problem, we really should be looking to even the 
younger population. Therefore we are concentrating on and have 
a major initiative to study under-age drinking problems and how 
to prevent the problem. We are pleased to announce that on 
March 6 the Surgeon General issued a call to action to prevent 
and to reduce under-age drinking problems and our Institute was 
responsible for providing the science base for that report and 
we are going to be working with the Surgeon General in 
disseminating the actions that are proposed in that call to 
action.
    Now, what is in the future? In the future, we are working 
actually with NIDA and with NIMH to look at what are the 
personality and temperament characteristics that predispose to 
harmful patterns of behavior in adolescence. I think this is an 
important common thread that speaks to comorbidity in this 
regard.
    The other thing, the second thing we are trying to do, is 
to improve our way of diagnosing the problem. Again, the 
criteria we use to diagnose alcohol, drug and mental health 
disorders is really 1990s vintage. For example, for alcoholism 
it is called a maladaptive pattern of drinking that leads to 
significant impairment and stress, but it does not say what 
pattern or how much, nor can the diagnostic criteria be scaled.
    Our research shows convincingly that we can scale it, the 
way of scaling both alcohol use and alcohol abuse and alcohol 
dependence by current diagnostics criteria and, as you can see 
in the figure here there is a single continuum of severity. See 
figure 3.




    Shown here in red and yellow are the different criteria for 
abuse and dependence, scaled by severity.
    The important question then is what pattern of drinking 
will predict this kind of severity of alcohol dependence? From 
our database we can say that if one drinks in a certain 
pattern, like drinking five or four drinks on an occasion, and 
you repeat this, then you can tap into the severity of alcohol 
use disorder scale, and this may be an important way of 
identifying those who are susceptible from their pattern of 
drinking.
    How does this compare to the rest of medicine? Well, it is 
similar to being able to measure blood pressure and to measure 
cholesterol as a risk for having a future heart attack. 
Therefore, knowing what the blood pressure and cholesterol is, 
then you can treat that and you can interdict in terms of 
future problems.
    So these are some of our current state of knowledge. We 
hope that we can be able to verify this pattern in the future 
and to use this in a clinical setting.

                           PREPARED STATEMENT

    Finally, just to talk a bit about personalized medicine. 
Because of the advances in knowledge of molecular medicine, we 
are developing better and better medications to treat alcohol 
dependence once it has developed. These are our goals for the 
future. Thank you very much.
    [The statement follows:]
                 Prepared Statement of Dr. Ting-Kai Li
    Mr. Chairman and Members of the Committee, thank you for giving me 
the opportunity to update you on the activities of the National 
Institute on Alcohol Abuse and Alcoholism. I am Ting-Kai Li, Director 
of NIAAA, the lead agency for research on the health effects of 
alcohol. I am pleased to be here today with my distinguished colleagues 
from NINDS, NIMH, NIDA, and NIDCD to speak to the theme of Mind, Brain 
and Behavior. Those of us addressing you today have a fundamental 
mission--to reduce the substantial burden of illness caused by 
neurological and mental disorders, and by drug and alcohol abuse. Many 
of these disorders tend to manifest early in life, produce lifelong 
disability, derail individual potentials, and create tremendous burdens 
for families and significant cost to society. In fact, excessive 
alcohol use alone costs the United States an estimated $185 billion 
annually.\1\ The fiscal year 2008 budget for NIAAA includes 
$436,505,000.
---------------------------------------------------------------------------
    \1\ Harwood, H. Updating Estimates of the Economic Costs of Alcohol 
Abuse in the United States: Estimates, Update Methods and Data (2000). 
http://pubs.niaaa.nih.gov/publications/economic-2000/
---------------------------------------------------------------------------
    The HHS Centers for Disease Control and Prevention ranks alcohol as 
the third leading cause of preventable death in the United States 
(figure 1), and the World Health Report ranks alcohol as the third 
leading risk factor for disease in developed countries. Although 
alcohol primarily targets two organs, the brain and liver, it has a 
wide range of effects throughout the body and NIAAA's research 
portfolio encompasses all aspects of alcohol and health. In keeping 
with the theme of this Hearing, I will focus on the brain and behavior.


    As illustrated in figure 2, alcohol can negatively affect the body 
and brain at all stages of life resulting in a range of consequences, 
including consequences from maternal alcohol consumption on the 
developing embryo/fetus to alcoholic liver disease and dementia in 
later life. Throughout the lifespan, it is important to recognize the 
contribution of developmental stage, individual differences--both 
genetic and environmental, and dose and duration of alcohol exposure to 
potential outcomes. The substantially different effects and 
consequences of alcohol exposure at different stages of life 
necessitate different research strategies.



    Today I would like to give you an overview of NIAAA's progress in 
three areas to reduce the burden of illness due to alcohol. First, I 
will describe prevention efforts focused on early life stages. Second, 
I will describe new findings that can be used to improve the diagnosis 
and early detection of alcohol use disorders (AUDs). Finally, I will 
describe efforts to personalize medicine for those suffering from 
alcohol dependence.
                               prevention
    Prevention is a key focus of NIAAA, especially for pregnant women, 
children and adolescents. By altering harmful drinking behavior we can 
significantly reduce the burden of illness due to alcohol. Exposure of 
the developing embryo/fetus can result in alcohol-induced birth 
defects, the most severe of which is fetal alcohol syndrome (FAS), a 
devastating developmental disorder that may include mental retardation. 
Individuals who do not exhibit the extent of symptoms characteristic of 
FAS may still have lifelong physical and/or neurological deficits as a 
result of in utero alcohol exposure. In addition, prenatal alcohol 
exposure itself may be a risk factor for subsequent alcohol dependence 
later in life. Therefore, NIAAA is supporting research to develop 
effective outreach to pregnant women, and approaches to intervene to 
protect against injury in the affected fetus and ameliorate deficits in 
the affected child.
    Prevention in young children is also important, especially for 
those at high risk for early alcohol use. The period from birth to age 
10 is a remarkable period of development, and although relatively few 
children in this age group are drinking alcohol, much is happening that 
will influence their path toward or away from early alcohol use. A 
number of the factors that put children at risk for early alcohol use 
are common to a wide range of adverse behavioral outcomes such as 
delinquency and other substance use. Even as young as preschool age, 
such children often have difficulties with impulse control and exhibit 
unusually high levels of aggression. NIAAA, NIMH, and NIDA are working 
to understand the personality/temperament characteristics that 
predispose to early-onset mental and alcohol/drug use disorders.
    It is also essential to prevent and reduce underage alcohol use. 
Analyses of NIAAA's National Epidemiologic Survey on Alcohol-Related 
Conditions (NESARC) showed that 40 percent of individuals who reported 
drinking before the age of 15 also described their drinking behavior in 
a way consistent with a diagnosis of alcohol dependence. In fact, the 
highest prevalence of alcohol dependence in the United States occurs in 
the 18-24 year old age group. In addition, binge-drinking (i.e. 
drinking five or more drinks per occasion), which is popular with 
today's young people, results in acute consequences such as traffic 
fatalities, alcohol poisoning, suicides, homicides and drownings. Non-
fatal, but potentially life altering consequences such as sexual 
assault and violence also result. As part of a larger effort focused on 
underage drinking research, NIAAA provided the scientific foundation 
for the Surgeon General's Call to Action to Prevent and Reduce Underage 
Drinking and continues to inform the work of the Interagency 
Coordinating Committee on the Prevention of Underage Drinking.
    Recognizing that the brain continues to develop throughout 
adolescence and into early adulthood, NIAAA is investing in research to 
determine the short and long-term effects of alcohol on the developing 
brain and the degree to which it can recover from these insults. Such 
studies, including one in collaboration with NIMH intramural 
scientists, may identify changes in brain wiring that are associated 
with dependence or affect cognitive functioning. In addition, given the 
difference in patterns of alcohol use between boys and girls as they 
move through adolescence, NIAAA is investigating the interplay of 
hormones, brain development and alcohol use.
                               diagnosis
    It is important to identify individuals who are at risk for adverse 
alcohol-related health outcomes because of their drinking behavior. 
Excessive alcohol intake over time leads to cumulative organ damage, 
especially alcoholic liver disease and increased risk of coronary 
artery disease, stroke and dementia. Early diagnosis of harmful 
drinking would enable health care providers to intervene to prevent a 
range of adverse health outcomes.
    As shown in figure 3, diagnostic criteria for Alcohol Abuse 
currently rely on an individual experiencing one or more alcohol-
related problems associated with either the social or legal system, 
such as being cited for Driving While Intoxicated or problems with a 
spouse or family member. Diagnosis of Alcohol Dependence requires 
meeting three of seven criteria relating to physiological changes such 
as the development of tolerance to increased amounts of alcohol or the 
experience of withdrawal symptoms, behavioral maladaption characterized 
by loss of control and compulsion to drink, and negative consequences 
from this drinking pattern. This categorical approach does not favor 
early diagnosis and intervention.



    Today I report recent findings from analyses of NESARC that will 
improve the diagnosis of alcohol dependence. Further, alcohol abuse and 
dependence have long been treated as independent disorders. New 
findings indicate that they represent a continuum of severity of 
alcohol use problems. The analyses suggest we may be able to use 
questions that reveal an individual's pattern of drinking to identify 
the risk of developing AUDs. In much the same way that numerical 
measurements of blood pressure, cholesterol and triglycerides relate to 
relative risk for cardiovascular disease, the best indicators of 
developing alcohol problems are measures of how frequently an 
individual engages in a harmful pattern of drinking. Specifically, 
recent findings relate data on the frequency of binge drinking and the 
maximum number of drinks consumed to risk for organ damage and to 
alcohol dependence. Through clinical studies, we may be able to 
determine appropriate cut points to define AUDs and also to gauge one's 
risk of developing alcohol problems. Just as physicians treat high 
cholesterol before an individual experiences a heart attack, they will 
be able to intervene before an individual loses control of drinking. 
Diagnosis centered on harmful drinking patterns should also help health 
care providers differentiate between alcohol related neurocognitive 
deficits in the elderly and Alzheimer related dementia.
                        medications development
    NIAAA is supporting research on a number of fronts to improve 
treatment options for alcohol dependence. Studies in animal models 
focusing on signaling pathways in the brain have produced additional 
targets for human studies. For example, the anxiety that people with 
alcohol dependence experience when they stop drinking is a powerful 
motivator for them to resume. In addition, stress can trigger relapse 
to heavy drinking after a period of abstinence. Therefore, medications 
are being tested that target molecules involved in biological pathways 
that mediate stress and anxiety such as corticotrophin-releasing 
factor, neuropeptide Y, and nociceptin receptors. Also being tested are 
medications that target the metabolism of endocannabinoids, naturally 
occurring substances in the brain that act on the same receptors as the 
active ingredients of marijuana and have been shown to play a role in 
regulating appetite for alcohol.
                           treatment research
    In addition to developing new medications and determining the 
genetic and environmental factors that contribute to the initiation and 
escalation of drinking, it is equally important to understand how 
individuals change harmful drinking patterns. The majority of young 
adults change harmful drinking behaviors without treatment. Adults seek 
treatment when alcohol dependence becomes chronic and relapsing, 
generally in the period of midlife. Data from clinical trials raise the 
question of whether treatment itself is responsible for the improvement 
in drinking behavior or if the positive motivation to seek treatment 
actually underlies a substantial part of the treatment success. 
Further, evidence has shown that a wide array of available therapeutic 
approaches yields similar results, suggesting that it is not the 
particular technique that is responsible for change but other common 
underlying factors. As a result, NIAAA is focusing on addressing 
underlying mechanisms of change across all behavioral treatments, 
identifying the factors that contribute to behavioral change and lead 
to sustained recovery. This research will improve clinical practice 
both by identifying key aspects of therapy that must be present for 
maximum effectiveness and by facilitating the delivery of more finely 
tuned individualized treatment. We also need to be particularly mindful 
of health disparities. A recent study suggests that Hispanics and 
Blacks with higher levels of problem severity were less likely to have 
used treatment services than Whites with problems of comparable 
severity.
    Taken together, these strategies of improved prevention, better 
diagnosis and personalized treatment are expected to reduce the burden 
of alcohol-related illnesses over the long term and lead to better 
health outcomes for the nearly 18 million American adults who, in any 
year, struggle with alcohol use disorders.\2\
---------------------------------------------------------------------------
    \2\ Grant BF, Dawson DA, Stinson FS, Chou SP, Dufour MC, and 
Pickering RP. Drug and Alcohol Dependence 2004. 74: 223-234.
---------------------------------------------------------------------------

                   MEDICATIONS FOR ALCOHOL DEPENDENCE

    Senator Harkin. Well, now that you are on that, what 
medications?
    Dr. Li. Well, we have several. Fifteen years ago all we had 
was Antabuse. Now in the last 8 years or so we have approved 
two other medications. One is Naltrex, both orally taken and 
also by injection; and third is a medication called 
Acamprosate. So these drugs seem to work better for certain 
aspects of alcohol dependence based on severity. We have others 
in the pipeline being developed that will target different 
molecules, different receptors, and these are an important 
vision for the future.

                             NIAAA OUTREACH

    Senator Harkin. Doctor, every Institute out there needs to 
do outreach. Every Institute does outreach to the communities 
around the country.
    Dr. Li. Yes, sir.
    Senator Harkin. How well are you doing in reaching out to 
States and local communities to put into practice some of your 
findings?
    Dr. Li. The three so-called ADM Institutes, we are 
fortunate in that we have a partner in this regard. That is 
SAMHSA. This was created before the three Institutes joined 
NIH. So we do have a partner out there that does the outreach. 
We work with them as well as ourselves in promoting, providing 
the outreach to the public. I think that we do this together. 
There is an inter-agency group that does this.
    Senator Harkin. So you are doing outreach?
    Dr. Li. Yes, sir.

                          ALCOHOL ADVERTISING

    Senator Harkin. Well, I would like to know more about how 
that is done. I will get my staff to get some more information 
on it.
    I wonder about messages that young people receive about 
drinking, all the advertising about the glamorizing of drinking 
alcohol. Of course, it is a free country. People can advertise. 
But I just wonder about the impact of these messages and how 
they are reinforcing young people that it is all right to drink 
and it is all right to maybe even drink a lot, although I 
noticed that some of the beverage companies, if they want to be 
called that, are now putting out things about being responsible 
in drinking. I see a lot of that advertising going on.
    But I am just wondering about the messages young people get 
about drinking. What have you looked into that? How have you 
looked into that?
    Dr. Li. I think this is a very complex issue because there 
are a lot of background of messages coming in, and the 
advertising is only one part of it. So how children respond to 
advertising is a little different depending on how old they are 
and what their context.
    Senator Harkin. Are you doing any research into this?
    Dr. Li. Yes, sir.
    Senator Harkin. You are doing some research in that, the 
different messages and how young people are affected by this?
    Dr. Li. Yes.
    Senator Harkin. Any results?
    Dr. Li. Well, we have some, but as I said, it is difficult 
to be able to dissect out which part is advertising that causes 
an increase in drinking or whether all they are doing is 
changing brands. I think the issue is whether there is an 
increase in drinking because of advertising but data on that is 
very, very slim. I mean, the result is that it is not a major 
influence.

                             BINGE DRINKING

    Senator Harkin. What kind of research are you doing into 
binge drinking, especially among college students?
    Dr. Li. Binge drinking on that model there is the most 
harmful pattern, because physiologically it makes sense. You 
need that much drinking in order to get your blood alcohol to a 
level that is impairing and that is the nature of binge 
drinking, namely drinking to intoxication. Why people do it is 
something we would love to find out.
    Senator Harkin. Are you doing research into this?
    Dr. Li. Yes, we are. It has to do with expectancies, it 
relates to problems which are stress and stressors. When we 
talk to people, young people, why are you drinking, they say, I 
want to drink because I want to get drunk. So it is a different 
approach.
    You must understand that alcohol is the most ancient 
intoxicant, mind-altering drug. There is a lot of history 
there, and to be able to change the culture and what people 
think of it is not easy.
    Senator Harkin. One of the biggest fears that parents have 
when their kids go off to college is just this, binge drinking. 
I do not know the answer to it, but I just wonder if we are 
doing any research into that, what is happening, how it is 
happening, what is motivating young people to do this. I do not 
know. I do not have the answer to that.
    Dr. Li. We have, for example, a site demonstration project 
on college drinking. This is a cooperative agreement. It is a 
demonstration project to look into that, and the study is now 
in its fourth year. I have been on the job 4 years. This is 
something we started when I took over.
    We also have eight or more sites to study under-age 
drinking, meaning in adolescents, in high school level and 
middle school level.

                        CRIMINAL JUSTICE SYSTEM

    Senator Specter. A few questions now, Mr. Chairman.
    Dr. Volkow, since I was district attorney in Philadelphia 
many years ago the incidence of drug addiction has been a 
causative factor in 70 percent of the crimes, and we have not 
been willing to invest in realistic rehabilitation to try to 
stop the chain of recidivism. Is there any answer from your 
research to deal with drug addiction which is within the 
financial reach of what society is prepared to spend on 
corrections?
    Dr. Volkow. Absolutely. In part one of our priorities is 
the criminal justice system, because----
    Senator Specter. You said absolutely not?
    Dr. Volkow. No. Absolutely. It is extraordinarily important 
to actually target substance abuse treatment in the criminal 
justice system. Data have----
    Senator Specter. How do we deal with it effectively within 
some reasonable cost parameter?
    Dr. Volkow. You save out of every $4--out of every $1 that 
you spend on treatment in the criminal justice system, you save 
$4.
    Senator Specter. I am not interested in how much you save. 
I am interested in how much we spend. I am interested in how we 
get my colleagues to spend money for corrections, and the 
inquiry goes to whether there is any answer within what the 
cheapskates in government are willing to spend, to ask the 
question more specifically.
    Dr. Volkow. The cost, what I can tell you, the cost for a 
treatment program on substance abuse is around $10,000 in the 
criminal justice system, and it is $20,000 to incarcerate an 
individual, correct, more or less, on average? So that gets you 
an idea.
    Senator Specter. There is a willingness to spend money for 
incarceration.
    Dr. Volkow. Correct.

                        BRAIN INJURY AND ALCOHOL

    Senator Specter. But not for rehabilitation.
    Dr. Li, I have heard martini drinkers, illustratively, 
express concern about killing brain cells with the alcohol. Is 
that a real risk?
    Senator Harkin. Just martinis?
    Senator Specter. That is what I drink.
    Dr. Li. We know alcohol kills brain cells.
    Senator Specter. It does kill brain cells?
    Dr. Li. Yes, sir.
    Senator Specter. How many and at what rate?
    Dr. Li. I do not know the rate or the number. But we 
certainly----
    Senator Specter. Is it a real danger?
    Dr. Li. It is a result. Is it a real danger to whom?
    Senator Specter. To the people who drink the martinis.
    Dr. Li. Certainly over long periods of time, yes, sir.
    Senator Specter. What would be consumption so that you do 
not become an alcoholic or to a lesser extent impair your 
brain?
    Dr. Li. Well, this is exactly the kind of research we want 
to do, to be able to do to put a quantitative basis to the 
clinical observations----
    Senator Specter. How much more money do you need than $30 
billion that Senator Harkin has provided for you?
    Dr. Li. We have just over $400 million for our Institute's 
appropriation.
    Senator Specter. Dr. Landis, you are the chairman of the 
stem cell----
    Senator Harkin. Could we just finish their testimony so I 
can get their testimony before?
    Senator Specter. That was my suggestion.
    Senator Harkin. I would like to turn to the other 
Institutes and have them at least make their presentations 
before we ask for questions.

                         TRAUMATIC BRAIN INJURY

    Senator Specter. All right. I will go to Dr. Insel.
    We talk a lot about the 3,200 or more men and women killed 
in Iraq. We now find that there are an enormous number coming 
back from Iraq with brain injuries. We do not focus as much on 
the 24,000-plus who have been injured in Iraq. Now medical 
procedures can save lives, but with very material brain 
impairment. There are reports that these young men and women 
are coming back in their 20s, teens, and that they are going to 
need care for a lifetime.
    To what extent can you evaluate those kinds of brain 
injuries and what might be done to provide therapy from the 
kind of research you are undertaking?
    Dr. Insel. I am going to leave the traumatic brain injury 
question to Dr. Landis, whose Institute is more involved with 
that. Let me add what you did not say, which was that the 
greatest proportion are coming back with what looks like post-
traumatic stress disorder. The numbers are significant: 1.4 
million individuals have served in Iraq and Afghanistan. The 
rate now already is about 12-13 percent PTSD. My calculation is 
about 170,000 people who will have PTSD currently or in the 
next couple of years.
    We know that after the Vietnam War the rate went up to 
between 20 and 30 percent overall, so even higher than where we 
are now. So you are talking about a very significant amount of 
disability and high cost. Eighty percent of the time in the 
Vietnam case this was associated with substance abuse, usually 
drug addiction, often leading to criminal behavior as well--a 
tremendous disability at a very high rate from a mental 
disorder that is trauma-induced.
    Senator Specter. Well, what should be the governmental 
response, either through the Veterans Administration of the 
Department of Defense, so that these young men and women and 
their families do not have to bear the burden and the cost when 
it is really not a war of their choosing and their making, but 
a war for the Government, that ought to be borne by the 
Government? What is an equitable response by the Government to 
these kinds of injuries?
    Dr. Insel. Let me talk about what the science can tell us, 
because I think that is where the biggest hope may be. I think 
we can use the science we have now to develop better 
treatments, and that is part of why we have got a major effort 
with the VA and DOD to do just that. More importantly, what we 
do not know is who is going to be sensitive to this. So if 100 
people come back, 13 of them will develop PTSD currently. We 
would like to know who those 13 are and be able to preempt 
this, actually help them to recover before they develop the 
full syndrome. That is right now the target for the 
intervention.
    Senator Specter. Thank you very much.
    Thank you, Mr. Chairman. Let me comment that I think this 
procedure is a good one and the informality is conducive to a 
little easier reparte. I regret that I have to excuse myself. 
We are very heavily engaged right now with the U.S. Attorneys 
and I have to tend to that this afternoon. But Senator Taylor 
will be here in my place and I will be following it closely. I 
know that Senator Harkin joins me in this. We will provide the 
kinds of resources you need to the maximum extent of our 
capabilities, which is now more limited than it used to be. 
Thank you.
    Senator Harkin. That is true. That is very true. Well, 
thank you very much.
    Now we will turn to Dr. James Battey, who has served as 
Director of the National Institute on Deafness and Other 
Communications Disorder since 1998. Dr. Battey got his B.S. 
from the California Institute of Technology and his M.D. and 
Ph.D. degrees from Stanford.
    Dr. Battey, please proceed.
STATEMENT OF JAMES F. BATTEY, JR., M.D., DIRECTOR, 
            NATIONAL INSTITUTE ON DEAFNESS AND OTHER 
            COMMUNICATIONS DISORDERS
    Dr. Battey. Thank you very much, Mr. Specter and Mr. 
Harkin. It is a pleasure to be here today and I would like to 
begin by thanking you for your time, interest, and support over 
the years. It is deeply appreciated by those of us at NIH and 
in particular by the research community that we serve.
    If I could direct your attention to figure 1. I am going to 
refer to some things on them.
    Senator Harkin. By the way, I want you to know I appreciate 
the fact that all of you gave me your testimony last week. I 
was able to look at it over the weekend. I appreciate that very 
much.
    Dr. Battey. It is a particular pleasure to be here with my 
colleagues with whom I work every single day and to share the 
wonderful things that are happening in their Institutes and 
tell you a little bit about what is happening with NIDCD.
    If you turned back the clock to the beginning of the 20th 
century, most Americans made their living with physical labor 
and did not really need great communications skills or a well-
trained mind. But here as we enter the 21st century the 
situation is entirely different. The good jobs, the interesting 
jobs, the important jobs, the high-paying jobs, all involve an 
intact mind that is not impaired by drugs or alcohol, that is 
not bedeviled by mental illness, that allows one to communicate 
effectively.
    One of the most important issues with communicating 
effectively is hearing impairment. It is one of the most common 
causes of a communication disorder and we estimate that roughly 
one American in six has a significant communication disorder 
that compromises their ability to access these high-paying, 
high quality jobs.

                          HOW HEARING HAPPENS

    Now, to help you understand what we are trying to do about 
this problem, I would like to introduce you to the science 
behind how we hear. Now, if you can focus your attention for a 
moment on the center image, you will see a pink snail-shaped 
structure. See figure 1. That is the cochlea. A cross-section 
across that cochlea is shown in the right-hand image. 



    You will see four little blue cells with some little 
projections coming out of the top of them. Those four cells are 
called hair cells, and it is nanometer deflections of those 
little tufts that signal hearing and tell those cells to send 
an electrochemical impulse to the brain. That is how we hear.
    These hair cells are the weak link. They are the vulnerable 
aspect of the hearing organ. They are what is generally lost or 
never developed in individuals who either cannot hear from 
birth or lose their hearing progressively throughout their 
life.
    As long as there are some hair cells left we can amplify 
sound with a hearing aid and help those individuals hear. But 
when virtually all the hair cells are gone, amplification 
simply does not work. That is where research, supported 
initially by NINDS and then by NIDCD after we became an 
institute in 1988, on the cochlear implant has changed 
everything.

                           COCHLEAR IMPLANTS

    There is a picture of a child on the left-hand side wearing 
a cochlear implant, which is also shown in an image in the 
center. It is an array of 22 electrodes that a surgeon inserts 
into that snail-shaped cochlea. See figure 1. It coils around 
and bypasses the damaged hair cells, stimulating the hearing 
nerve directly.
    In an adult that loses their hearing, the cochlear implant 
can often restore the ability to understand speech to the point 
where that deaf individual can now use the telephone. In a 
young child who is born unable to hear, cochlear implantation 
before the second year of life can result in that child being 
mainstreamed in normal schools and be on grade level for 
language literacy and spoken skills. This is really an enormous 
testament to the plasticity of the human brain, to be able to 
go from losing 30,000 hair cells, replace it by stimulation 
from 22 electrodes, and still have the brain be able to 
interpret what it hears as speech. I consider this to be simply 
remarkable.

                         HAIR CELL REGENERATION

    But it would be far better to replace the hair cells that 
have been lost, to undo the damage, rather than simply bypass 
it with an array of electrodes. Birds and fish can regenerate 
their hair cells if they are damaged. Mammals and humans 
cannot. We are looking to understand why there is this 
difference between species who can regenerate hair cells and 
why others cannot. We are beginning to understand the molecular 
mechanisms that underlie how hair cells develop in the first 
place and also how potentially regenerated.

                           PREPARED STATEMENT

    For example, recent studies supported by NIH have shown 
that there is a master regulatory gene called Math-1 whose 
expression is necessary and sufficient for hair cells to 
develop in the first place. Animal models missing the Math-1 
gene never develop hair cells and are deaf. We have preliminary 
data from one laboratory that they can, by stimulating the 
expression of Math-1 in an animal model that has been deafened 
by damaging the hair cells, that partial hair cell regeneration 
could take place and perception of sound can be restored, which 
gives us the hope that the day may come some day when, instead 
of simply bypassing damaged hair cells, we can regenerate new 
ones and provide a whole new approach to helping individuals 
who have lost their hearing.
    Thanks very much for your attention and I will do the best 
I can to answer any questions you might have.
    [The statement follows:]
             Prepared Statement of Dr. James F. Battey, Jr.
    Mr. Chairman and Members of the Subcommittee: I present the 
President's budget request for the National Institute on Deafness and 
Other Communication Disorders (NIDCD). The fiscal year 2008 budget for 
NIDCD includes $393,682,000. The NIDCD conducts and supports research 
and research training in the normal and disordered processes of 
hearing, balance, smell, taste, voice, speech, and language. These 
processes are fundamental to the way we perceive the world and to our 
ability to communicate effectively in modern society. Disorders of 
communication impose significant economic, social, and personal costs. 
Accordingly, the goal of the NIDCD strategy is to produce outcomes with 
a significant impact on the health of Americans. Driven by the public 
health need and scientific opportunity identified in the NIDCD 
Strategic Plan, NIDCD prioritizes its research investment to fund the 
most promising scientific opportunities in diagnosis and treatment of 
communication disorders. The following are notable highlights from the 
past year that are the result of NIDCD support:
                   genes and communication disorders
    The NIDCD recognizes that functional genomics--determining the 
identity, structure, and function of genes--is one of the most rapidly 
developing areas of research. Inherited genes account for approximately 
50-60 percent of the severe to profound cases of childhood hearing 
loss. NIDCD scientists are working to understand the normal function of 
these genes, and how they are altered in individuals with communication 
disorders (such as hearing loss, stuttering, speech-sound disorders, 
autism, and dyslexia). These research investments to understand the 
genetic basis of communication disorders will help scientists develop 
diagnostic tests and better treatments for the millions of Americans 
with hereditary hearing impairment.
           preventing and diagnosing communication disorders
    The Centers for Disease Control and Prevention (CDC) reports that 
two to three out of 1,000 babies born each year in the United States 
have a detectable hearing loss, and estimates the average lifetime cost 
for one individual with hearing loss to be $417,000 (in 2003 dollars). 
Accordingly, NIDCD places a high priority on understanding causes, 
possible treatments, and progression of hearing loss during early 
childhood. NIDCD-supported research demonstrates that children not 
exposed to language during their first 3 years of life due to hearing 
loss will have more difficulty developing spoken or signed language and 
reading skills. Early identification of hearing loss enables parents to 
pursue interventions early enough that their child can learn to 
communicate on par with his or her hearing peers.
    However, childhood hearing loss does not always show up right away. 
Congenital cytomegalovirus (CMV) is the most common viral infection 
passed from a mother to her unborn child, with 40,000 infants born 
infected each year. According to the CDC, approximately 10 to 15 
percent of these children have some degree of hearing loss. Scientists 
believe that CMV infection present at birth is a leading cause of 
sensorineural hearing loss in children. Hospitals do not test newborns 
for CMV unless they already show signs of the disease. NIDCD is funding 
the CMV and Hearing Multicenter Screening (CHIMES) Study to identify 
asymptomatic children and follow them to determine if hearing loss 
develops. Scientists will screen approximately 100,000 children at 
birth for CMV infection, and those who test positive will undergo 
follow-up diagnostic hearing testing to determine the onset, severity, 
and progression of hearing loss. The scientists will use these data to 
understand the relationship between CMV infection and hearing loss and 
to determine whether CMV screening together with hearing testing can 
improve the detection and prediction of permanent hearing loss in 
children.
    Although success in establishing early screening programs has 
identified a new population of children with hearing loss, we do not 
know which interventions provide the best outcomes. Current 
intervention and outcome data are limited to those children whose 
hearing loss was detected later in life. Hearing health specialists 
need research data that considers not only the intervention strategy 
but also the parent-child interaction, socio-economic factors, and 
language exposure. To address this need, NIDCD held a workshop on 
``Outcomes in the Child with Hearing Loss'' in December 2006. NIDCD is 
using information from this workshop to develop fiscal year 2008 
initiatives focused on prospective and longitudinal research. These 
initiatives will be part of a multi-agency collaboration designed to 
close the gap between children with hearing loss and their hearing 
peers, and will provide sorely-needed information on the best 
strategies to achieve this goal.
                      developing assistive devices
    NIDCD-supported basic research on the ears of the tiny fly Ormia 
ochracea has inspired a new generation of hearing aids. The fly's ear 
structure permits ultra-sensitive time coding and localization of 
sound, and scientists used it as a model to develop miniature 
directional hearing aid microphones that can selectively amplify speech 
rather than amplifying all sounds. NIDCD-supported scientists are now 
working to make these directional hearing aids widely available. 
Individuals with hearing loss who use hearing aids fitted with these 
improved directional microphones will experience improved quality of 
life because the aids will do a better job of helping them to 
understand spoken language amidst background noise.
    Some individuals with severe to profound sensorineural hearing loss 
may benefit from a cochlear implant (CI). The NIH's support has played 
a significant and important role in the development of CI technology 
over the last three decades. A CI converts sound into electrical 
impulses on an array of electrodes surgically inserted into the inner 
ear, bypassing the damaged hair cells that normally detect sound. The 
CI stimulates the auditory nerve directly and restores the perception 
of sound to individuals who are deaf.
    The Food and Drug Administration (FDA) estimates that approximately 
36,000 Americans have received CIs, and one-half of the recipients were 
children. The FDA approved the use of CIs in children as young as 12 
months of age. NIDCD-supported research demonstrates that the sooner a 
child with profound hearing impariment receives the benefit of a CI, 
the greater the benefits and improvements in speech perception and 
language production. Because of the rapid development and plasticity of 
their brains, young children implanted with a CI usually show age-
appropriate brain responses within 6 to 9 months after the CI is turned 
on.
    CIs are expensive (costing approximately $60,000 for the device, 
associated surgical expenses, and postoperative fitting and training) 
and many insurance companies were initially unwilling to reimburse for 
this cost, citing a lack of evidence that the device is cost-effective. 
To address this concern, NIDCD-supported scientists conducted an 
initial cost-utility analysis of the CI in children to examine whether 
the benefits of the implant outweigh its costs. The study showed that 
CIs improve the children's quality of life, and result in a net saving 
to society. The cost benefit is the result of fewer demands on special 
education and greater wage-earning opportunities for CI recipients, 
providing an estimated life savings per child at $53,198. This landmark 
study has helped make CIs a standard treatment for severe-to-profound 
nerve deafness, and many insurance companies now cover them.
    An NIDCD-supported study assessed the sound-localization abilities 
of children (ages 5 to 14 years) wearing two cochlear implants as 
compared to one. Children in the study located the source of a sound 
more accurately when they were wearing two implants as opposed to one. 
The greater the experience with two implants, the more adept he or she 
became at localizing sound. The research team is now investigating the 
effects of bilateral implants on word learning and language acquisition 
in infants and toddlers receiving CIs at a young age.
    NIDCD-supported scientists are currently using lessons learned from 
their cochlear implant research experiences to develop an implanted 
device to help restore the sense of balance. The prototype vestibular 
implant has the potential to benefit over 90 million Americans who have 
experienced a dizziness or balance problem.
                   strategies to protect your hearing
    The NIDCD shares Congress's concerns that approximately 10 percent 
(over 22 million) of American adults have suffered permanent damage to 
their hearing from exposure to loud sounds or noise at work or in 
leisure activities (CDC NHANES). In 1999, the NIDCD collaborated with 
the National Institute for Occupational Safety and Health (NIOSH) to 
launch WISE EARS!. WISE EARS! is a national campaign to prevent noise-
induced hearing loss (NIHL) in the general public, including the 
workplace. NIDCD has built a coalition of nearly 90 partner 
organizations and disseminated information and promotional materials 
through the media, at professional conferences and health fairs, and 
over the Internet. In 2006, the NIDCD conducted an evaluation on the 
WISE EARS! Public Health Campaign to obtain an accurate picture of how 
far WISE EARS! has progressed in achieving its goals and to identify 
those needs that have not yet been addressed through current 
educational and promotional methods.
    Finally, Mr. Chairman, I would like to thank you and members of 
this subcommittee for giving me the opportunity today to present 
exciting scientific advances from the NIDCD. I am pleased to answer any 
questions that you have.

                       REGENERATION OF HAIR CELLS

    Senator Harkin. Dr. Battey, thank you very much.
    Let us get into the whole thing of regeneration of hair 
cells. I do not remember the exact year, but somewhere around 
1990, 1991, I remember getting a paper on the regeneration of 
hair cells and how certain birds exhibited the fact that they 
could regenerate hair cells.
    I engaged in questions with the then-Director----
    Dr. Battey. Is that James Snow?
    Senator Harkin. Dr. Snow, thank you very much. Dr. Snow, 
about that. Yes, and I have asked that question repeatedly. 
That is at least 17 years ago and almost what I hear you saying 
is what I heard 17 years ago. Are you telling me----
    Dr. Battey. Seventeen years ago we were not regenerating 
hair cells in mammals.
    Senator Harkin. Are you now?
    Dr. Battey. Yes, we are. In a guinea pig model----
    Senator Harkin. I thought you told me that it was just 
birds.
    Dr. Battey. They can do it spontaneously. In a guinea pig 
animal model that is deafened--I do not do it; Yehoash Raphael 
does it at the University of Michigan--that deafens the animal 
in one ear by administering a drug called gentomycin, he can 
then express Math-1 in that inner ear and see hair cells 
regenerate, and can show physiological evidence of auditory 
percept in the ear that had been deafened.
    Senator Harkin. How long has he been doing this?
    Dr. Battey. I would have to go back to look. I think 
Yehoash's paper is from 2005.
    Senator Harkin. Recent.
    Dr. Battey. Yes.
    Senator Harkin. Is there more than one locus of this 
research going on right now?
    Dr. Battey. It is now being studied in other laboratories 
and others are hopefully going to replicate his findings. And 
then maybe if that works out we will move forward to non-human 
primates, with the hope of ultimately moving into phase 1 
clinical trials.
    Senator Harkin. When do you think you will be ready to go 
to higher mammals?
    Dr. Battey. I really do not know. I could give you a guess, 
but it would be nothing better than a guess.
    Senator Harkin. Well, you are funding this research?
    Dr. Battey. Yes.
    Senator Harkin. Where is that? University of where?
    Dr. Battey. University of Michigan.
    Senator Harkin. Michigan. Well, if they have been doing 
guinea pigs for a couple years and they have gotten some pretty 
good results, I am just wondering how soon they might be ready 
to take it to a higher order of mammals.
    Dr. Battey. I would say if it replicates nicely in several 
other laboratories, which is the cornerstone of good science, 
then we would be ready to try to stimulate research in non-
human primates. It is a couple of years.
    Senator Harkin. This is a genetic intervention?
    Dr. Battey. Yehoash's work--I am going to get technical 
here a little bit--it is a viral vector that expresses a gene 
called Math-1, which is a master regulatory gene.
    Senator Harkin. Are you saying ``MATH?''
    Dr. Battey. MATH, M-A-T-H, dash 1.
    Senator Harkin. Math-1.
    Dr. Battey. It stands for Mouse Atonal Homolog 1.
    Senator Harkin. That is a little bit hard for me, okay.
    Dr. Battey. I warned you.
    Senator Harkin. It is a viral vector. I understand that. 
Yes, I do have a good feel for that. But I do not know that 
much about how much regeneration they have had and a 
percentage. Is it like 10 percent of the hair cells are 
restored, is it 20, 30? Do you have any idea?
    Dr. Battey. Roughly a third.
    Senator Harkin. About a third?
    Dr. Battey. Yes. Again, it varies from animal to animal 
exactly how well this works.
    Senator Harkin. I thought you said they were just doing it 
in guinea pigs.
    Dr. Battey. I am sorry, from guinea pig to guinea pig.
    Unfortunately, you have to do it in a number of guinea pigs 
to show if the result is reproducible.
    Senator Harkin. A big question then, why is it more in some 
and less than others.
    Dr. Battey. It is a great question. Probably there are 
other genes involved as well. The genetic background may be 
different in one guinea pig than another.
    Senator Harkin. But that is kind of the holy grail of this, 
of what we are looking at in terms of deafness, right?
    Dr. Battey. Hair cell regeneration would be wonderful, not 
just for hearing impairment, but also for balance disorders, 
because there are another class of hair cells in the balance 
organ, which is that part of the inner ear that is right next 
to the snail-shaped cochlea.
    Senator Harkin. Which is why so many older people fall and 
break hips and stuff. As you get older you lose your sense of 
balance.
    Dr. Battey. Yes, roughly--well, dizziness is the most 
common reason why an elderly person consults a physician.
    Senator Harkin. Well, I would like to know more. Anything 
that you have got on what they are doing at Michigan in any 
kind of a form that I can halfway understand, I would 
appreciate seeing it.
    Dr. Battey. I will have my staff abstract something in 
educated lay terms describing the results from the University 
of Michigan.
    Senator Harkin. I appreciate that. How many more 
universities are doing this? What is their timetable, that type 
of thing.
    Dr. Battey. We will get that information for you.
    Senator Harkin. I would like to know about that. Understand 
my concern. I have been hearing about this. Seventeen years I 
have been hearing about regenerating hair cells.
    Dr. Battey. It is a hard problem.
    Senator Harkin. Well, I understand.
    Dr. Battey. I wish that science progressed faster, but 
usually our understanding is incremental and often it is 
serendipitous. For example, the discovery of the importance of 
the Math-1 gene took place in a lab that was not interested in 
hearing at all. They simply knocked the gene out in a mouse and 
the mouse was deaf.
    Senator Harkin. Fascinating.
    Well, that is all I have for right now. I may have others. 
Now we will turn to the National Institute of Neurological 
Disorders and Stroke. Dr. Story Landis has been Director since 
September 2003. Dr. Landis received her undergraduate degree in 
biology from Wellesley and her master's and Ph.D. from Harvard.
    Dr. Landis, welcome and please proceed.
STATEMENT OF STORY LANDIS, Ph.D., DIRECTOR, NATIONAL 
            INSTITUTE OF NEUROLOGICAL DISORDERS AND 
            STROKE
    Dr. Landis. Thank you very much. I, like my colleagues, am 
delighted to have this opportunity to be able to testify today 
about research on mind, brain, and behavior. As I have heard 
from each of us, disorders of brain function are leading causes 
of disability in the modern age, and I think that Dr. Batte did 
a very good job of pointing out some of the issues.
    NINDS is responsible for reducing the burden of several 
hundred neurological disorders. These range from very common 
disorders, like stroke, Parkinson's, epilepsy, to relatively 
rare but individually devastating disorders like ALS--
amyotrophic lateral sclerosis--and spinal muscular atrophy. So 
in addition to the burden in terms of lost life, disability and 
suffering, neurological diseases cause billions of dollars each 
year in medical expenses and reduced productivity.
    Neurological disorders affect people of all ages. We have 
increasing disability in children as a growing problem because 
of brain injury in premature infants who now survive when they 
would not have before. As Americans live longer lives, age-
related disorders like dementia, stroke, Parkinson's, and 
epilepsy are increasing in incidence. Meeting the challenge of 
neurological disorders therefore has never been more important. 
The good news is that the advances in basic and clinical 
neuroscience provide enormous opportunities.
    Now, 20 years ago neurology was really regarded as a 
diagnostic discipline because neurologists had relatively few 
therapies to offer patients. They could tell you what the 
lesion was, but they could not necessarily do anything about 
it. Through NINDS-funded research we have actually made 
extraordinary progress. For example, there used to be only a 
handful of drugs to treat epilepsy and now we have more than 
20. Steroids used to be the only treatment for multiple 
sclerosis, but now there are three FDA-approved drugs and more 
in the pipeline. Deep brain stimulation (DBS) dramatically 
helps many people with Parkinson's disease who are no longer 
benefited by medicines. Turn off the stimulator and they are 
frozen, unable to walk. Turn on the stimulator and in the best 
cases, the ones that make it to ``Dateline'', they can dance.
    Now, while DBS is very exciting, it, like other treatments 
for Parkinson's disease, addresses the symptoms but not the 
underlying causes. The underlying cause is death of brain 
cells. So we need desperately to figure out treatments that 
will protect the neurons that remain. Just last week, NINDS 
began to enroll patients in large phase 3 clinical trials to 
determine whether we can slow the loss of brain cells and 
prevent the slow decline of patients with Parkinson's. We hope 
to begin a second trial of a neuroprotective agent soon.
    As you or someone else alluded to, even just the small 
change in the rate of progression of any of these chronic 
neurodegenerative diseases would make a very big difference in 
the quality of life and how people fared.
    Now, the scientific rationale for the two drugs that we are 
studying in these neuroprotective trials is strong or else we 
would not be funding them. But we really believe, because of 
the discovery of eight genes that cause familial Parkinson's 
disease and our ability to understand how the proteins that 
those genes encode for, we should have much better and more 
targeted drugs soon, and we would then put these drugs into 
neuroprotective trials that would prevent neuron loss.
    So I would like to talk a little bit about stroke. NINDS is 
the lead Institute for stroke. It is in our name. Stroke is the 
third leading cause of death and disability in the United 
States. The good news is that CDC data demonstrate that age-
adjusted stroke deaths have declined from 180 per 100,000 in 
1950 to 50 in 2004. That is age-adjusted, though. So the bad 
news is actually that because our population is aging we are 
barely keeping pace in terms of incidence of stroke.
    NINDS has three strategies for stroke. First is prevention, 
then minimizing damage when a stroke occurs, and finally 
developing better strategies for recovery. In terms of 
prevention, the most important thing is to know what increases 
your risk of a stroke. NINDS has a number of epidemiological 
studies that look at that. The largest of these is called 
REGARDS which has recruited over 30,000 people, half of them 
African American, many in the stroke belt. The goal is to study 
how race and geography influence the incidence of stroke.
    Now, there are already two important findings in this 
study. The first is that there are many more silent strokes--
that is a stroke that does not take someone to the hospital or 
give you an obvious disability--than anybody expected, 
particularly in the middle aged population. The second is that, 
while we have always thought of hypertension as the principal 
risk factor for stroke, we now, based on this REGARDS study, 
understand that diabetes is also very important. So obviously 
NINDS not only needs to partner with NHLBI and the American 
Heart Association for reducing hypertension, but we also need 
to look at partnering with NIDDK and diabetes groups for 
reducing diabetes.

                          DIABETES AND STROKE

    Senator Harkin. Excuse me for interrupting at this point. 
Are you saying that diabetes is a leading indicator for having 
a stroke?
    Dr. Landis. In this population, being diabetic 
significantly increases your risk of having a stroke.
    Senator Harkin. In this population.
    Dr. Landis. In this population of 30,000 people, many of 
them who are not patients yet. We did not expect that but we 
knew about hypertension and not about diabetes. This is not 
surprising. Diabetics are often overweight and do not exercise 
so it is not surprising, but it had not actually been 
demonstrated.
    Senator Harkin. I am just curious again to take this a step 
further. Okay, diabetic, but then have you screened all those 
to look at what has been their cholesterol levels, all the 
other factors?
    Dr. Landis. This has been a recent study, 4 years old, and 
we are just beginning to see the fruits of these initial 
analyses of data. So the first publications are just beginning 
to come out and we are in the process now of accepting an 
application to refund the study. Obviously, the more things 
that we could look at, the better data we would get in terms of 
identifying risk factors and being able then to think about 
interventions.
    So if prevention fails, obviously we want to minimize 
damage when someone has a stroke. The NINDS Institute a decade 
ago had a clinical trial that showed that the clot-busting 
drug, TPA, could restore blood flow to the brain and prevent 
brain damage if it was given within 3 hours of stroke onset. I 
can tell you very honestly that this transformed acute stroke 
care in this country. You did not get shuttled off to a dark 
room and given an aspirin. You actually got aggressively 
treated. I think it has been a model for how other neurological 
diseases can be treated.
    Now, this treatment really benefits patients, obviously. A 
third of the patients who get this treatment leave the hospital 
with no sequelae whatsoever. It reduces long-term disability-
related costs and there is a net savings of more than $4 
million for each 100 patients treated because you do not have 
to do long-term care and rehabilitation.
    We are currently running clinical trials to boost the 
effectiveness of TPA, to select patients who might benefit 
beyond the current 3-hour limit, and to determine whether if 
you inject the TPA into the blocked brain artery you get more 
benefit than if you just do it intravenously.
    Now, if you have a stroke, we need to help people recover 
from it. Because of animal studies, we know that there is 
remarkable plasticity in the adult brain. Because of that 
plasticity, investigators that were funded both by NINDS and 
NICHD forced stroke patients to use the affected arm and this 
stimulated the formation of new brain connections, and a 2-week 
study of rehabilitation based on this insight showed lasting 
clinical improvement in arm function for stroke survivors.
    So it is very clear that increasing the brain's latent 
capacity to rewire and/or repair itself is an extremely 
exciting area for research in NINDS, and will also impact many 
other brain disorders.
    I want to, in closing, underscore two points that were made 
by the panel of outside scientists at last week's hearing. I 
thought they were very impressive. I watched it on C-SPAN. The 
first is we need to encourage new ideas and new investigators. 
You go to any scientific meeting and most of the people in the 
audience, who are speaking and presenting have grey hair and, 
while they will make advances--I mean no offense to the grey 
hair because I have it myself--they will make advances over the 
next decade, but we will not cure many of our diseases. We will 
improve treatment, but not cure them in the next 10 years so 
that is a very important issue.
    The second is the importance of NIH basic research, both 
for the public health of the Nation and the competitiveness of 
our private sector. Now, while each of the institutes that we 
represent has a distinct mission, the structure requires that 
we answer fundamental and shared questions about the brain, 
such as how genes and the environment shape the brain and how 
the brain represents thoughts, emotions, memories, sounds, and 
leads to behavior. Answers to these questions are key to 
preventing all kinds of brain diseases, as well as learning how 
to optimize brain health and help all our citizens realize 
their full potential.

                           PREPARED STATEMENT

    So recognizing that we share the brain and the significant 
synergy that will come from collaboration, the institutes 
represented here along with others who will testify in 
different hearings created the Neuroscience Blueprint for the 
extramural community and the Porter Neuroscience building in 
the intramural program, which I would say is not completed. We 
would be pleased to tell you more about the blueprint and the 
Porter building during the question period.
    I would like to thank you very much for your attention and 
your support.
    [The statement follows:]
               Prepared Statement of Dr. Story C. Landis
    Mr. Chairman and Members of the Committee: I am pleased to present 
the fiscal year 2008 President's budget request for NINDS. The mission 
of NINDS is to reduce the burden of neurological disorders by 
developing ways to prevent or to treat these diseases. The fiscal year 
2008 budget is $1,537,019,000.
    Disorders of the nervous system, common and rare, affect people of 
all ages. They cause an enormous burden in lost life, disability, and 
suffering, as well as billions of dollars each year in medical expenses 
and reduced productivity. Because Americans are living longer, stroke, 
dementias, Parkinson's disease, epilepsy, and other neurological 
disorders that rise in frequency with age are increasing. Abnormalities 
in nervous system development rob many children of a normal life. As 
more premature infants survive through intensive care, neurological 
disability in children is a growing problem. Many people, often young 
adults, now survive trauma to the spinal cord or brain, but confront a 
lifetime of disability. Meeting the challenge of neurological disorders 
has never been more important, but the opportunities for progress have 
never been greater. Advances in neuroscience are transforming the 
practice of neurology from diagnosing patients, with only inadequate 
treatments to offer, to intervening to stop or prevent disease, with 
treatments tailored to each person. Neurosurgery is likewise 
increasingly capable of preventing or repairing damage to the brain.
                      impact of clinical research
    NINDS has its most immediate impact on public health through phase 
III clinical trials, which test the safety and efficacy of 
interventions. It is essential to assess the return on this investment 
in improving quality of life. At the request of the National Advisory 
Neurological Disorders and Stroke Council, the institute contracted for 
an independent evaluation of the costs and benefits of all NINDS phase 
III clinical trials conducted from 1977 to 2000 [The Lancet 367:1319-
27, 2006]. The total cost of the clinical trials in the study was $335 
million (adjusted to 2004 dollars). Over 10 years, the benefits 
exceeded $15 billion and added 470,000 healthy years of life to people 
in the United States. For the entire period of the study, the benefits 
surpassed $50 billion, which was greater than the total NINDS budget 
over that period ($29.5 billion). Advances in neuroscience are yielding 
more clinical trial opportunities than ever before, but trials are 
expensive and take years to complete. NINDS is developing computer 
models to estimate in advance which trials would have the most impact 
on public health.
                   translating promise into progress
    Because of progress over the last decades, thousands of strokes are 
prevented each year and emergency treatment lessens chronic disability 
for many people who do have a stroke. Data this year from the Centers 
for Disease Control and Prevention (CDC) show that age-adjusted stroke 
deaths are continuing to decline, from 65.3/100,000 in 1990 to 50.0/
100,000 in 2004, compared with 180/100,000 in 1950. Better surgical 
treatments and drugs also help people who have chronic pain, dystonia, 
epilepsy, migraine, multiple sclerosis, neuropathies, Parkinson's 
disease, and many other diseases. Brain imaging has revolutionized 
neurology and neurosurgery. For many people, genetic testing eliminates 
arduous and expensive diagnostic odysseys to determine which of the 
hundreds of neurological disorders is responsible for their problems. 
NIH research drives this progress.
    A decade ago an NINDS clinical trial showed that the clot busting 
drug tPA was the first emergency treatment that could improve the 
outcome from stroke. This engaged the community in stroke education, 
stimulated the organization of more than 250 certified primary stroke 
centers nationally, and energized researchers to develop even better 
emergency care. In the future, combinations of tPA and neuroprotective 
therapies will rescue brain tissue from permanent damage, and rapid 
diagnosis will identify which patients will benefit from what 
interventions while the critical time window for intervention is still 
open. This year NINDS investigators showed how MRI brain imaging can 
improve diagnosis for patients who come into emergency rooms with 
suspected strokes, and other scientists are developing rapid blood 
tests for stroke using genomic fingerprinting. Several strategies to 
boost tPA's effectiveness are in development, including clinical trials 
of ultrasound to help break clots quickly, and direct injection of tPA 
through a catheter threaded into the blocked brain artery for patients 
with large clots that are difficult to clear. Clinical trials of 
interventions, studies of risk factors, and gene studies will also 
continue the momentum of stroke prevention, with increasingly 
personalized guidance. This year, to illustrate that trend, NINDS-
funded researchers discovered a gene variation, more common in African-
Americans, that predisposes young women who smoke to have strokes.
    For people who do have a stroke, neuroscience is offering new 
approaches to recover lost functions. New understanding of brain 
plasticity suggested that, counter to intuition, forcing patients to 
use an affected arm would stimulate adaptive changes in the brain. A 
two week behavioral rehabilitation regimen based on this insight 
yielded lasting clinical improvements for stroke survivors who had 
chronic weakness in one arm. Studies are building on this strategy, 
using behavioral methods, drugs, and brain stimulators to engage the 
brains' natural capacity to adapt, and even generate new brain cells. 
Enhancing the brain's latent capacity to repair itself may also help 
people recover from traumatic brain injury and many other disorders.
    A decade ago, spinal muscular atrophy (SMA) was one of hundreds of 
poorly understood inherited disorders that affect the nervous system, 
and the outlook for developing treatments was bleak. The discovery of 
the gene defect that causes SMA revealed a rational strategy for 
developing drug therapy. In just a few years, the NINDS SMA Project 
developed a detailed drug development plan and tested hundreds of new 
compounds in laboratory tests. Most recently, some of these potential 
drugs increased the amount of the critical missing protein to normal 
levels in cultured cells from patients who have SMA. The SMA Project is 
testing the effectiveness of these compounds in animals with SMA and 
assessing their safety to bring these potential drugs to clinical 
trials, offering significant promise for helping people who have SMA.
    Research on SMA illustrates the path from gene to understanding to 
treatment. Researchers have now characterized well over 200 mutations 
that cause neurological disorders. For inherited ataxias, Batten 
disease, Down syndrome, Huntington's disease, muscular dystrophy, Rett 
syndrome, neurofibromatosis, and many other previously baffling 
disorders, researchers have genetically engineered animals that mimic 
the human disorder and then replaced genes, turned harmful genes off, 
turned up compensatory genes, or counteracted gene defects with drugs 
that target the affected cellular functions. In the future, application 
of these strategies to patients could preempt or even reverse the 
damage caused by gene defects. NINDS is aggressively pursuing 
opportunities to translate science advances such as these to 
treatments.
    The goal for epilepsy is ``no seizures, no side effects,'' or 
better yet, to prevent epilepsy from developing. In the 1960's only a 
handful of drugs were available to treat epilepsy. Today there are more 
than 20, which control seizures in about two-thirds of people who have 
epilepsy. Ten were developed with special programs at the NIH, and the 
NINDS Anticonvulsant Screening Program continues to catalyze academic 
and industry efforts. New animal models will allow screening potential 
drugs for people who have treatment-resistant epilepsy and for blocking 
epilepsy development. Clinical trials are now testing interventions to 
prevent epilepsy after head trauma, a major risk factor. Gene studies, 
now underway, will enable physicians to personalize treatment, choosing 
the best drugs or other therapies for each person with epilepsy, 
avoiding the current trial and error process.
    Drugs that are the mainstay of Parkinson's disease treatment mask 
symptoms but ultimately fail because they do not slow the underlying 
neurodegeneration. Deep brain stimulation (DBS) dramatically helps many 
people with advanced Parkinson's disease. NIH research, from technology 
development to clinical trials, is improving DBS and expanding its use 
for other neurological and psychiatric diseases. Researchers are also 
developing drugs to slow neurodegeneration itself. NINDS assessed 
candidate neuroprotective drugs for Parkinson's disease, conducted 
early phase clinical trials, and is beginning a large clinical trial of 
a neuroprotective drug. Even a modest slowing of Parkinson's or other 
neurodegenerative diseases would have an immense impact on public 
health, so drugs to forestall neurodegeneration are a high priority.
    Stem cell research has captured the public's attention. Research on 
animals with Parkinson's-like disease illustrates the promise and 
challenge of stem cell therapy. In recent tests, stem cell-derived 
transplants dramatically improved movement, but also produced tumors in 
some animals. Stem cell therapies for spinal cord injury, muscular 
dystrophy, and many other neurological disorders continue to advance 
toward the clinic. However, better control of stem cells is necessary 
before these therapies are ready for people, so understanding the basic 
biology of stem cells is essential.
    Scientists are also making progress in answering fundamental 
mysteries, such as how genes and the environment shape the brain and 
how the brain represents thoughts, emotions, and memories. Answering 
basic questions such as these is the key to not only treating disease, 
but knowing how people can maintain a healthy brain and realize their 
full potential at every age.
                        planning for the future
    NINDS continuously monitors research needs and opportunities. The 
institute recently posted a mid-course review of the Stroke Progress 
Review Group and a new plan for Parkinson's disease. An epilepsy 
conference this month will follow up the meeting that launched the 
epilepsy benchmarks planning process. More broadly, NINDS is beginning 
a process to update its strategic plan. With input from all 
stakeholders, we will identify aspirational goals that will guide us to 
best achieve our mission and then focus on what steps NINDS can take to 
realize this vision. In order to achieve our paramount goal of reducing 
the burden of neurological disorders, we must certainly continue to 
support young scientists, to engage the ingenuity of the scientific and 
medical community, to work with the private sector, and to collaborate 
with other components of the NIH, as we now do through the NIH Roadmap, 
the NIH Blueprint for Neuroscience, working groups on specific 
diseases, as well as dozens of specific inter-institute initiatives.
    Thank you, Mr. Chairman. I would be pleased answer questions from 
the Committee.

    Senator Harkin. Dr. Landis, thank you very much.
    Let me--I have got quite a few questions here. First of 
all, talk to me about something that you mentioned in your 
written statement. I am hearing more and more about the 
debilitating effects of migraine headache.
    Dr. Landis. Right.

                           MIGRAINE HEADACHES

    Senator Harkin. I saw some figures, I cannot repeat them 
here because I do not have them here, but just how prevalent 
migraine headaches are. More and more I am meeting people who 
have migraine headaches. I have had some people who have worked 
for me in the past who have had them and it is just very 
debilitating.
    So what is happening? Why? What is the story?
    Dr. Landis. It is not completely clear. What is completely 
clear is that there are several different causes of migraine 
headaches and that if you have mutations in particular kinds of 
ion channels you can have migraine, and that it can be a 
spreading depression. We have, fortunately, over the past 
decade developed a number of treatments which can forestall a 
migraine once it begins. We also have learned in some cases 
that long-term treatment with calcium channel blockers can 
prevent migraines.
    We do not know as much as we should. It is an area that has 
not received as much attention as it might. NINDS recently 
released a request for applications specifically in the area of 
migraine headaches. We recognize it is an underserved area and 
hope to stimulate research in it.
    Senator Harkin. I do not know whether I am just hearing 
more about it now and finding more people. Is it increasing in 
prevalence?
    Dr. Landis. I do not think it is increasing. I think people 
are more attentive to it than they have been before. One of the 
problems with being an Institute like NINDS is making choices 
between stroke and Parkinson's and migraine. We are hoping in 
our planning process to undertake over the next 2 years, a look 
across all the diseases that we are responsible for and see the 
ones that we have perhaps not invested in as much as we might.
    Senator Harkin. One disease that you know that I have been 
interested in, I did not even know about it until a few years 
ago, but the more I have looked at it the more I have seen what 
you have been doing at the Institute on it. It seems to me that 
you are making great progress in understanding spinal muscular 
atrophy, which I had not heard of until a few years ago. I have 
met with some people in my home State with children who have 
that and others.
    The more I have learned about it, the more I think that 
there may be in this research area applicability to other 
diseases. You have identified the gene, I think.
    Dr. Landis. We did not, but it has been identified.
    Senator Harkin. It has been identified. Somebody did.
    Dr. Landis. Right. The Europeans actually, I think.

                        SPINAL MUSCULAR ATROPHY

    Senator Harkin. Oh, is that right? Sorry to hear that. But 
that is all right.
    Tell me about the progress on spinal muscular atrophy, 
because I keep hearing that this has some connectivity to other 
types of diseases.
    Dr. Landis. There are two pieces of our investment in 
research in spinal muscular atrophy that I think are important. 
The first was the Institute decided a number of years ago that 
we would try an experiment, which was to identify a particular 
disease, a devastating disease. In SMA, kids lose their motor 
neurons, and in babies many of them die within the first year. 
Some of them die within 4 to 5 years depending on the type. We 
would try to identify a particular disease which was amenable 
to a concentrated investment, a focused effort in therapeutics 
development.
    After a survey of many of the diseases that we were 
responsible for, SMA emerged as the likeliest candidate for 
this experiment. Mutation occurs in the SMN-1 gene. There is a 
second gene, SMN-2, which codes for the same protein, but does 
it much less effectively. We had compounds which we knew could 
increase the levels of SMN, Survival of Motor Neuron protein. 
So we put a big chunk of money, $20 million, into a contract to 
actually come up with at least one drug that would have an 
investigational new drug designation within 4 years, or the end 
of 2007. We are not going to make the end of 2007 because it 
turned out that what we had to do is actually create a virtual 
biotechnology company through this contract.
    But we are making significant progress. We recently filed a 
patent for one chemical backbone and have a number of compounds 
in there which cross the blood-brain barrier which 
significantly increase the amount of SMN protein. We are taking 
those compounds to animal studies to see which is the most 
effective in increasing the survival of these animals.
    So it is an experiment for the Institute to see if we can 
actually push forward therapeutics in a very significant way 
and make a difference. Then the other issue is that these are 
the same neurons that die in ALS. The kinds of things that 
might promote survival of motor neurons in SMA might also be 
instructive for ALS. The mechanism--the failure to make a 
splice--again a technical term--is apparent in a number of 
other diseases we are responsible for. If we can figure out a 
way to make the splice work, we might use that same strategy in 
other diseases.
    So it has a number of very interesting implications for the 
Institute in how we manage rare diseases and how we move from 
one rare disease to another.

                                 STROKE

    Senator Harkin. You mentioned that deaths have declined due 
to stroke, but I just wonder about the incidence of stroke. I 
do not think the instance of stroke is down.
    Dr. Landis. No. Age-corrected deaths due to stroke have 
decreased. The incidence is not decreasing because our 
population is aging.
    Senator Harkin. Well, also I think we have better 
interventions, too, for stroke.
    Dr. Landis. Right.
    Senator Harkin. I think stroke remains still one of the 
feared things that can happen to someone. They are just so 
unexpected and can happen to anyone at any time. It is that 
early intervention if you can get to it right away that helps, 
if you get that----
    Dr. Landis. TPA.
    Senator Harkin. What is it called? TPA.
    Dr. Landis. Tissue Plasminogen Activator.
    Senator Harkin. TPA.
    Dr. Landis. TPA.
    Senator Harkin. I am also interested in Parkinson's 
disease. In your testimony you talked about deep brain 
stimulation for Parkinson's disease. Again, how much progress 
is being made in this?
    Dr. Landis. We are presently conducting with the Veterans 
Administration a clinical trial to determine whether deep brain 
stimulation is better than best medical treatment. A group in 
Europe has already produced some data that are consistent with 
that, but we want to make sure that that is in fact true.
    The second issue is where do you put the stimulating 
electrode. So some people, some surgeons, put it in something 
called the GPI and others put it in the STN, and we do not know 
which locus is better. So the second part of this NINDS-VA 
study is to determine where is the best place to put it.
    One of the most surprising things is that deep brain 
stimulation actually works for a number of other neurological 
diseases--dystonia, Tourette's--and has shown to have benefit 
for chronic untreatable depression. So the notion of putting 
stimulating electrodes in the brain and altering patterns of 
brain activity may be applicable to more than just neurological 
diseases.

                   TRANS-CRANIAL MAGNETIC STIMULATION

    Senator Harkin. A year ago or so maybe, I was visiting my 
office. A friend of mine brought a person in, a woman who had 
been to Greece--she had Parkinson's disease--to undergo some 
new therapies. The way she described it to me, she had pictures 
of it. It was some doctors in Greece, some scientists, had 
developed like a helmet they put over her head, but it did not 
penetrate the skull, but it was like----
    Dr. Landis. Trans-cranial magnetic stimulation probably.
    Senator Harkin. Thank you. I had no idea. Probably so if 
you say so.
    Dr. Landis. Well, that is a strategy that we are looking at 
in this country as well.
    Senator Harkin. This woman came back, and it did not cure 
her of Parkinson's, but it really alleviated the symptoms 
greatly for her. So I do not know if you are looking at 
anything like that.
    Dr. Landis. Obviously, if you could get changes in 
activity, circuitry, without having to stick electrodes in the 
brain, that would be preferable. NINDS and the Department of 
Defense are exploring the use of trans-cranial magnetic 
stimulation as an alternative to deep brain stimulation.
    Now, the problem with deep brain stimulation is it does not 
stop neuron cell death. I think Dr. Fischbach when he testified 
and said that we would have a cure for Parkinson's in 5 or 
maybe 10 years actually really believed in his heart that the 
change in activity from deep brain stimulation would promote 
survival of neurons in Parkinson's, and that has been a 
disappointment. It has not done that. But it does provide 
symptomatic relief.

                     POST-TRAUMATIC STRESS DISORDER

    Senator Harkin. Dr. Insel, I have been told that 1 out of 
every 3 returning Iraqi veterans--this is sort of a follow-up 
on what Senator Specter asked--1 out of 3 seeks mental health 
help some time during the first year. Now, whether that is 1 
out of 3 or 1 out of 4, it is very high. That is just those who 
actually seek it. What about those that do not? How many more 
out there that are trying to tough it out?
    Any thoughts on why it is so prevalent and why these 
returning vets are having mental health problems and why the 
incidence? It seems to me--now, maybe I am wrong, but the 
incidence of post-traumatic stress disorder is going up, and 
sometimes PTSD does not exhibit itself for months afterward, 5 
months, 6 months, 7 months afterward.
    Talk to me a little bit more about post-traumatic stress 
disorder. What is it? Is it more prevalent now than in the 
past? How about all these returning veterans who are having 
mental health problems? Is this more than any war in the past? 
Do we know? Maybe we do not even know that. I do not know.
    Dr. Insel. We do not know yet. Post-traumatic stress 
disorder plays out over many, many months and sometimes years. 
We often now think about post-traumatic stress disorder as a 
failure of recovery. Everyone after a traumatic event is, in 
lay terms, shell-shocked. They have symptoms. They have trouble 
sleeping. They may be preoccupied by the event. They have a 
need to talk about it all the time. We would all feel negative 
impactly if the event is traumatic enough, and it does not have 
to be combat. It could be a car accident. We have all 
experienced this.
    Most people can talk it through and recover and 6 months 
later, it is a distant memory. They are able to sleep and not 
use alcohol or illicit drugs to cope with this. For some 
reason, and it is not due necessarily to the degree of trauma. 
It has more to do with the individual vulnerability to 
traumatic events and their psychological sequelae. Some people 
do not recover in the way that most of us do. Those are the 
people who develop PTSD. The numbers range from 13 to 16 
percent in the current war. In the Vietnam War the numbers were 
higher. But that is over a longer period of time.
    We will have to see. The assumption would be that if the 
numbers are 13 percent now--and as I mentioned before, that 
equates to about 170,000 affected individuals. One would think 
that they will go up even further over the next year or so. 
Often the way it happens is that people are coping well enough 
until there is a second hit. They watch a movie that reminds 
them of the trauma. They have a loss in their life. They have 
some stressor that then tips the balance, and they then emerge 
with full-blown symptoms.
    Senator Harkin. Of course, your institute is actively doing 
research in post-traumatic stress disorder?
    Dr. Insel. Absolutely. We have decided through much of this 
effort to collaborate with DOD and with the VA. So we have a 
large effort. Actually we have a joint RFA, a request for 
applications, that has been funded, where we have half the 
grants and they have the other half. We work together with them 
because this is where we think the need is greatest.
    Where we would really like to go with this is to understand 
this individual pattern of vulnerability, to identify who needs 
the early intervention, before the point where someone develops 
all of the secondary aspects of PTSD, the depression, the 
alcohol abuse, the substance abuse, and at that point preempt 
all of that by being able to get to them early.

                              NIMH BUDGET

    Senator Harkin. Your Institute's budget for next year is 
$1.4 billion.
    Dr. Insel. Right.

                           BASIC NEUROSCIENCE

    Senator Harkin. What would be the largest sector where that 
money would go for research?
    Dr. Insel. The single largest--we have five research 
divisions and the largest one of them is in the basic 
neuroscience arena. We really are trying to get at the question 
you asked before, actually the critical question, understanding 
the pathophysiology of these illnesses. It is not just a matter 
of tweaking the drugs that we have now and figuring out how to 
use them best. That is important, but we want to get to a point 
where we have a new generation of compounds that we can think 
of as either preventive interventions or cures, really raising 
the bar on what we expect for interventions. That is going to 
require having a much better fundamental understanding at the 
level of molecules and cells and brain systems about how 
something goes wrong to give you the psychosis of 
schizophrenia, the hopelessness of depression, the symptoms of 
PTSD. We do not know that. We know a little bit about how to 
treat them, but we need to know a lot more of the fundamentals.
    That has been our biggest effort.

                                 STRESS

    Senator Harkin. Dr. Insel, would you be the proper person 
that I would ask this question of? I am going to ask it, but 
maybe it is another Institute. I do not know. The effect that 
stress plays in diseases. I have read a lot about in science 
magazines and other things that more and more the high factor 
of stress, both in perhaps getting a disease, but in the 
generation of that disease after you get it and how it 
progresses, that stress is an indicator for how ill you might 
become.
    So are you looking at stress? Is this part of your $1.4 
billion, looking at stress and how stress levels affect a 
person's ability to ward off diseases and illnesses or become 
more susceptible because they have a higher level of stress? Is 
that you or is that somebody else?
    Dr. Insel. That is a number of us. Dr. Volkow talked about 
that at great length and her specific interest is on 
developmental stress and how it can tease up an individual to 
be responsive later with pathological behaviors like addiction. 
NIMH has a similar interest, but it is more focused on 
depression, where we know that children who have been stressed, 
particularly at certain vulnerable times in development, are at 
much, much greater risk for depression after puberty or even 
into young adulthood.
    The mechanism by which that happens is where our interest 
now is taking us. We want to know, what is it about stress that 
affects one individual to make them subsequently very depressed 
or drug addicted and the next individual takes the same event 
and they somehow get immunized, they get stronger from having 
been challenged in some way. We do not know enough to 
understand those individual differences.
    So that is where a lot of our effort is going, finding 
again the molecular and cellular substrates of how stress 
affects the brain is we think one of the ways to get there.
    Senator Harkin. But you are--somewhere in this whole big 
$1.4 billion, you do have research on stress that is ongoing, 
dealing with how stress relates to physiological problems?
    Dr. Insel. Absolutely. It is a big part of our effort in 
terms of mechanisms, understanding mechanisms, and a lot of 
that is going on in animal research, where we can really 
control many of the variables and look specifically at what 
stress is doing. Dr. Volkow can tell you about some of the work 
they are doing as well in looking at the long-term effects of 
stress.

                     GENETIC FACTORS FOR ADDICTION

    Senator Harkin. I was going to ask Dr. Volkow about that. 
Oh, yes, I know. You were talking about the environmental 
factors to drug abuse, but you said that genes--I wrote this 
down because it really sounded almost too neat--50 percent of 
the factors are genetic for addiction.
    Dr. Volkow. Correct.
    Senator Harkin. You really hold that it is 50 percent?
    Dr. Volkow. 50 percent, and actually this is very 
consistent and reproducible. The vulnerabilities for becoming 
addicted is at least 50 percent, analytically determined. The 
other 50 percent is your environmental factors involved with 
it. You know, with animal experiments what we are trying to do, 
of course, is identify which genes make you vulnerable. We have 
come to recognize that there are going to be genes that make 
you vulnerable to experiment with drugs which are going to be 
different from those genes that are going to make you 
vulnerable--if you get repeated exposure, you may or may not 
become addicted. Approximately 10 percent of people will. Those 
genes that we identified evidently are linked with the process 
of plasticity and also involving learning and memory.
    So it appears that for you to have the vulnerability, you 
have the genes that will be much more likely to be modified by 
environmental exposure to drugs to create new connections, but 
then are likely to be driving the compulsive intake of drugs.

                          STRESS AND ADDICTION

    Senator Harkin. Following up on that, it would seem that 
stress does play a high part, a big part, in people getting 
addicted to drugs, to relieve stress or they get stressed out. 
They want to smoke or they want to drink or they want to----
    Dr. Volkow. Take marijuana.
    Senator Harkin [continuing]. Take marijuana or more serious 
drugs.
    Dr. Volkow. Yes, and we are very much interested, and we 
have from the perspective of basic science, we have known for 
many years with the epidemiological data that environmental 
stressors, and in particular social stressors are some of the 
most profound in human subjects. We are very, very sensitive to 
social stressors. We have known that they affect our 
vulnerability to addiction. It is clear when people are in war, 
for example, which is very stressful, drug abuse can go up in a 
way to cope with the stress. Or if you come up with an 
environment where you have been physically abused or sexually 
abused, more likely to take drugs.
    What we did not know is why and what is the social stressor 
doing to your brain that makes you more vulnerable. For 
example, there have been studies now both in rodents and in 
primates that show that social hierarchical structure and 
pending on the level, if you are dominant versus subordinate, 
can modify specific proteins that regulate, modulate your 
vulnerability to take drugs.
    So if you are in an environment and very subordinate in a 
system that is very stressful to be a subordinate, then those 
proteins go down and that leads you to a facilitation of taking 
drugs. That is what I was highlighting. Of course, the 
challenge now is how can we buffer. If someone is born into 
that environment, if we learn how does that stress produce 
those changes, how can we buffer an intervention to be able to 
rehabilitate, to go back to recover some of those changes that 
is the basic perspective.
    We are also very interested in the mean time to do 
interventions and to evaluate the extent to which specific 
prevention interventions are useful. For example, we take for 
granted social skills. A child that has poor social skills 
predicts higher likelihood that they will take drugs. So 
something that makes a lot of sense, intuitive sense. Why do we 
not as a prevention strategy identify those kids that are 
unable to negotiate interactions with their peers as a 
prevention effort? It will be beneficial not just for drug use, 
but also for mental illness.
    So that is the sort of thing that we are also encouraging 
from the prevention behavioral intervention.

                               HEAD START

    Senator Harkin. That is what the Head Start program is for. 
Yet Head Start I think gets about half of the eligible 
preschoolers now. By the way, Head Start is not an educational 
program; it is a social skills program with education added in. 
A lot of people think Head Start is education. It is not that. 
That is why it is in the Department of Health and Human 
Services, not in the Department of Education. I do not know why 
I am telling you all this, but anyway.
    But the idea was to give these kids that kind of social 
interaction and that type of thing. But the problem is that we 
do not pay Head Start teachers well enough. We do not get 
qualified, a lot of qualified people in there with Head Start.
    So anyway, it just goes back to what you say about getting 
those early interventions.
    Dr. Volkow. Correct.
    Senator Harkin. Which we know are predictors for drug abuse 
and for mental health problems and for drug abuse.
    Dr. Volkow. Also can, for example, prevent criminal 
behavior, which is something that of course we just hinted at.

                             NIH BLUEPRINT

    Senator Harkin. Well, that is for a different thing.
    One last question and this is for all of you. All the 
Institutes here today have been involved in a collaborative 
effort called the NIH Blueprint for Neuroscience Research. Dr. 
Landis, I will start with you and we will just go down. What is 
this effort? What has been achieved? What are you doing, and 
what are the plans for next year, and how do you all 
participate and kick into this? So just tell me about the NIH 
Blueprint for Neuroscience Research so I can better understand 
it.
    Dr. Landis. A number of years ago we recognized that 
Institutes which funded research in the neurosciences had 
common interests, common goals, and common needs, and set out 
to actually create a collaborative environment. Once a month 
all the Institute Directors or Center Directors participate in 
this meet to discuss important initiatives, fund workshops and 
requests for applications and share best practices.
    We have a modest budget. Each of us chips in money to a 
central pot that represents a fraction, a very small fraction, 
of the amount of money from our budget that funds neuroscience. 
We discuss as a group what are the most important and the most 
interesting ways we can spend that money. We have funded 
training programs that benefit all the institutes. We have 
funded the generation of mutant mice which benefit all the 
Institutes.
    Several years ago we thought, instead of just investing in 
tools, that we might want to invest in some science. We picked 
three themes, neural degeneration, neural development, and 
plasticity, and have been working through those themes once a 
year. I have to say, you know, it is pretty amazing that we can 
get each of the Institute Directors to show up once a month to 
talk about science and initiatives, but we have done it. I 
think all the institutes in the neurosciences are a lot 
stronger for having done this.
    I am sure this is a little like an elephant, where I have 
just given you the trunk, someone else might give you a leg.
    Senator Harkin. Are you a leg, or what are you?
    Dr. Landis. He is the ear.
    Senator Harkin. Oh, he is the ear, of course.
    Dr. Battey. There is not a lot I can add to Story's 
beautiful description of the blueprint, other than to maybe 
make two observations. We were talking earlier about Math-1 and 
the mouse knockout that led us to the discovery that it was 
essential for hair cell development. That was not my grantee. 
That was her grantee [indicating], Louis Ogbee in Texas, did 
that.
    Dr. Landis. He actually was picking up on a gene discovered 
in drosophila that is required for the development of a 
particular kind of external sensory neurons, and he said, gee, 
why do we not figure out what it does in mammals.
    Dr. Battey. So my point is that the neuroscience Institutes 
have remarkable overlap in the experiments that need to be done 
to move this forward. We also have remarkable overlap in the 
needs. For example, Story has mentioned many times neuronal 
degeneration and I have told about hair cell degeneration. It 
is almost certain that many of the mechanisms that underlie 
degeneration of neurons are going to be the same ones that are 
going to be involved in degeneration of hair cells.
    So by pooling our resources and generating common reagents 
and resources, we leverage each other's science and advance the 
science of my relatively modest sized Institute is advanced 
enormously by the discoveries made in mental health, neurology, 
and the other neuroscience Institutes.
    So in particular for the smaller Institutes, the blueprint 
has been a really wonderful thing.
    Senator Harkin. Anybody else? Dr. Volkow, Dr. Li?
    Dr. Li. I would echo what Dr. Battey said. The NIAAA being 
a small Institute, we benefit tremendously from this 
collaboration, especially when it comes to not only just 
providing resources, but in having projects that are of joint 
interest, such as neural degeneration, neural development, and 
neural plasticity. This is the value of it.
    Dr. Volkow. I think I want to commend the notion that the 
big frontier after the genome is to understand how the human 
brain works, which is extraordinarily complex. We now have 
extraordinary tools to actually look inside the human brain, 
and not just look at its morphology but how it functions. So 
this has given us an opportunity, all of us together, to invest 
resources to understand how, for example, the brain changes as 
a function of development, something that would have been 
extraordinarily costly for one single institute. By putting our 
funding together, we can start to get the standardized data set 
that any investigator outside can go in to query, and that 
gives us the perspective to start with, for example how does 
the brain change as we grow from childhood to adolescence to 
adulthood. This is just an example about how powerful it is to 
integrate our efforts.
    Dr. Insel. I know we are going to be having to stop in a 
moment, so I would say that in terms of both the Neuroscience 
Blueprint and everything else that you have heard for the last 
almost 2 hours, we could not have done any of this without your 
support and the support of Senator Specter when he served as 
chair. I think I speak for all of us to say how grateful we are 
for all that you have done on our behalf.
    We are entirely committed to making a difference for the 
American people, but we only do it because you are there to 
help us along. We are delighted to have a chance to tell you a 
little bit about, and this is really a very little bit, about 
what all of us have been involved with. But most of all, we 
want to say thank you for being such a leader for us in this 
regard.
    Senator Harkin. You are very kind, Dr. Insel, but I will 
not let you have the last word on that.
    I want to thank all of you. It has been very enlightening. 
I enjoy this kind of a setting. I just learn things. I think it 
is very helpful to have this kind of a discussion among the 
institutes over at least a couple hour period of time. We will 
be continuing this process with other institutes.
    But in that regard of what you were just saying, Dr. Insel, 
let me return the favor and the compliment by thanking each one 
of you, each one of you, for a lifetime of dedication to 
research, to science, to doing the things that help to try to 
improve our quality of life and the way people live, to cure 
illnesses and diseases, to help people who may be at rope's 
end, and especially in mental health. They just have nowhere to 
go and they do not know what to do. You have been making great 
progress in these areas, all these areas. There is great hope 
out there for all of the things we have done, the genetics and 
stem cells, with new interventions coming on, some of the 
things that you talked about, Dr. Landis. Of course, you know 
of my intense interest in deafness and communications 
disorders. We are making significant progress in areas, 
although I want to move faster, as you can imagine.
    Dr. Battey. So do I.
    Senator Harkin. I know you do, Dr. Battey.
    Alcoholism, drug abuse, again all these areas.
    I just close by saying thank you. I thank each of you. I 
just hope that young people today will look upon each one of 
you as role models, as something to aspire to, to get involved 
in research, to get involved in science, to take it up as life 
work, and to think about the good that they can do during a 
lifetime of service.
    What we do at NIH, what each of you do, leaves a legacy 
that just cannot be expressed in monetary terms. It can only be 
expressed in terms of people's lives and how much better kids 
are today and how much better their lives are. To me it is just 
the best work that I can imagine anyone doing. I hope that we 
have another generation of Dr. Insel's and Volkow's and Li's 
and Battey's and Landis's coming along.
    That is my way of saying thank you very much, and I look 
forward to continuing our discussions and information that you 
would have for the subcommittee at any time. We will be doing 
our budget, getting our things worked out. But I think you have 
a lot of support here and I know that Senator Specter and I 
have worked together on this now for, we are going on almost 20 
years together on this committee. We have a great partnership. 
I could not ask for a better friend and partner. Whether he is 
chairman or I am chairman, it has not made a lick of 
difference. I just hope that we will have the finances and the 
budget and the money in order to help you do your work and to 
encourage these younger scientists coming along to know that 
this is something that they can dedicate their lives to and 
that they will be able to get the funding that will enable them 
to do their research and to do their work.
    It is going to be very tough. It is going to be very tough. 
I remember when I was a kid watching--it is funny I would think 
of this right now, but we used to watch GE Theater on 
television and the host was Ronald Reagan. I remember GE's 
theme at that time was ``At General Electric Research Is Our 
Most Important Product.'' I think that is what we have got to 
be about here. Research is our most important product, and you 
do it well.

                     ADDITIONAL COMMITTEE QUESTIONS

    There will be some additional questions which will be 
submitted for your response in the record.
    [The following questions we not asked at the hearing, but 
were submitted to the Department for response subsequent to the 
hearing:]
               Questions Submitted by Senator Tom Harkin
                    clinical trials network and nimh
    Question. Dr. Insel, I understand that the large clinical trials 
that NIMH has undertaken in recent years (CATIE on schizophrenia, STEP-
BD on bipolar disorder, STAR-D on treatment resistant depression, TADS 
for child and adolescent depression) are now coming to an end. Each of 
these studies involved development of multi-site clinical trial 
networks that served a large number of subjects in real world treatment 
settings. What efforts are underway at NIMH to ensure that the 
important clinical research infrastructure that has been developed 
continues to help answer important questions about new treatments for 
mental illness?
    Answer. The National Institute of Mental Health (NIMH) is providing 
infrastructure support to maintain three large networks of 
investigative clinical teams that have evolved from the practical 
clinical trials on major depressive disorder (Sequenced Treatment 
Alternatives to Relieve Depression--STAR*D); schizophrenia (Clinical 
Antipsychotic Trials of Intervention Effectiveness--CATIE); and bipolar 
disorder (Systematic Treatment Enhancement Program for Bipolar 
Disorder--STEP-BD). At the same time, NIMH has been funding a child and 
adolescent clinical practice network. The networks comprise over 60 
sites throughout the United States with continual outreach and 
engagement to diverse groups of patients and families with mental 
illnesses. Therefore, the networks are ideally suited for addressing 
the kinds of real-world ``effectiveness'' questions that require large 
and diverse samples and aim to have an impact on clinical practice.
    The overarching principle guiding the networks is to conduct 
research designed to improve the mental health of the public and help 
better inform clinicians. To accomplish this, research must be informed 
by broad scientific and public input. In December 2006, NIMH issued a 
Request for Information (RFI) to solicit suggestions for the most 
important research directions and projects for the networks. The RFI 
sought input from investigators, stakeholders, and individuals living 
with mental illnesses, as well as additional expert advice and guidance 
from the National Advisory Mental Health Council. Advice was also 
sought from the NIMH Alliance for Research Progress--a group of patient 
and family advocates representing national voluntary organizations 
devoted to public mental health. Feedback from these efforts is being 
used to develop a list of key research questions and topics. The 
Institute is currently reviewing this input and will give high priority 
to those that have the greatest potential for using resources of the 
networks to improve the effective use of existing treatments and 
further development of new interventions.
                       bipolar disorder research
    Question. Dr. Insel, several years ago, Congress requested NIMH to 
undertake a national research plan on bipolar disorder. This request 
resulted in the current research plan on mood disorders at NIMH. Please 
update the subcommittee on the mood disorders research plan and what 
NIMH is learning about the causes and new treatments for bipolar 
disorder.
    Answer. NIMH continues to make strides in elucidating the causes of 
and determining new treatments for mood disorders, including bipolar 
disorder (BD). Much of this work is guided by goals laid out in 
``Breaking Ground, Breaking Through: The Strategic Plan for Mood 
Disorders Research.'' In addition, yearly progress in research on 
depression is reported through the Government Performance and Results 
Act as one of the stated goals for GPRA is to demonstrate through 
research, reductions in the burdens associated with depression. As one 
example, in fiscal year 2006 NIMH and its NIH collaborators were able 
to report significant progress as a result of the Sequenced Treatment 
Alternatives to Relieve Depression (STAR*D) study of nearly 2000 
depressed patients treated at 41 sites across the nation, including 
several primary care sites. This landmark study showed that up to 70 
percent of those with persistent depression can be successfully 
treated, yet may need to try several different treatment strategies. By 
analyzing specific individual patient characteristics, including genes, 
NIMH funded scientists are now discovering the keys to personalizing 
and optimizing treatments for depression.
    As outlined in the mood disorders strategic plan, NIMH undertakes 
numerous approaches toward the determination of the underlying causes 
of BD. While BD has long been known to be heritable, scientists have 
been unable to identify the key genes involved. Recently, BD has been 
the focus of a large international effort using whole genome 
association, a powerful, new approach that permits a screen for 
variations across the entire genome. Results from 7,000 BP patients and 
controls should be available later this year, providing the first 
large-scale, comprehensive scan of genes which contribute risk for BD. 
Even with these genes, we know that bipolar disorder is not easily 
diagnosed, especially in children. A recent NIMH-supported study found 
that BD could be distinguished from another similar childhood syndrome, 
severe mood dysregulation, through the measurement of the brain's 
electrical signals. This finding could significantly inform future 
efforts in diagnosing BD as early as possible.
    In terms of improving treatment, in 1998, NIMH undertook a large, 
national research program to determine best treatment practices for BD. 
Concluded in 2005, the Systematic Treatment Enhancement Program for 
Bipolar Disorder continues to inform the field. Recent publications 
addressed predictors of recurrence for those that had achieved recovery 
and the effectiveness of different medications in treating those 
patients who had not shown improvement despite several treatment 
attempts. According to another recent report, for depressed people with 
bipolar disorder who are taking a mood stabilizer, adding an 
antidepressant medication is no more effective than a placebo. These 
results indicate that careful management of mood stabilizer medications 
is a reasonable alternative to adding an antidepressant medication for 
treating bipolar depression. In addition, patients taking medications 
to treat bipolar disorder are more likely to get well faster and stay 
well if they receive intensive psychotherapy.
                     obsessive-compulsive disorder
    Question. Dr. Insel, what recent advances have been made in the 
area of obsessive-compulsive disorder?
    Answer. Obsessive-Compulsive Disorder is an anxiety disorder that 
is characterized by recurrent, unwanted thoughts (obsessions) and/or 
repetitive behaviors (compulsions). NIMH has funded several areas of 
research to understand the causes of and potential treatments for OCD. 
By studying families with members affected by OCD, NIMH-funded 
scientists have discovered regions of several chromosomes that may 
contain OCD susceptibility genes. Previous studies have suggested that 
the brain chemical serotonin may mediate the compulsive behaviors 
associated with OCD. Recent work has shown that mice with deletion of 
certain serotonin receptor genes exhibit impulsive and compulsive 
behaviors (e.g. burying marbles), suggesting that these mice could be 
used as models of OCD, and further studies of the serotonin system may 
provide clues to the etiology of OCD.
    Using magnetic resonance imaging, NIMH-funded researchers found 
that the pituitary glands of children with OCD were smaller than those 
of healthy children. The investigators speculate that the smaller 
volume in patients with OCD might be an effect of abnormal regulation 
of endocrine function. Further studies might lead to methods for early 
detection of the disorder.
    OCD in adults is known to be a disorder of many different symptoms, 
but studies have shown that certain symptoms tend to cluster together. 
Recent NIMH-funded research has revealed several types of symptom 
clusters--or symptom dimensions--in children and adolescents (e.g. 
hoarding obsessions and compulsions; symmetry, ordering, and 
repeating). These symptom dimensions closely mirror those reported in 
adults with OCD, suggesting relative stability across the course of 
development. Understanding how these symptoms cluster may help 
researchers identify the underlying causes of OCD.
    Other NIMH-funded studies have suggested a possible link between 
psychosocial stress and exacerbation of OCD symptoms. In a recent study 
of children who had OCD, Tourette syndrome (TS), or both OCD and TS, 
psychosocial stress significantly predicted whether OCD symptoms would 
worsen in the future. The results suggest that monitoring parental 
reports of stress, and intervening as appropriate, may help to prevent 
symptom exacerbations.
    Several NIMH-funded studies have focused on treatments for OCD. A 
recently completed study led to the development of a manual for 
psychosocial treatment of young children with OCD, with encouraging 
results on the efficacy of its use. A newly funded study is testing a 
treatment approach that incorporates self-administered, exposure-based 
behavior therapy as a low-cost option before implementing therapist-
administered exposure. Another study has yielded encouraging pilot 
results on the efficacy of deep brain stimulation for severe treatment-
refractory OCD. Finally, NIMH intramural researchers have evaluated 
azithromycin and penicillin as a prophylactic treatment for a subtype 
of OCD; both treatments appeared to reduce exacerbations of OCD 
symptoms.
                                 stroke
    Question. Dr. Landis, the NINDS made a great advance against stroke 
with the advent of tPA, the clot-busting drug that can reduce 
devastating disabilities if given within three hours of the onset of 
stroke symptoms. Please highlight any recent advances that will help 
alleviate the burden of this disease.
    Answer. Researchers funded by the National Institute of 
Neurological Disorders and Stroke (NINDS) are making considerable 
headway into alleviating the burden of stroke, both in preventing new 
strokes and in treating strokes acutely and chronically. With respect 
to stroke prevention, NINDS-funded researchers have recently 
demonstrated that individuals at risk for stroke may benefit from 
taking multiple preventative therapies, including antiplatelet 
inhibitors like aspirin, angiotensin-converting enzyme (ACE) 
inhibitors, and/or statins. These agents exhibit a variety of effects 
that may lower the risk for future strokes, including reducing cellular 
stress and inflammation and improving blood flow in the brain. To test 
the impact of these therapies in combination, investigators conducted a 
retrospective study of more than 200 patients who presented within 24 
hours of stroke onset. Results indicated that individuals taking all 
three drugs exhibited less severe strokes than did people on a two-drug 
combination, antiplatelet inhibitors alone, or no stroke prevention 
therapy. Imaging data also suggested that patients on triple therapy 
had less at-risk tissue surrounding the damaged regions of their brains 
and that triple therapy appeared to be linked to shorter hospital stays 
and better function at hospital discharge. Although these data are 
preliminary, they provide support for the further exploration of the 
impact of this combination regimen on the prevention of severe strokes.
    With respect to acute stroke treatment, many potential new 
therapies are in the pipeline. Research teams in the NINDS-funded 
Specialized Programs of Translational Research in Acute Stroke 
(SPOTRIAS) are exploring many different options to treat acute stroke, 
including a combination of ethanol, caffeine and hypothermia for 
neuroprotection; the efficacy of using a clot-removal device to improve 
post-stroke outcomes; adding extra drugs to the clot-buster tissue 
plasminogen activator (tPA) that may increase the potency of tPA in 
disrupting a clot, so that less tPA is needed; and the delivery of the 
potential neuroprotectant magnesium sulfate by emergency responders, to 
try to prevent cell loss by intervening as early as possible for acute 
ischemic stroke.
    Rehabilitation following stroke has also entered a new era, since 
National Institute of Child Health and Human Development (NICHD) and 
NINDS-funded research demonstrated in 2006 that constraint-induced 
movement therapy--a rehabilitative technique that involves forced use 
of a partially paralyzed arm--could promote a 34 percent faster 
recovery in the affected arm than could standard therapy if applied 3-9 
months after stroke, and could contribute to an increased ability to 
perform tasks of daily living with the impaired arm and hand. These 
results provide evidence of significant intervention efficacy from one 
of the first major large-scale randomized trials of stroke 
rehabilitation and investigators are now hoping to test this therapy in 
a phase III trial at even earlier time points after stroke.
                          parkinson's disease
    Question. Dr. Landis, despite the constraints presented by a flat 
proposed budget, there are agreed-upon, high-priority research areas 
for Parkinson's disease. Please describe what the NINDS is doing to 
ensure that those high-priority areas are getting treated as high 
priorities and are being funded, and in a timely manner. Do you have a 
strategic plan for Parkinson's disease research that includes a budget? 
Are you following it? Does it include funding for those high-priority 
research areas?
    Answer. The National Institute of Neurological Disorders and Stroke 
(NINDS) leads the implementation of PD research efforts at the National 
Institutes of Health (NIH), in large part by following the priorities 
outlined in its 2006 PD Research Plan (http://www.ninds.nih.gov/
funding/research/parkinsonsweb/PD_Plan_2006.htm). The Institute 
considers these needs, along with those in many other disease areas, 
each time it assesses potential grant solicitations and other programs 
for future implementation. While NINDS does take priorities from its PD 
planning efforts very seriously, it does not develop specific budgets 
for any of its disease plans prior to their implementation, since 
appropriations and other emergent public health needs and opportunities 
are not known in advance. In the past, the absence of specific budgets 
for disease priorities has not hindered progress. In the first five 
years of the implementation of the PD Research Agenda, NIH and NINDS-
funded researchers made tremendous progress on several fronts, 
including advances in understanding the genes involved in inherited PD 
and the unexpected contributions made by screening large numbers of 
genes for clues regarding the role that genetic variability may play in 
sporadic PD. Researchers also made substantial progress in 
understanding how PD occurs at a cellular level and how treatments like 
gene therapy may be able to protect against further brain 
deterioration. NINDS is poised to continue this progress, and the 
Institute has already provided funding to address a number of 
priorities identified in the 2006 PD Research Plan. Examples of two of 
these programs are provided below.
    First, the 2006 PD Plan highlighted further exploration of the non-
motor aspects of PD--which can include sleep abnormalities, fatigue, 
behavioral and cognitive impairments, anxiety, and depression--as a 
major research priority. As just one example of possible implementation 
of this priority, the external scientists and members of the PD patient 
community who developed the Plan's recommendations strongly suggested 
that non-motor manifestations of PD be assessed in more clinical 
trials. The NIH Exploratory Trials in Parkinson's Disease (NET-PD) 
phase III trial--a large, randomized clinical trial of the potential 
neuroprotective agent creatine--will address this need directly, by 
exploring the ability of creatine to improve some of the non-motor 
features of PD in addition to its ability to slow the progression of 
the motor symptoms.
    Second, the 2006 PD plan also identifies PD biomarkers, which 
enable clinicians and researchers to track disease risk, activity, 
progression and response to treatment, as a very high priority for the 
field. In October 2006, the NINDS and the other NIH Institutes and 
Centers participating in the NIH Blueprint for Neuroscience Research 
program addressed this recommendation by issuing a grant solicitation 
to encourage research on biomarkers for neurodegenerative diseases, 
including PD. This solicitation elicited a vigorous response from the 
research community and the grant applications are currently under 
review.
                     outreach on addiction research
    Question. Dr. Volkow and Dr. Li, what are your institutes doing to 
infuse your research on addiction into local treatment centers--where 
the rubber meets the road? How does NIDA and NIAAA work with States, 
and the directors of State substance abuse systems, to ensure that the 
research done by NIDA and NIAAA reaches into our local clinics and 
treatment systems to make a difference?
    Answer. NIAAA is engaged in considerable outreach to increase use 
of research-proven treatments in community treatment centers. First, 
NIAAA has produced a variety of research summaries and practical tools 
to assist in dissemination and implementation of research findings. The 
2005 Edition of the NIAAA Clinicians Guide (updated in 2007) has been 
very popular for health care professionals. NIAAA staff are currently 
working on training programs for health care professionals centered 
around the Guide, a version of the Guide for non-prescribing 
professionals, and a Self-change Guide (called ``Rethinking Drinking'') 
aimed at consumers and concerned others. Second, NIAAA staff work 
closely with SAMHSA staff, providing research summaries, advice, 
participation in various work groups, and written and computerized 
tools to assist SAMHSA staff in their interactions with States systems 
and directors. Third, NIAAA works with other federal agencies such as 
VA, AHRQ, DOD, CDC and CMS to facilitate implementation of new research 
on treatment.
    NIDA is taking a collaborative approach aimed at proactively 
involving all entities invested in changing the system and making it 
work better--so that research results do not linger the customary 15-20 
years before they are implemented as part of routine patient care. One 
way this occurs is through the testing of drug abuse treatment 
approaches directly in the community settings where they will be used 
with real-world populations by counselors trained to implement them. 
This is the work of NIDA's National Drug Abuse Treatment Clinical 
Trials Network (CTN), which not only involves practitioners from 
community treatment programs (CTPs) in formulating research protocols, 
but also in providing real-world feedback on their success and 
feasibility.
    NIDA is taking a similar approach to enhance treatment for drug-
addicted individuals involved with the criminal justice system through 
our CJ-DATS (Criminal Justice-Drug Abuse Treatment Studies) initiative. 
Research supported through CJ-DATS is designed to effect change by 
bringing new treatment models into the criminal justice system and 
thereby improve outcomes for offenders with substance use disorders. It 
seeks to achieve better integration of drug abuse treatment with other 
public health and public safety forums, and represents a collaboration 
of NIDA, the Substance Abuse and Mental Health Services Administration 
(SAMHSA), the Centers for Disease Control and Prevention, Department of 
Justice agencies, and a host of drug treatment, criminal justice, and 
health and social service professionals.
    In addition to testing and evaluating protocols in the settings in 
which they will be used, NIDA works with our colleagues to create 
change at multiple levels and bridge the divide between scientific 
findings and their implementation. Our Blending Initiative exemplifies 
this approach and involves regular stakeholder conferences, a 
partnership with SAMHSA to support the work of Addiction Technology 
Transfer Centers (ATTCs) in training and disseminating research-based 
practices to community practitioners, and our ongoing relationship with 
State representatives and substance abuse directors. The Blending 
Initiative is helping to catalyze change by ``seeding'' the field with 
research-based practices and innovative products to facilitate their 
use. Specifically, Blending Teams made up of practitioners and 
researchers develop training modules and other dissemination products 
based on NIDA research, and thereby help implement and sustain 
effective drug abuse treatments in myriad settings.
    On way in which NIDA continues to build and enhance our productive 
partnership with state directors of substance abuse agencies is through 
annual meetings with their national association--the National 
Association of State Alcohol and Drug Abuse Directors (NASADAD)--to 
identify strategies for accelerating the adoption of evidence-based 
practices into State drug abuse prevention and treatment programs. We 
are gratified that State directors now consistently look to NIDA for 
credible information about selecting, implementing, and sustaining 
science-based and cost-effective treatment and prevention 
interventions.
    For example, NASADAD has embraced the promise of buprenorphine as 
an opioid abuse treatment option, developing a State Issue Brief on the 
topic and probing States for their specific needs. In response, States 
have identified technical assistance needs and areas where their 
Addiction Technology Transfer Centers (ATTCs) could provide support 
(e.g., training, best practice guidelines, dissemination packets, and 
strategies to further partnerships with physicians). Their feedback 
suggests new and expanded roles for existing treatment program medical 
directors of State Alcohol and Drug Abuse agencies. Moreover, most 
States have already begun aggressive outreach programs to approved 
physicians to provide them with expanded training and educational 
opportunities, both directly and in partnership with other entities.
    NIDA views the translational process as comprising systems-level 
factors aimed at continuous improvement. In that vein, a collaborative 
initiative--the NIDA-SAMHSA RFA, ``Enhancing State Capacity to Foster 
Adoption of Science-Based Practices''--encourages state agencies to 
team with research organizations to optimize their research 
infrastructure for evaluating delivery of publicly supported drug abuse 
treatment or prevention services. Several grants received initial 
funding in fiscal year 2006 to facilitate adoption of meritorious 
science-based policies and practices, including developing ways to 
measure and track program fidelity, promote adoption of research-based 
practices in addiction treatment, and streamline data collection and 
reporting requirements.
    Enhancing the adoption of research-based practices by state-based 
systems is a strong NIDA commitment and will continue to be a top 
priority since it ensures that new scientific discoveries are 
translated into prevention and treatment interventions that are adopted 
by the community.
                         addiction and obesity
    Question. Dr. Volkow, how are findings from your research linked to 
obesity?
    Answer. Animal studies and brain imaging studies in humans reveal 
similarities in the way circuits and neurotransmitter systems act in 
the rewarding effects of both food and drugs of abuse (e.g., opioids 
and other peptides, dopamine, cannabinoids). When imaged, the brains of 
both obese and drug-addicted people show a surge in dopamine when 
presented with food- or drug-related stimuli, respectively, and both 
show similar reductions in availability of dopamine receptors, 
suggestive of a less responsive reward system. Further, both obesity 
and drug addiction can be characterized by excessive, repetitive 
behaviors often marked by the inability to change or stop in the face 
of severe negative health consequences.
    Given these parallels, few fields offer as much potential for 
cross-fertilization as addiction and obesity research. In the treatment 
arena, it is noteworthy that some of the behavioral interventions 
beneficial for treating drug addiction (e.g., incentive motivation, 
cognitive--behavioral therapy) may also be helpful in treating obesity, 
and several potential candidates for the pharmacological control of 
food intake (e.g., the cannabinoid receptor antagonist Rimonabant and 
the appetitive molecule orexin) also show promise for drug addiction.
                           underage drinking
    Question. Dr. Li, on March 6, the U.S. Surgeon General issued a 
``Call to Action on Underage Drinking'', which underscored that alcohol 
``remains the most heavily abused substance by America's youth.'' It 
also calls for changing public attitudes toward youth alcohol use. That 
includes making it harder for young people to have access to alcohol. 
Are you doing any research on the most effective ways to reduce the 
availability of alcohol to underage youth?
    Answer. NIAAA's comprehensive research portfolio on reducing 
underage drinking addresses both the demand for alcohol by youth as 
well as their access to it. Both components include approaches that 
target individuals, families, schools, communities and the overall 
environment. To reduce the appeal of alcohol to youth, NIAAA supports 
research on positive youth development including the ability to resist 
alcohol and other drugs. To address the supply of alcohol to youth, 
NIAAA supports a number of studies on the most effective ways to reduce 
the availability of alcohol to underage youth from late childhood 
through age 21. For example, some studies are testing the effectiveness 
of campus-community coalitions in reducing underage alcohol use by 
students in America's colleges and universities. These include 
promising studies comparing campuses that adopt comprehensive community 
interventions with control campuses that are doing business as usual. 
Other research studies are addressing neighborhood and community level 
interventions. For example, a recent study showed that an intervention 
for 15-29 year olds incorporating community mobilization, community 
awareness, responsible beverage service, underage alcohol access law 
enforcement and intoxicated patron-law enforcement was effective in 
reducing sales to minors as well as adverse outcomes related to alcohol 
in the targeted age group. At the community and state level NIAAA is 
funding studies evaluating the effects of policy changes on underage 
drinking. In addition, NIAAA is evaluating two separate community based 
OJJDP initiatives both of which include components aimed at reducing 
the availability of alcohol to youth. One is focused on rural 
communities in seven states and the other is focused on four Air Force 
bases and their surrounding communities.



    Question. We all know that young people are exposed to a wide range 
of messages in the media about alcohol--both positive and negative. Are 
you doing any research on how their exposure to these messages affects 
whether they will become dependent on alcohol?
    Answer. Given that early initiation of alcohol use, and especially 
early binge drinking, is associated with an increased risk of future 
alcohol dependence, it is important to identify factors that influence 
a young person's decisions about drinking. With respect to media 
influences, NIAAA funds research addressing the relationship between 
underage drinking and exposure to messages about alcohol, including 
advertising. However, assessing the effect of advertisements on the 
drinking behavior of individuals or populations is complicated. It is 
often difficult to ascertain the specific effects of advertising since 
they must be measured against a background dense in alcohol messages 
and images. Nevertheless some interesting findings have emerged. For 
example, in a widely-cited recent study, investigators interviewed a 
sample of youth aged 15 to 26, from 24 Nielsen media markets, on four 
occasions over a period of 21 months about their drinking. Advertising 
exposure in the study was measured both subjectively in terms of 
reported exposure and objectively in terms of advertising expenditures. 
It was concluded that each additional advertisement seen increased the 
number of drinks consumed in the past month by 1 percent. Further, 
youth in markets with greater advertising expenditures drank more: for 
each additional dollar spent per capita, the number of drinks consumed 
per month increased by 3 percent. More longitudinal studies such as 
this are needed.
    In addition, who sees/hears alcohol advertising and who is affected 
by it is an important issue. While almost all persons are exposed to 
significant amounts of alcohol advertising, youth may be at risk for 
overexposure. Others such as dependent drinkers, or those in recovery, 
for whom alcohol ads may provide drinking cues or triggers, may be 
especially vulnerable to advertising. A recent study comparing teens 
with and without alcohol use disorders (AUD) found that teens with AUD 
showed substantially more brain activation to pictures of alcoholic 
beverages than controls (Tapert et al. 2003).
    Additional research on adolescent decision-making will provide 
greater understanding of the factors that influence underage drinking 
behavior including initiation and escalation of alcohol use and binge 
drinking. This includes but is not limited to studies on media 
influence.
    Question. This question is about treatment, and why some people 
improve their behavior. I was interested to read in your testimony that 
there's a debate whether the treatment itself is responsible, or 
whether it results from the positive motivation in seeking treatment. 
You also write that a wide array of approaches yield similar results, 
suggesting that it's not the particular technique that's responsible 
for change but other common underlying factors. Tell me more about 
this--are most forms of treatment being used today generally equally 
effective? Is the most important thing simply getting the person into 
treatment?
    Answer. Research has established that several forms of behavioral 
treatment (cognitive-behavioral treatment (CBT), motivational 
enhancement therapy (MET), and twelve-step facilitation (TSF), yield 
roughly equivalent outcomes. In the year following treatment with one 
of these therapies, drinking is reduced by about 85 percent compared to 
the period immediately prior to treatment. Overall, about one-third of 
alcohol dependent persons undergoing treatment will either be abstinent 
or not engaging in any high-risk drinking, about one-forth will not 
respond to that episode of treatment (although they may respond to 
future treatment), and the remainder have markedly reduced drinking and 
alcohol-related consequences, but are not entirely well. Over time, 
many of this latter group eventually become abstinent. Naltrexone, a 
medication for reducing relapse, yields similar results when combined 
with brief counseling by a doctor or nurse. Since there is no single 
type of treatment that is generally more effective than others, 
``simply getting the person into treatment'' does seem to be more 
important than which treatment the engage in. However, on a practical 
level, people have clear preferences about what kind of treatment they 
would like, so offering a menu of currently supported approaches is 
likely to maximize the likelihood that one of them will be appealing 
enough to engage the affected individual.
    How well treatment provided in the community compares with the 
treatments used in the studies undoubtedly varies. Although a precise 
estimate of the effect of this deviation is not available, there is 
evidence that some practices that are not helpful still persist in some 
community programs. Additionally, most treatment programs fail to make 
patients aware of various treatment options available, including 
medications. One study found that 93 percent of programs offer only 
twelve-step oriented behavioral treatment. Although this type of 
program may be as effective as others, it means that most people do not 
have a meaningful choice if they wish to receive treatment.
    Although treatment appears to improve outcomes, the most 
significant are those commonly seen among all treatment-seekers. Common 
examples include a driving while intoxicated charge, an employer 
referral, or an ultimatum from a spouse. This process is the focus of 
an innovative new research program called the Mechanisms of Behavior 
Change Research Initiative.
                                 ______
                                 
            Questions Submitted by Senator Daniel K. Inouye
                                suicide
    Question. Dr. Insel, suicide is a major, preventable public health 
problem. In 2004, suicide was the 11th leading cause of death in the 
United States, accounting for 32,439 deaths. In Hawaii, for young 
people age 15-34 years, suicide is the second leading cause of death--
second only to accidents. What type of research is NIH conducting with 
respect to the causes of and the best practices for the prevention of 
suicide?
    Answer. NIMH has a long-standing commitment to supporting research 
on suicide risk and prevention. In response to the 2002 Institute of 
Medicine Report, ``Reducing Suicide: A National Imperative,'' NIMH, 
NIDA, and NIAAA issued a request for applications and funded three 
centers focused on intervention and prevention of suicide. Now in their 
third year of support, the centers have conducted pilot intervention 
studies with patients suffering from mental and substance use 
disorders.
    These centers have also engaged in a number of collaborative 
efforts. Federal staff (NIH, CDC, VA, SAMHSA, IHS) and investigators 
from the centers have interacted via workgroups focused on 
methodological challenges in suicide research, such as developing 
common measures of suicidality as well as understanding the role of 
impulsivity in suicide risk. The American Foundation for Suicide 
Prevention funded a pilot project with the centers to create a registry 
of suicide attempters. This registry will facilitate understanding of 
the quality of care across services settings, as well as the longer-
term outcomes of acute treatment of adolescent suicide attempters. One 
of these centers also played a key role in re-reviewing suicidal events 
for the FDA's 2005 review of potential suicidal side effects of 
antidepressants. As a follow-up to the FDA review, in 2006, NIMH funded 
five research projects to examine the association between 
antidepressant medications, notably selective serotonin reuptake 
inhibitors (SSRIs), and suicidal thoughts and actions. These projects 
will help determine why and how SSRIs may trigger suicidal thinking and 
behavior in some people but not others, potentially leading to new 
tools that can be used to screen individuals who are most vulnerable.
    Suicide patterns in the United States vary significantly in terms 
of demographics and cultures. For example, older white males have the 
highest suicide rate; are likely to have had a late onset of major 
depression; and are likely to have been seen in a primary care setting 
within the month of their death, without being diagnosed or treated for 
depression. To address this issue, NIMH funded a study called the 
Prevention of Suicide in Primary Care Elderly: Collaborative Trial 
(PROSPECT) to test approaches to improve identification and treatment 
of older adults with depression in primary care settings. Results from 
PROSPECT indicated that a collaborative care approach to treating 
depression in primary care more effectively reduced suicide ideation as 
well as depressive symptoms, compared to treatment as usual.
    American Indian, Native Alaskans, Native Hawaiians, and other 
indigenous peoples in the United States. Territories have the highest 
suicide rates among youth. To address the problem, NIMH, in 
collaboration with other NIH offices and Institutes, worked with the 
Indian Health Service, Health Canada, and the Canadian Institutes of 
Health to convene a bi-national conference in 2006 entitled 
``Indigenous Suicide Prevention Research and Programs in Canada and the 
United States: Setting a Collaborative Agenda.'' Community members and 
research partners discussed the importance of cultural knowledge in 
developing interventions and considered best practices that could be 
shared in developing partnerships and infrastructure.
    NIMH-supported research has demonstrated that several promising 
treatments significantly reduce the risk for suicide re-attempts; these 
treatments include cognitive behavioral interventions provided to 
individuals who have made a recent suicide attempt, as identified 
through emergency room departments, as well as dialectical behavior 
therapy provided to individuals with borderline personality disorder. 
NIMH is also using knowledge gained from previous research studies to 
guide the conduct of clinical trials involving individuals at high risk 
for suicide. The Institute recently completed a series of practical 
clinical trials focused on treatments for schizophrenia, depression, 
and bipolar disorder. The individuals enrolled in these trials were 
closely monitored for suicidal behavior and were provided appropriate 
crisis treatment when necessary.
                              alzheimer's
    Question. Dr. Insel, less than two weeks ago a new report was 
released indicating that there are now 5 million Americans with 
Alzheimer's disease and that this number is projected to increase by 50 
percent to 7.7 million by 2030. Given that advancing age is the 
greatest risk factor for Alzheimer's disease and that the number of 
Americans surviving into their 80's and 90's is expected to grow, what 
specific studies are underway at NIMH to address the challenges posed 
by Alzheimer's disease?
    Answer. NIMH supports research on a broad range of topics 
pertaining to older adults with Alzheimer's disease, ranging from basic 
research on the disorder to clinical interventions and services 
research that may assist affected individuals with their symptoms and 
problems in day-to-day living. A primary concern in NIMH research is to 
improve our understanding of, and techniques for managing, the 
psychiatric disorders and behavioral disturbances that often accompany 
Alzheimer's disease and related dementias.
    Recently published results from NIMH's large scale Clinical 
Antipsychotic Trials for Intervention Effectiveness in Alzheimer's 
Disease (CATIE-AD) study highlight the challenge of managing agitation 
and behavioral problems in Alzheimer patients. Although some patients 
with these problems may benefit from treatment with atypical 
antipsychotic medications, the evidence from this study suggests that 
these medications hold limited value for the majority of patients and 
that the benefits are often offset by intolerability of medication side 
effects. These results indicate the need for research on alternative 
treatment approaches, including nonpharmacological interventions. 
Additional analyses of the data from the CATIE-AD trial are ongoing.
    Earlier work supported by NIMH established criteria for assessing a 
specific syndrome of depression that is commonly manifested in 
Alzheimer's disease and making this a target for treatment. The 
Institute is now in the fifth year of supporting a multi-site clinical 
trial studying pharmacologic treatment of Depression in Alzheimer's 
Disease (DIADS-2) and its impact on functional capacities in Alzheimer 
patients.
    NIMH supports various basic and intervention studies designed to 
improve clinical management of other psychiatric and behavioral 
disturbances associated with Alzheimer's disease, such as the common 
pattern of sleep disturbance and nocturnal agitation. For example, one 
current NIMH study investigates sleep disorder in people who have mild 
cognitive impairment, a precursor to Alzheimer's disease, and an 
intervention trial is evaluating alternative treatments for insomnia 
among older patients with dementia.
    Numerous NIMH studies examine potential risk factors for developing 
Alzheimer's disease in the hope that understanding these factors may 
inform efforts to develop preventive interventions. Research areas 
include genetics, brain structure, cognitive performance, and various 
other risk factors in young and middle-aged adults to determine whether 
it is possible to identify elements of risk prior to the appearance of 
clinical manifestations of illness. One study has been examining the 
deleterious effects that depression may have over time, potentially 
leading to central nervous system damage, cognitive decline, and the 
development of states of Mild Cognitive Impairment and dementia.
    NIMH also supports basic neuroscience research on etiological and 
athophysiological actors in Alzheimer's disease, including numerous 
studies investigating key cognitive processes and how these are related 
to normal and abnormal brain functioning.
                                 ______
                                 
            Questions Submitted by Senator Richard J. Durbin
                             fabry disease
    Question. There are a number of individuals currently participating 
in efforts conducted by the Developmental and Metabolic Neurology 
Branch at NINDS. There is concern that when the Branch closes, as it 
will due to the retiring of Principal Investigator (PI) Roscoe Brady, 
the efforts that are benefiting the lives of so many, in particular 
those that are living with Fabry Disease, Gaucher Disease, Tay-Sachs 
and others, will also cease. Can you explain the rationale behind the 
NINDS' decision to close the Branch indefinitely and not continue these 
efforts under the leadership of another PI?
    Answer. Following Dr. Brady's retirement, NINDS made the decision 
to close the Developmental and Metabolic Neurology Branch (DMNB), which 
is part of NINDS' intramural program (the component of the NINDS that 
is located on the NIH campus in Bethesda, MD). However, the closing of 
this branch certainly does not mean that NINDS efforts in lysosomal 
storage disorders (LSDs), including Fabry and Gaucher disease, will 
cease. Groundbreaking research on lysosomal storage disorders conducted 
by this Branch has provided a strong foundation for research in these 
areas to continue through the NINDS extramural program (research funded 
by NINDS that is carried out at universities, medical centers, and 
small businesses throughout the United States). In fact, the extramural 
program accounts for approximately 90 percent of NINDS' annual budget 
and NINDS already funds a large portfolio of extramural grants focused 
on understanding and treating these disorders. In addition to NINDS, a 
number of other Institutes and Centers at NIH also support research 
through their extramural programs on lyososmal storage disorders, 
including Fabry disease. These grants aim to better understand and 
treat these disorders, with a number of projects focused specifically 
on developing gene therapy approaches to treatment. Furthermore, based 
on the successes from forty years of research in the DMNB led by Dr. 
Roscoe Brady, companies have developed and marketed enzyme replacement 
therapy for several of these diseases and are conducting additional 
clinical trials to improve treatment using other therapeutic 
strategies. In terms of clinical care, there are currently over 100 
medical centers across the country with experience in diagnosing, 
treating, and managing care of patients with lysosomal storage 
disorders.
    NINDS' decision to close the DMNB was reached after much 
deliberation and after receiving input from the NINDS Board of 
Scientific Counselors, an external advisory group that reviews and 
evaluates the NINDS intramural program. NINDS and the Board of 
Scientific Counselors determined that the research and clinical care 
efforts that used to be unique to the Branch are now well represented 
at medical schools, research institutes, and tertiary care centers 
throughout the country. They recommended that the NINDS intramural 
program identify other rare neurological disorders that have lagged 
significantly behind Gaucher and Fabry disease and could benefit as 
they have from an intramural effort.
    Question. Can you provide additional information regarding the 
efforts of the branch on solving the problems that still exist with 
enzyme replacement therapy? How will the progress that has been made on 
these issues continue if the efforts of this Branch are stifled due to 
its closing?
    Answer. The DMNB was instrumental in developing enzyme replacement 
therapy, which is used to treat a number of the LSDs, including Fabry, 
Gaucher, and Pompe disease. While enzyme replacement therapy 
significantly improves the quality of life for patients with these 
disorders, the treatment is not sufficient to address all the symptoms, 
particularly those resulting from deficits in the central nervous 
system. This is due in part to the incomplete access of the enzyme 
replacement to the central nervous system (CNS) because of the blood-
brain barrier (a semi-permeable barrier that prevents materials in the 
blood from entering the CNS). NINDS, through its extramural program, 
funds a number of grants focused on facilitating the access of enzyme 
replacement to the CNS by protein reengineering, increased dosing 
regimen, and alternative delivery routes. NINDS also funds extramural 
research focused on developing other therapeutic approaches including 
substrate reduction (decreasing the production of the molecule that is 
accumulating in the disease), and pharmacological chaperones (small 
drugs that can specifically target and stabilize the defective enzyme, 
enhancing any residual activity). Longer-term therapeutic strategies 
such as stem cell transplantation and gene therapy are also being 
funded by NINDS.
    One of the goals of the NINDS intramural program is that research 
conducted there lay the groundwork for a broader based research effort 
in the extramural community. Historically, closure of other NINDS 
programs has proven the intramural program's success and shown that the 
research initiated by these branches can be effectively graduated into 
the extramural research community. For example, research carried out in 
a branch that focused on therapeutics for Parkinson's disease set the 
stage for a rigorous therapeutics development program on Parkinson's 
disease through the NINDS extramural program. Similarly, work carried 
out by an NINDS lab that demonstrated the transmissibility of 
Creutzfeldt-Jakob disease (CJD) helped stimulate research in the 
extramural community to better understand this and other disorders in 
the class of transmissible spongiform encephalopathies. It is our 
expectation that ongoing and future research through NINDS's extramural 
program will continue to improve the lives of individuals with LSDs.
    Question. What other work are you planning to do to improve both 
the quality and quantity of life of those living with Fabry disease?
    Answer. As I have just described, NINDS, through its extramural 
research program, funds research projects focused on developing new and 
more effective treatment strategies to improve the quality and quantity 
of life for those individuals with Fabry and other disorders. A number 
of these grants have been submitted through an ongoing NINDS Program 
Announcement with Set-aside funds (PAS), entitled ``CNS Therapy 
Development for Lysosomal Storage Disorders.'' This funding opportunity 
announcement was started in 2004 and since then many new promising 
therapeutic approaches are being investigated.
    Partnering with patient voluntary groups is another way that NINDS 
hopes to advance research and improve the lives of patients with these 
disorders. The PAS mentioned above is co-sponsored by the Lysosomal 
Storage Disease Research Consortium (LSDRC), a collaborative research-
funding group comprising LSD patient support groups and private family 
research foundations. In addition, the NINDS organizes a number of 
workshops in order to identify scientific gaps and opportunities 
related to various LSDs, and to foster collaboration between the 
researchers. Several of these workshops have been organized in 
conjunction with some of the patient voluntary groups. To promote the 
exchange of ideas on research across the many LSDs, the NINDS helped 
form the Lysosomal Disease Network. This consortium of scientists, 
healthcare professionals and clinics work to improve basic knowledge 
and understanding of LSDs, improve diagnosis, and advance therapeutic 
options for individuals affected by these disorders. The NINDS has 
supported the first two annual meetings of the Lysosomal Disease 
Network.
                                epilepsy
    Question. I understand that last week, NINDS hosted the second 
Conference on the Cure for Epilepsy. What new information did this 
conference yield about epilepsy and are we any closer to finding a 
cure?
    Answer. In March 2007, the NINDS co-sponsored a large conference, 
entitled: ``Curing Epilepsy 2007: Translating Discoveries into 
Therapies.'' The Conference was well-attended by the basic and clinical 
research communities, and specific sessions at the Conference focused 
on research conducted by junior investigators; the translation of 
advances in the genetics of epilepsy and our understanding of how 
epilepsy arises (epileptogenic mechanisms) into therapies; cognitive 
and psychological issues in epilepsy; and emerging technologies in 
diagnostics and cellular and molecular therapeutics. The meeting also 
involved presentations from several patients and patient 
representatives on their personal experiences with epilepsy.
    Several very exciting trends in epilepsy research were emphasized 
at the meeting. First, the ideal way to treat (and cure) epilepsy would 
be to prevent the development of seizures in the brain, not just to 
stop them from progressing or diminish their behavioral effects (e.g., 
seizures). A growing appreciation in the scientific community as to why 
neuronal circuits in the brain develop abnormal patterns of 
overexcitation is now enabling investigators to identify tangible 
therapeutic targets that may interfere with the earliest molecular 
events in the development of seizures. This shift heralds the 
availability of substantially more effective therapies for epilepsy. 
Second, advances in imaging are also making a dramatic impact on a 
number of disciplines in epilepsy research, including the development 
of biomarkers of seizure-prone brain regions, the characterization of 
the effects of epilepsy on brain development, and the cognitive impact 
of the disorder. The use of these techniques will facilitate epilepsy 
diagnostics as well as treatment. Third, completely new therapeutic 
approaches are emerging in epilepsy research, including the possibility 
that cell-based therapies may be able to restore normal patterns of 
activity in seizure-prone brain circuits and advancements in 
nanotechnology may improve devices that sense impending seizures with 
greater accuracy than ever before.
    Question. Are we putting adequate resources toward epilepsy 
research at NINDS to find a cure for epilepsy? In addition, I 
understand that new cases of epilepsy are most prominent in seniors 
(those aged 65 and older). What are we doing to better understand the 
cause of seniors having seizures and will NIH partner with other 
entities to study this emerging area?
    Answer. The National Institute of Neurological Disorders and Stroke 
(NINDS) has invested considerable funding to identify and test 
potential therapies for epilepsy. Currently, the NINDS is funding nine 
clinical trials in epilepsy, including phase III trials of drug therapy 
for childhood absence epilepsy and the use of progesterone therapy to 
reduce intractable seizures in women whose seizure severity is linked 
to their menstrual cycle. In addition to these and other ongoing 
trials, the NINDS also continues to support its Anticonvulsant 
Screening Program (ASP), a public-private partnership program designed 
to evaluate the potential efficacy and toxicity of pre-clinical 
candidate compounds in validated epilepsy model systems. In 2006, the 
ASP screened several hundred molecules for potential activity against 
epilepsy and related disorders. The Program has participated in the 
evaluation and development of eight currently marketed antiepileptic 
drugs, and nine new ASP compounds are currently in clinical testing.
    In addition to these efforts, the NINDS has also funded a number of 
epilepsy grants as part of its broad translational research program, 
which is designed to accelerate therapeutics research towards early 
clinical testing. Topics of these awards range from a study of specific 
chemical pores on neurons and their role in neonatal seizures to the 
preclinical development of the anticonvulsant chlorokynurenic acid--
which effectively accesses the brain when administered systemically--as 
a therapeutic agent for both adults and children with epilepsy.
    With respect to the study of epilepsy and the elderly, the NINDS 
has provided funding to several grants including a large multi-
investigator award focused on patterns of use of antiepileptic drugs in 
the elderly and the differences in breakdown of antiepileptic 
medications in older versus younger individuals. Understanding these 
patterns and differences is critical to their proper treatment 
(including dosing and avoidance of toxicity). In addition, stroke is a 
primary cause of epilepsy in the elderly, and NINDS-funded basic 
science researchers are developing a model of this form of epilepsy for 
subsequent use in understanding how seizures develop after stroke and 
how therapies might prevent and/or treat these events. The NINDS also 
meets regularly with a number of other National Institutes of Health 
(NIH) Institutes as part of the NIH Interagency Epilepsy Coordinating 
Committee meeting and would welcome potential collaborations in the 
area of aging and epilepsy as they emerge.
    Question. In 2002 NINDS conducted research on TBI and epilepsy. 
Given the increased number of cases of TBI due to the war in Iraq, will 
NINDS be studying the relationship between TBI and epilepsy for updated 
statistics and data?
    Answer. The primary role of the National Institute of Neurological 
Disorders and Stroke (NINDS) with respect to all types of epilepsy 
research--including that induced by traumatic brain injury (TBI)--is to 
provide support for research on the prevention, diagnosis, underlying 
causes, and treatment of this condition. The NINDS is currently 
supporting several studies that may reveal links between TBI and 
epilepsy, including an exploration of early post-injury changes in 
brain activity and its impact on affected neurons; the effects of 
structural changes in neuronal circuitry on the development of 
posttraumatic epilepsy--particularly in those circuits that help to 
prevent overexcitability in the brain--and the impact of head injuries 
on abnormal sprouting of undamaged neurons and the tendency of these 
new nerve pathways to become overly active. In addition to these basic 
studies, the NINDS is also funding a pilot clinical trial to test 
whether very early administration of the anticonvulsant drug 
levetiracetam can prevent posttraumatic epilepsy in adults as well as 
children. In this early-phase trial, researchers will explore the 
safety and tolerability of the drug in individuals with TBI and the 
feasibility of initiating treatment within eight hours of injury. If 
the pilot data are promising, the research team will utilize the 
results to build a larger-phase clinical trial.
    The mechanisms that underlie the development of epilepsy were also 
a focus of the March 2007 Curing Epilepsy Conference; specifically, the 
meeting included an entire session on the development of epilepsy, 
including TBI as a major environmental contributor. Discussions in this 
part of the meeting and during a session on the NINDS Epilepsy 
Benchmarks--a series of specific scientific goals for the epilepsy 
research community--confirmed that understanding how epilepsy develops 
is a very high research priority and should be a focus for the epilepsy 
community in the coming years.
    Although these and other studies funded by the NINDS are likely to 
inform researchers and ultimately clinicians on the best way to prevent 
and/or treat posttraumatic epilepsy, it is the Centers for Disease 
Control and Prevention (CDC) that typically collect statistics and 
study trends on medical conditions. Because of the increasing number of 
war injuries that involve TBI and the urgency in addressing the medical 
needs of these soldiers, the NINDS staff has established a working 
group with relevant government partners, including the Department of 
Defense, the Department of Veterans Affairs, the CDC, and others to 
discuss scientific topics of mutual interest and develop collaborations 
in these areas. Following the first meeting of the group last 
September, NINDS set up a listserv for timely dissemination of 
information on TBI research across these multiple agencies. The NINDS 
staff is planning another meeting for the summer of 2007.
               funding research on severe mental illness
    Question. What is NIMH doing to fund more research on severe mental 
illness, as called for by national organizations such as the National 
Alliance for Mental Illness and Mental Health America?
    Answer. NIMH supports innovative research that promises to 
profoundly transform the diagnosis, treatment, and prevention of mental 
disorders, paving the way for a cure. Mental disorders are the leading 
cause of disability in the United States and Canada for ages 15-44,\1\ 
and each year, roughly 12 million people report symptoms of mental 
illness so severe as to cause significant disability and interference 
with everyday living.\2\ To address these critical health needs, the 
Institute supports, conducts, and promotes research that spans the 
continuum from basic research on brain and behavioral processes that 
provides the foundation for understanding mental disorders, to 
investigations of improved pathways for the rapid dissemination of 
evidence-based practices into mental health care and service efforts.
---------------------------------------------------------------------------
    \1\ The World Health Organization. The World Health Report 2004: 
Changing History, Annex Table 3: Burden of disease in DALYs by cause, 
sex, and mortality stratum in WHO regions, estimates for 2002. Geneva: 
WHO, 2004.
    \2\ Kessler RC, Chiu WT, Demler, O, Merikangas, KR, Walters, EE. 
Prevalence, Severity, and Comorbidity of 12-Month DSM-IV Disorders in 
the NCS-R. Arch Gen Psychiatry. 2005 Jun; 62: 617-627.
---------------------------------------------------------------------------
    Along this continuum, the Institute is supporting several key areas 
to ensure that each step along the pathway from scientific discovery to 
the implementation of improved interventions is fully supported. For 
example, NIMH is providing infrastructure support to maintain three 
large networks of investigative clinical teams that have evolved from 
the recent NIMH practical clinical trials on major depressive disorder, 
schizophrenia, and bipolar disorder. These practical trials were 
``effectiveness studies'' designed to examine not only changes in 
symptoms but changes in ``real world'' functioning. The networks 
comprise over 60 sites throughout the United States with continual 
outreach to, and engagement of, diverse groups of patients and families 
with mental illnesses. The overarching principle guiding the networks 
is to conduct research designed to improve the mental health of the 
public and to help better inform clinicians, families, and policy 
makers--efforts that require participation from the diversity of people 
and settings involved in health care.
    NIMH continues its strong commitment to investment in research to 
elucidate the causes of and best treatments for schizophrenia. Although 
current medications are reasonably effective in treating symptoms such 
as hallucinations and delusions, these treatments provide little relief 
for the cognitive problems (e.g., memory, attention) responsible for 
much of the long term disability associated with schizophrenia. To 
address this issue, NIMH funded the Measurement and Treatment Research 
to Improve Cognition in Schizophrenia (MATRICS) program. MATRICS 
brought together representatives from academia, industry, and 
government in a consensus process to address obstacles that are likely 
to interfere with the development of pharmacological agents for 
treating cognitive deficits associated with schizophrenia. As a result 
of MATRICS, researchers developed several comprehensive assessment 
tools to measure cognitive functioning abilities in patients with 
schizophrenia. To build upon the work from MATRICS, NIMH has also 
supported a network of Treatment Units for Research on Neurocognition 
and Schizophrenia (TURNS). The network is about to begin testing the 
safety and efficacy of new therapeutic compounds for treating the 
cognitive deficits of schizophrenia.
    In fiscal year 2008, through a Requests for Applications, NIMH will 
invite research grant proposals focused on early detection, prevention, 
and treatment of schizophrenia. These initiatives will foster research 
to define critical moments in the disease course, such as a first 
psychotic episode, and will promote the development of unique early 
interventions to pre-empt the serious disability caused by 
schizophrenia.
              services research for severe mental illness
    Question. How is NIMH working to promote more research on what 
services lead to recovery for people with severe mental illness, as 
called for by the President's Mental Health Commission?
    Answer. NIMH supports research to establish an evidence-base for 
interventions and service systems that will provide citizens with the 
best possible care. Within this context, NIMH funds a program of 
research on disability and community reintegration, which focuses on 
ways to reduce the disability of people with mental illness through 
connective services within their communities. For example, an NIMH-
funded study is identifying the most effective strategies for building 
a partnership between university-based clinical services researchers 
and practitioners and consumers from a psychosocial rehabilitation 
service agency. This research aims to improve the effectiveness of 
community-based psychosocial rehabilitation interventions for 
functional disability in schizophrenia.
    NIMH supports a program of dissemination and implementation 
research, with the goal of building the knowledge base on how best to 
integrate effective mental health interventions into service systems. 
This research portfolio includes over thirty ongoing studies to better 
identify the means by which people with mental illness can receive the 
evidence-based services most likely to alleviate the burden of mental 
illness and lead to recovery. One recently funded project provided 
funding to the state of Illinois to determine the best way to implement 
supportive employment services for people with mental illness returning 
to the community. Another project is examining factors that improve the 
statewide implementation of an evidence-based treatment intervention 
for children in foster care across the state of California, using 
community development teams to optimize the use of the intervention for 
children and adolescents in the foster care system. Another study is 
determining the impact of consumer-run organizations to improve 
outcomes for individuals with mental illness in communities.
    NIMH supports a program of systems research, which focuses on ways 
in which systems (e.g. criminal justice, schools, welfare) can improve 
the access to care of persons with mental illness. One NIMH-funded 
researcher is studying a service system that helps people with mental 
illness transition from the justice system into a community with 
services to support their recovery. Another investigator is studying 
how a nurse manager intervention might improve the health and reduce 
disability of homeless people with schizophrenia.
            collaborations with samhsa on services research
    Question. How is NIMH working with SAMHSA to develop a research 
agenda focused as much on services research as on clinical trials 
research?
    Answer. NIMH collaborates with SAMHSA on a number of activities to 
identify key priorities for services research. NIMH continues to 
collaborate with SAMHSA on research related to the transformation of 
mental health services in America. The Center for Mental Health 
Services, (CMHS) within SAMHSA, provides infrastructure support for 
nine states to collaborate across state agencies to determine how best 
to transform the delivery of services for people with mental illness. 
NIMH is supporting the cross-site evaluation of this program--an effort 
that will facilitate the augmentation of research to the state 
transformation efforts. In addition, SAMHSA established five 
interagency priority workgroups to address recommendations from the 
Commission Report.\3\ NIMH and the Agency for Healthcare Research and 
Quality are working with each of these workgroups to better connect 
services research to priorities in the areas of emergency response, 
suicide prevention, employment, financing, and the integration of 
mental health care and primary care.
---------------------------------------------------------------------------
    \3\ New Freedom Commission on Mental Health, Achieving the Promise: 
Transforming Mental Health Care in America. Final Report. DHHS Pub. No. 
SMA-03-3832. Rockville, MD: 2003.
---------------------------------------------------------------------------
    NIMH is actively engaged with SAMHSA to generate research based on 
SAMHSA's major services agendas. An example of this is the research 
program on ``Effectiveness, Practice, And Implementation in CMHS' 
Comprehensive Community Mental Health Services Program for Children and 
their Families Service Sites.'' This three year research effort funds 
researchers who specifically work within CMHS funded service systems.
    NIMH and CMHS have organized a series of Regional meetings for 
researchers, consumers, policymakers, clinicians, and other key 
stakeholders to identify research and services needs for state systems. 
NIMH is also working with CMHS on several meetings to identify the 
state of the science in specific services areas. The first, on shared 
decision-making, will bring together expert researchers, consumers, and 
service providers to discuss the current knowledge base regarding 
shared decision-making and to develop research priorities. A similar 
meeting on health promotion for people with mental illness is being 
planned.
                      research on self management
    Question. In light of the Institute of Medicine's endorsement of 
the importance of patient-centered mental health care, what is NIMH 
doing to promote research on models such as illness self-management, 
patient education, and self-help?
    Answer. NIMH has a growing portfolio of research on approaches to 
improve patient education, self-help, and self-management of mental 
disorders. NIMH supports a Program Announcement titled ``Information 
Technologies and the Internet in Health Services and Intervention 
Delivery'' to test models of education and self-management for mental 
disorders.
    Current medications used to treat those with chronic and severe 
schizophrenia often lead to significant metabolic side effects, so a 
number of NIMH studies are testing models of self-management to promote 
healthy lifestyles and to reduce diabetes and weight gain in this 
population. Obtaining evidenced-based care remains a challenge for many 
individuals with schizophrenia. One study tests an interactive web-
based system that allows the individual consumer or family member to 
compare current treatment to evidence-based standards and to discuss 
treatment approaches with his or her clinician.
    Peer- and community-based programs to support families of adults 
with serious mental illness typically incorporate elements of self-
help, empowerment, trauma recovery, stress and coping theories, as well 
as mutual assistance for family members. NIMH currently supports 
several studies to provide scientific evidence that these programs 
effectively achieve their goals, including for example, the National 
Alliance for the Mentally Ill's Family-to-Family Education Program--a 
12-week class with a highly-structured standardized curriculum 
developed and conducted by trained family members.
    The collaborative care model, developed initially for diabetes 
medication management, has been successfully applied to depression 
treatments in primary care. Collaborative care combines patient 
education about the disorder and its treatment approaches with a 
depression specialist to assist in case management and treatment 
adherence. Collaborative care has been shown to be effective in 
reducing depression and suicidality in older depressed primary care 
patients, and is currently being studied among women with post-partum 
depression in two health care plans.
    One aspect of patient-centered care is psychoeducation, providing 
information about mental illness and its long-term care to families and 
patients. Psychoeducational models originally used with adult patients 
and their families have been adapted and are currently being tested for 
use with youth with various mental disorders to strengthen the person's 
understanding of the illness, to improve treatment adherence, and to 
facilitate overall illness management. Family-focused treatment as an 
adjunctive treatment to medication management is being tested with 
adolescents with bipolar disorder in a three-site clinical trial. An 
adapted version of this same approach is also being pilot tested with 
younger youth with mood disorders who are at risk for development of 
bipolar disorder. A similar approach involved multi-family 
psychoeducation groups designed as adjunct to medication management was 
tested for use with families of 8-11 year old youth with mood disorders 
(depressive disorders or bipolar disorder).
              research on family-based treatment programs
    Question. In light of the disproportional impact of meth on mothers 
with children, and the continued impact of crack among our poor and 
urban families, please discuss what research initiatives are being 
undertaken to recognize and expand the best practices of family-based 
treatment programs for substance abusing mothers and their children.
    Answer. NIDA recognizes the importance of family support as part of 
drug abuse treatment, particularly for drug-abusing mothers with 
custody of children. Family therapy that addresses the needs of mothers 
and that involves their children and other pivotal family members in 
the treatment program can strengthen and extend program benefits. 
Findings from research on Brief Strategic Family Therapy (BSFT)--a 
treatment intervention aimed at adolescents--einforce the benefits of a 
family-based paradigm to change problem-sustaining family patterns and 
increase treatment engagement and retention, even in patients with 
multiple comorbidities.
    NIDA supports a variety of research approaches to address the needs 
of substance-abusing mothers and their children. These include 
interventions that actively reach out to disadvantaged women at the 
community level, longitudinal studies that follow children prenatally 
exposed to drugs, services research to bring evidence-based treatments 
to the criminal justice system, and clinical research on medications 
and behavioral treatments in pregnant women and females of childbearing 
age.
    Recognizing the need for culturally-appropriate and gender-
sensitive interventions, NIDA-supported researchers are adapting 
behavioral treatments for substance-abusing female populations, 
including African American women who abuse crack cocaine, pregnant 
women in treatment, women with or at risk for HIV, and low-income women 
in community treatment programs. One study is adapting an empirically 
based behavioral therapy for drug abuse to a church-based system to 
intervene with cocaine-addicted African American women, while another 
is modifying an integrated family behavioral therapy for adolescents to 
intervene with pregnant women at risk for HIV. Other studies are 
looking at the quality of maternal-child feeding interactions (during 
the child's first year) among mothers who used cocaine during their 
pregnancy, as well as examining the serious risks faced by children 
exposed to methamphetamine use and manufacture. Results of such studies 
will help determine how to strategically intervene with mothers and 
their children.
       better treatments for women in the criminal justice system
    Question. Presently, the fastest growing prison population is women 
convicted of non-violent drug felonies. Most of these women are mothers 
and most of them are untreated addicts. At the same time, upwards to 
eighty percent of the families who come to the attention of child 
welfare are substance abusing. How can we work, or what is NIDA doing 
specifically, to stop this downward cycle of mothers being displaced 
into the prison system and children being placed in foster care while 
the underlying issue of parental addiction remains unaddressed.
    Answer. As reflected in the answer to the previous question, NIDA 
supports research aimed at treating women and mothers with children in 
the community to prevent their entering the criminal justice system in 
the first place. These efforts involve a variety of approaches--from 
adapting evidence-based interventions for use in multiple settings to 
conducting trials of family-based therapies to using a combination of 
medications and behavioral approaches to treat drug abusers in the 
community and help them achieve a healthier lifestyle.
    Unfortunately, far too often, drug abuse and addiction remain 
untreated and escalate to the point of criminal justice involvement, a 
problem intensifying for females. Indeed, the population of 
incarcerated women has more than doubled in this country from 1995 to 
2005, the problem of female criminal justice involvement characterized 
by gender-specific factors related to the pathways to substance abuse 
and recovery, socio-cultural roles and responsibilities, and certain 
co-occurring mental illnesses. A primary concern for women, which this 
question addresses, is the greater likelihood of parenting and 
childcare responsibilities.
    NIDA has addressed many of these differences in our recently 
released landmark publication--principles of Drug Abuse Treatment for 
Criminal Justice Populations--which conveys effective principles of 
substance abuse treatment to the criminal justice community and the 
treatment professionals working with drug-abusing offenders, including 
women with children. In addition to childcare services, female 
offenders are more likely than men to need medical and mental health 
services (given high rates of depression, anxiety, and trauma) and 
assistance in finding housing and employment. It is important to 
examine these special needs, for while treatment programs serving both 
genders can be effective for females, gender-specific programs may be 
more effective, particularly for women with histories of trauma and 
sexual or physical abuse. For female offenders with children, parental 
responsibilities can conflict with their ability to participate in drug 
treatment--and yet regaining or retaining custody of their children can 
also motivate mothers to participate in treatment. Treatment programs 
may therefore improve retention by offering childcare services and 
parenting classes.
    NIDA is examining these and other methods to make treatments more 
effective for women, including supporting development of a gender-
specific re-entry model to help women reintegrate into the community 
once released. In addition, a drug court study is looking specifically 
at ways to improve treatment engagement for women and children. NIDA is 
also supporting studies of adolescents involved with foster care, 
identifying the prevalence and heightened risk of substance use 
disorders among this population. It is worth noting that involvement 
with foster care is often a marker of prior adversities, including 
parental addiction, and an antecedent of negative adult outcomes, most 
of which stem from childhood adversities rather than from foster care 
per se. In fact, research has shown that therapeutic foster care can be 
beneficial, particularly to adolescent girls.
               violence, trauma and female drug addiction
    Question. Please talk about the interrelationship between physical 
and sexual iolence, trauma, and addiction among women, and what 
research is being done to excavate that interrelationship, especially 
as it relates to the experience of maternal addiction.
    Answer. It is well-established that childhood maltreatment (in the 
form of sexual abuse, physical abuse, or neglect) leads to enhanced 
risk for substance abuse, including earlier incidence of alcohol and 
drug abuse in adolescents. One study has shown that up to 65 percent of 
the variability in addiction risk is linked to childhood stress; with 
children who have been subjected to five or more ``insults'' (i.e., 
incidents of trauma) being ten times more likely to develop an 
addiction than those without such exposure. Many of the biological 
responses to stress have been implicated in the pathophysiology of both 
substance use disorders and Posttraumatic Stress Disorder (PTSD).
    The relationship of substance abuse and addiction to female 
victimization by sexual violence or other traumatic abuse presents a 
vicious cycle that can turn both ways, sustained in part by long-
lasting negative emotions and behaviors that elicit drug craving and 
use. Indeed, PTSD and depression are common results of sexual and/or 
physical abuse and primary risk factors for subsequent drug abuse in 
females. A multitude of factors influences these events, including age 
of exposure to physical or sexual abuse, family history, criminal 
justice involvement, race, co-occurring mental disorders, and other 
genetic and environmental variables--a tangle of risk factors that 
NIDA-supported research is investigating to help devise more effective 
interventions.
    Prior research has revealed, disturbingly, that most rape victims 
(62 percent) are girls under the age of 18, with 28 percent of victims 
under age 11. This finding reflects the early age at which violence 
often occurs, and the importance of understanding a person's history in 
determining how best to provide treatment. For women, violence more 
often precedes substance use than the other way around, although both 
patterns can occur. Thus, treatment that evaluates family history and 
exposure to violence at various ages might yield important information 
about chronology of critical variables and relative contributions of 
environmental and biological factors to comorbid mental and substance 
abuse disorders.
    The effects of trauma are complex and can be manifested in diverse 
ways. For example, longitudinal and developmental research suggests 
that girls' involvement in the juvenile justice system often follows 
from exposure to trauma and physical or sexual abuse and often co-
occurs with anxiety and mood problems. In a recent longitudinal 
analysis of women who lived in shelters or experienced major violence, 
study participants had a two-fold increase in their risk of depression 
over a 6-month follow-up period. And because substance abuse and 
addiction also significantly increase the risk of subsequent 
victimization that could lead to PTSD (the reverse direction of the 
vicious cycle), NIDA also supports studies seeking to add a violence 
prevention component to substance abuse treatment, particularly for 
male perpetrators of intimate partner violence. Research on 
cohabitating substance-abusing patients is offering options to 
treatment providers who deal with intimate partner violence--40 to 60 
percent of couples reporting episodes of partner aggression in the year 
preceding treatment entry.
    Finally, NIDA research has revealed encouraging results for a 
trauma-focused cognitive behavioral therapy (CBT) known as ``Seeking 
Safety,'' designed specifically for women with trauma histories. 
Compared to standard substance abuse treatment, the therapy improved 
both substance abuse and PTSD symptoms in female patients who 
identified the trauma's effects on their lives and practiced techniques 
to ease emotional pain, stop self-blame, and cope with difficult 
interpersonal and potential relapse situations. NIDA is now testing 
``Seeking Safety'' in its National Drug Abuse Clinical Trials Network, 
which uses ``real-world'' community treatment programs to validate 
treatment practicality and effectiveness. This therapy has also shown 
promising results in adolescent girls, suggesting the need for dual-
diagnosis treatment that more directly targets trauma-related symptoms 
and areas of individual difficulty. Such findings with adolescents are 
encouraging, as they suggest that comorbid PTSD and substance abuse may 
be amenable to change early to counter its typical persistence into 
adult
                                 ______
                                 
              Questions Submitted by Senator Arlen Specter
                     effects of president's budget
        national institute of neurological disorders and strokes
    Question. If the President's budget were to be adopted by Congress 
and research funding were frozen or cut below existing levels, what 
specific research priorities at your institutes would be delayed or 
have to be set aside?
    Answer. The first priority of NINDS at any funding level is to 
maintain our existing research commitments, and the President's budget 
allows us to do that. However, progress against neurological disorders 
depends on maintaining robust investigator initiated basic, 
translational, and clinical research programs, and, as you heard in 
testimony from academic scientists, new and established investigators 
are struggling. They are spending more time writing and rewriting grant 
applications than doing research, and too often are forced to drop 
innovative work, lay off highly trained staff, or close down labs 
entirely. Under this budget scenario, we would have to reduce or 
eliminate programs and pass up promising opportunities in order to 
sustain our core research and ensure that we have a scientific 
workforce for the future. NINDS would, for example, move fewer 
promising early phase clinical trials from our SPOTRIAS stroke centers 
to large phase III trials, move more slowly in developing the Clinical 
Research Collaboration and Neurological Emergency Treatment clinical 
trials networks, and not undertake new initiatives, such as applying 
the model of therapeutics development from the SMA Project to other 
disorders.
    national institute on deafness and other communication disorders
    Question. If the President's budget were to be adopted by Congress 
and research funding were frozen or cut below existing levels, what 
specific research priorities at your institutes would be delayed or 
have to be set aside?
    Answer. With the resources requested in the fiscal year 2008 
President's Budget, NIDCD will be able to support its highest priority 
research. This includes support for a research contract for a multi-
center study entitled the ``CMV and Hearing Multicenter Screening 
(CHIMES) Study,'' on the role of congenital CMV in the development of 
hearing loss in children. The CHIMES study is one of the largest 
studies of its kind with approximately 100,000 children to be screened 
at birth for CMV infection. A major focus of this study is to identify 
asymptomatic children and follow their progress to determine if hearing 
loss develops. Those who test positive for CMV will undergo follow-up 
hearing screening to determine the onset, severity, and progression of 
hearing loss. If additional funds were to become available to NIDCD 
beyond these priorities, NIDCD would likely seek to increase the number 
of children who will be screened for CMV infection.
                  national institute of mental health
    Question. If the President's budget were to be adopted by Congress 
and research funding were frozen or cut below existing levels, what 
specific research priorities at your institutes would be delayed or 
have to be set aside?
    Answer. With the resources requested in the fiscal year 2008 
President's Budget, NIMH will be able to support its highest priority 
research. While the President's request did not propose to decrease 
NIMH's budget, if additional resources became available for NIMH to 
support research beyond these priorities, NIMH would likely seek to 
expand its support for in-depth analyses of data collected from whole 
genome association (WGA) studies for major mental disorders. WGA 
studies evaluate the subtle differences between the genomes of healthy 
people and those suffering from disease in order to determine how 
genetic variability may contribute to disease susceptibility. In 
addition to the WGA analyses, NIMH might invest in research to develop 
new compounds as fast-acting treatments for depression, with the 
ultimate goal of expanding treatment options so that physicians may 
offer more personalized care.
           national institute on alcohol abuse and alcoholism
    Question. If the President's budget were to be adopted by Congress 
and research funding were frozen or cut below existing levels, what 
specific research priorities at your institutes would be delayed or 
have to be set aside?
    Answer. The first priority of NIAAA at any funding level is to 
maintain our existing research commitments, and the President's budget 
allows us to do that. In addition, in the fiscal year 2008 
Congressional Justification, NIAAA has highlighted a number of 
promising areas for future research activity. For example, $3 million 
have been committed in fiscal year 2008 for research to investigate the 
short- and long-term effects of alcohol use on the developing 
adolescent human brain. This funding amount will allow us to conduct 
pilot studies to determine the best methodology for answering this 
critical question through future larger longitudinal studies. A second 
example relates to our funding of medications development. The fiscal 
year 2008 budget request provides for $2 million of additional funds 
for testing compounds and increasing the efficiency of the medications 
development infrastructure. Whereas it is cost effective to 
concurrently test multiple compounds, the fiscal year 2008 budget 
permits sequential testing of a few promising new compounds.
                    national institute on drug abuse
    Question. If the President's budget were to be adopted by Congress 
and research funding were frozen or cut below existing levels, what 
specific research priorities at your institutes would be delayed or 
have to be set aside?
    Answer. With the resources requested in the fiscal year 2008 
President's Budget, NIDA will be able to support its highest priority 
research. While the President's request did not propose to decrease 
NIDA's budget, if additional resources became available to NIDA beyond 
these priorities, NIDA would likely seek to pursue additional clinical 
trials and development of new addiction medications; develop a 
specialized NeuroChip for substance abuse to put in place a single 
standardized platform for researchers to rapidly screen thousands of an 
individual's relevant gene variants; support a Genes, Environment, and 
Development Initiative (GEDI)--a cross-disciplinary initiative designed 
to increase knowledge of the interactions between genes, environment, 
and developmental stage in relation to drug abuse risk; and expand 
NIDA's services research programs operating at the community level, 
such as its large research collaborations to improve drug abuse 
treatment for criminal justice populations.
                  economic benefits of ninds research
    Question. Dr. Landis, I am particularly interested cost-savings 
resulting from NIH research. I understand that NINDS has analyzed the 
economic benefit of NINDS-supported clinical trials. Could you 
highlight the results of this study for the Committee?
    Answer. At the request of the National Advisory Neurological 
Disorders and Stroke Council, the institute contracted for an 
independent evaluation of the costs and benefits of all NINDS phase III 
clinical trials conducted from 1977 to 2000. The total cost of the 
clinical trials in the study was $335 million (adjusted to 2004 
dollars). Over 10 years, the benefits from these trials exceeded $15 
billion and added 470,000 healthy years of life to people in the United 
States. For the entire period of the study, the benefits surpassed $50 
billion, which was greater than the total NINDS budget over that period 
($29.5 billion).
    Advances in neuroscience are yielding more clinical trial 
opportunities than ever before, but trials are expensive and can take 
years to complete. So, NINDS is now developing computer models to do 
this kind of analysis prospectively, that is to estimate in advance 
which trials would have the most impact on public health.
                      duchenne muscular dystrophy
    Question. Dr. Landis, I understand that NINDS recently funded a 
large-scale project in translational research for Duchenne muscular 
dystrophy. Can you tell me about this project, and how it fits into the 
bigger picture of finding cures for this disease?
    Answer. NINDS will soon fund a large-scale project to an 
investigator at the University of Pennsylvania to develop new small 
molecule drugs for the treatment of Duchenne muscular dystrophy (DMD) 
and potentially other forms of muscular dystrophy as well. DMD is a 
disease caused by mutations in the dystrophin gene, resulting in a lack 
of the dystrophin protein. Dystrophin is part of a complex structure 
involving several other protein components that is required for 
maintaining proper skeletal muscle structure and function. In the 
absence of the dystrophin protein, muscle weakening and wasting, and 
ultimately death, occurs.
    The project will pursue a number of strategies for therapy 
development, including stimulating muscle growth by modulating growth 
factor pathways, and upregulating proteins that may structurally and 
functionally substitute for dystrophin or that contribute to the 
dystrophin protein complex in normal muscle cells. The researchers have 
already completed a high-throughput screening process on each of these 
strategies in order to identify small molecules that are candidate 
therapies. The project will focus on improving the properties of these 
small molecules as drug candidates and carry out research that will 
help support further clinical studies using these compounds. One 
exciting aspect of this project is the fact that a patient voluntary 
organization (Parent Project MD) as well as a company (PTC 
Therapeutics) are contributing funds to this project, thereby creating 
a public-private partnership to leverage funds for this project.
    This project is one important component of the larger NIH effort to 
find cures for DMD and other forms of muscular dystrophy. The Senator 
Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers also 
fund translational research aimed at developing therapies for muscular 
dystrophy. In addition, a few years ago, NIH released a number of 
initiatives to stimulate translational research in muscular dystrophy, 
and grants are being funded through these initiatives, as well as 
through other mechanisms at NIH. A number of strategies for therapy 
development are being pursued in these studies including gene therapy, 
cell replacement therapy, enhancing muscle regeneration, and genetic 
modification strategies. In addition to these translational projects, 
it is important to note that the mechanistic knowledge obtained through 
NIH-funded basic research studies has yielded a range of therapeutic 
targets that NIH-funded research is now pursuing.
                        spinal muscular atrophy
    Question. Dr. Landis, can you tell us if any progress has been made 
toward a treatment for spinal muscular trophy? What continuing efforts 
is your institute making in this area? Also please describe the SMA 
Project, explain what makes it different than the traditional way of 
doing translational research at NIH, and comment on how it might serve 
as a model for research on other diseases.
    Answer. The goal of the SMA Project is to bring at least one new 
drug for SMA to readiness for clinical testing as quickly as possible. 
The project uses a performance-based contract. It is quite different 
from the usual way we do research because of the central direction and 
the way it is organized. A project steering committee, with extensive 
expertise in drug development from industry and the FDA, as well as 
from the NIH, put together a detailed drug development plan and is 
heavily engaged in guiding progress. The project is implementing the 
plan via a ``virtual pharma organization'' that develops and brings 
together all of the necessary resources through subcontracts to 
companies that serve the drug development industry.
    The Project has put more than 800 compounds through repeated cycles 
of modification and evaluation in laboratory tests and is making 
encouraging progress. Some of these potential drugs show dramatically 
improved potency and efficacy in simple laboratory tests, and NINDS 
gathered sufficient data to file a patent application in March 2007. In 
2007 and 2008, the most promising compounds will advance through more 
definitive tests of effectiveness in mice that have been genetically 
engineered to mimic human SMA. By June of 2007, the project intends to 
select a clinical candidate and begin the preclinical safety studies 
that will support clinical testing. We are already applying lessons 
from the SMA Project for other disorders through a similar contract 
mechanism planned for this year that will address a major barrier to 
drug development by providing access to medicinal chemistry services.
    We are also continuing other lines of SMA research in both the 
extramural and intramural programs. This year, for example, intramural 
researchers collaborating with Italian scientists showed for the first 
time that a drug treatment could be effective in an animal model of SMA 
when treatment is begun after the symptoms of disease have already 
appeared, which is an encouraging finding.
                               stem cells
    Question. Dr. Landis, you serve as the Chair of the NIH Stem Cell 
Task Force. What steps would NIH take to implement S. 5, the Stem Cell 
Research Enhancement Act of 2007?
    Answer. If the bill were to be passed, a panel of experts would 
need to be immediately convened to develop and issue guidelines for 
implementation. NIH's experience in implementing human embryonic stem 
cell (hESC) research the past years would be vital in developing these 
new guidelines. In addition, NIH would develop a format for reporting 
requirements mandated within sections 2 and 3 of the act.
                            clinical trials
    Question. Dr. Insel, when Dr. Zerhouni was here last week, he noted 
that to continue to support ongoing research projects and allow for new 
investigators to successfully apply for support, it has been necessary 
to reduce support for clinical trials research. Has this also affected 
your institute? Will you be able to continue important clinical trials?
    Answer. NIMH is providing infrastructure support to maintain three 
large networks of investigative clinical teams that have evolved from 
the recent NIMH practical clinical trials on major depressive disorder, 
schizophrenia, and bipolar disorder. The networks comprise over 60 
sites throughout the United States with continual outreach and 
engagement to diverse groups of patients and families with mental 
illnesses. NIMH plans to support research studies that utilize the 
resources established by these networks; these studies must be of 
significant public mental health importance, provide value to 
individuals living with mental illnesses and to practitioners, and 
incorporate input from broad scientific and public domains. Under the 
President's Budget request, NIMH would be able to support a few studies 
on these clinical trial networks.
    Other recent NIMH-funded research has led to several promising new 
pharmacological treatment approaches for mental disorders. For example, 
a recent study uncovered a new mechanism of action to target for the 
fast relief of depression. In addition, NIMH has supported a large 
research effort focused on identifying novel compounds for treating the 
cognitive deficits associated with schizophrenia. NIMH hopes to build 
on these research findings to develop new compounds as fast-acting 
treatments for depression and as cognitive enhancers for those 
diagnosed with schizophrenia. Under the President's Budget request, 
NIMH would support a limited number of trials to test the efficacy of 
these promising new compounds.
              economic benefits of mental health research
    Question. Dr. Insel, can you tell us about the economic benefits 
that have resulted from investment in mental health research?
    Answer. Mental disorders are associated with enormous economic 
burdens. The President's New Freedom Commission on Mental Health 
estimated that these economic costs are on the order of $150 billion 
each year in the United States alone.\4\  Much of this cost is due to 
the lost work productivity that results from mental illness. A large 
body of NIMH-supported research indicates that much of this economic 
cost, including that derived from impaired work performance, could be 
alleviated by standard treatments for mental disorders. Yet, the cost 
of mental illness persists in part because of widespread underuse and 
the poor quality of implementation of treatments that have been shown 
to be efficacious and tolerable. Recent effectiveness trials supported 
by NIMH have shown that a variety of models that enhance the care of 
mental disorders through aggressive outreach and improved quality of 
treatments are highly effective at improving clinical outcomes, and in 
some cases, on work performance outcomes as well. Economic analyses 
accompanying these effectiveness trials have also shown that these 
quality improvement interventions are cost-efficient. Unfortunately, 
widespread uptake of these enhanced mental health treatment programs 
has not occurred due to barriers at the level of providers, health care 
systems, and purchasers of health care. Additional ongoing research 
supported by NIMH is examining how to most effectively overcome these 
barriers to high-quality mental health care and to ultimately reduce 
the enormous adverse economic impact from mental disorders.
---------------------------------------------------------------------------
    \4\ New Freedom Commission on Mental Health, Achieving the Promise: 
Transforming Mental Health Care in America. Final Report. DHHS Pub. No. 
SMA-03-3832. Rockville, MD: 2003.
---------------------------------------------------------------------------
                              hearing loss
    Question. What recent progress has been made toward better 
treatments for partial and full hearing loss? Has there been any 
specific progress in better hearing aid technology?
    Answer. Approximately 28 million Americans have a hearing 
impairment. Hearing loss is one of the most prevalent chronic health 
conditions in the United States, affecting people of all ages, in all 
segments of the population, and across all socioeconomic levels. It 
affects approximately 17 in 1,000 children under age 18. Incidence 
increases with age: approximately 314 in 1,000 people over age 65 have 
hearing loss. Because of the immense public health need, for over 30 
years, the NIH has played a significant and important role in 
sponsoring the development of cochlear implant technology. The cochlear 
implant is the only sensory neural prosthesis in widespread clinical 
use and according to the Food and Drug Administration's 2005 data; 
nearly 100,000 people worldwide have received implants. In the United 
States approximately 22,000 adults and nearly 15,000 children have 
received them. Continued research on ways to assess how well current 
users benefit from their cochlear implants will enable scientists to 
design implants that will be more effective for all future implant 
users. Some individuals with severe to profound hearing loss are 
receiving a cochlear implant for each ear. Research is demonstrating 
that these dual implant users are significantly better at localizing 
sounds and hearing speech in a noisy room, when compared to individuals 
with a single implant. Scientists also are developing a new cochlear 
implant electrode designed to provide electrical stimulation of the 
auditory nerve for high-frequency sounds while preserving useful, 
residual hearing at low frequencies. Scientists can now study the large 
groups of newborns who are identified for hearing loss and use this 
knowledge to document how cochlear implants can lead to improved speech 
acquisition, academic performance, and economic outcomes for these 
children.
    While cochlear implants bypass damaged portions of the inner ear 
and directly stimulate the auditory nerve, hearing aids amplify sounds. 
Scientists are determining which individuals can most benefit from 
hearing aids and the best ways to select and fit hearing aids in 
children and other people whose hearing ability is difficult to test. 
One of the most exciting advancements in hearing aid technology 
resulted from NIH-supported research. The discovered technology is 
based on the ears of a parasitic fly, Ormia ochracea. Despite their 
small size and the short distance between them, Ormia's ears are able 
to rapidly pinpoint the location from which the sound of a potential 
host--a cricket--is coming, even in a noisy environment. The intriguing 
mechanism that enables Ormia to accomplish this feat has provided a 
model for scientists and engineers to use in developing miniature 
directional microphones for hearing aids that can better focus on 
speech in a single conversation, even when surrounded by other voices. 
This finding has revolutionized the technology used for directional 
microphones and will improve the quality of life for the million of 
individuals with hearing impairment.
    Scientists are continuing to develop treatments for hearing loss 
that can be tailored to individuals' unique needs. The combined use of 
a hearing aid and a variation of the cochlear implant is another 
treatment being explored. A hearing aid in one ear combined with a 
shortened electrode array inserted into a portion of the cochlea of the 
other ear have proven to be effective in allowing individuals with 
hearing loss in the high frequencies to improve hearing. More research 
needs to be done to determine which individuals should receive these 
combined devices and which devices yield the most benefit. Researchers 
continue to conduct studies to determine the age at which hearing aids 
provide maximum success in early language development.
                       basic research and hearing
    Question. Please give us an example of how basic research into the 
mechanics of hearing has led to better patient outcomes. Why is basic 
research important in the areas covered by your institute?
    Answer. Hearing aid users want devices that enable them to better 
understand speech. Two recent surveys demonstrate this desire. Poor 
benefit in noisy situations was listed among the top 20 reasons why 
hearing aid owners don't use their hearing aids. Another survey of 
2,428 hearing aid owners found that improved understanding of speech in 
noise was among the top 10 desired changes. Of all the available 
technologies, directional microphones for hearing aids have shown the 
most promise for addressing this problem, as demonstrated by clinical 
studies of individuals with hearing loss.
    Because of basic research, NIH-supported scientists successfully 
completed a fabrication process to miniaturize the prototype of a low-
power, highly directional hearing aid microphone so that it will fit 
into a hearing aid. This directional microphone mimics the auditory 
system of the parasitic fly, Ormia ochracea. The fly's system is an 
excellent model to imitate because its mechanically coupled ears enable 
it to detect the direction of sound and because it suggested a way to 
miniaturize a microphone for use in hearing aids. The scientists used 
silicon microfabrication technology to make a directional microphone 
that is small enough to be incorporated into a hearing aid. The 
directional microphone developed in fiscal year 2006 will ultimately 
help hearing aid users to better understand speech in a noisy 
background, such as in a crowded room. The microphone is able to do 
this by giving more weight to sound originating closest to the ear.
    This is an excellent example of why basic research is so important. 
Basic research often relies on studies in ``model organisms,'' such as 
mice, fruit flies, or bacteria. Because human cells contain the same 
molecular building blocks and pathways as those of most other living 
things, researchers can learn much about the way our cells work by 
studying these simpler organisms. These models allow scientists to 
design and control their experiments tightly and to select the type of 
organism best suited for examining a specific problem or process. The 
ability to conduct basic research on the ears of Ormia, has 
revolutionized the technology used for directional microphones and will 
improve the quality of life for millions of individuals with hearing 
impairment. This is one of the many examples of advances that grew out 
of basic research. In conclusion, while basic research studies do not 
always have an immediate impact on our health, such research often 
leads to new medicines, technologies, and research tools.
                          drug abuse treatment
    Question. Dr. Volkow, I understand that your Institute has released 
principles of drug abuse treatment for criminal justice populations. 
Could you please summarize for us how you recommend dealing with drug 
abuse treatment for criminal populations?
    Answer. NIDA's recently released booklet, Principles of Drug Abuse 
Treatment for Criminal Justice Populations: A Research Based Guide, 
reflects NIDA-supported research aimed at improving outcomes for 
offenders with substance abuse problems. The principles emphasize the 
need for customized strategies, which can include behavioral therapies, 
medication, and consideration of other mental and physical illnesses. 
The key message is that drug abuse treatment works, especially with 
community involvement and support, and brings about reduced drug abuse, 
criminal recidivism, and relapse to addiction.


    For that reason, treatment is cost-effective: for every dollar 
spent on drug abuse treatment an estimated $4-$7 in benefits ensues 
from avoided criminal justice costs--benefits that grow as addiction 
treatment continues over time. Data also show that treatment can work 
even when it is entered involuntarily. NIDA therefore recommends that 
treatment for criminal justice offenders be part of a continuum of care 
that begins in prison and continues throughout the difficult periods 
during and following re-entry into the community.
    To help ensure better outcomes for offender populations, NIDA 
recommends an integrated approach that cuts across multiple public 
health and public safety systems. In this vein, NIDA launched a 
Criminal Justice-Drug Abuse Treatment Studies (CJ-DATS) Initiative, a 
multisite and multiagency research initiative to focus on implementing 
new research-based drug abuse treatment models in the criminal justice 
system. And because effective interventions may include 
pharmacotherapies, or medicines for drug abuse and addiction, NIDA 
recommends their use in criminal justice settings as part of a 
comprehensive treatment regimen--which will necessitate a culture 
change.
    Another tenet of effective drug abuse treatment is a proper balance 
of rewards and sanctions to encourage prosocial behavior and treatment 
participation. It is important to reinforce positive behavior for those 
participating in drug abuse treatment, with sanctions applied 
gradually, in line with degree or persistence of noncompliance.
    To effect needed changes, NIDA will continue to reach out to judges 
and others in the criminal justice system to educate them about the 
behavioral and biological aspects of addiction through intensive 
training workshops. We will also continue to support studies examining 
ways to make quality treatment options available through drug courts 
and other alternatives to incarceration for substance abusers.
                      addiction as a brain disease
    Question. Dr. Volkow, I understand that many in the field of drug 
abuse research strongly argue that addiction is a brain disease. Do you 
agree with this assessment, and if so, why?
    Answer. Yes, I wholeheartedly agree that addiction is a brain 
disease. Decades of scientific research by NIDA and others have 
affirmed drug addiction as a disease that alters the brain in ways that 
affect behavior. The compulsive craving, seeking, and use of drugs, 
even in the face of dire life consequences, happens because addiction 
affects the same brain circuits that are also involved in reward, 
motivation, memory, and control over behavior. And when these are 
usurped by drugs, so is a person's capacity to freely choose not to use 
drugs, even when it means losing everything they used to value. In 
fact, the inability to stop is the essence of addiction.
    Brain imaging and basic neuroscience research have helped us to 
understand how drugs of abuse alter brain function. We depend on our 
brain's ability to release dopamine in order to experience pleasure and 
to motivate responses to the natural rewards of everyday life, such as 
the sight or smell of food. Drugs of abuse produce very large and rapid 
dopamine surges and over time the brain responds by reducing normal 
dopamine activity. Eventually, the disrupted dopamine system renders 
the addict much less sensitive to pleasure--even to the drugs they seek 
to feed their addiction. Drugs of abuse also affect the regions of the 
brain that help people control desires and emotions, as evidenced by 
brain imaging research in humans revealing changes in the functions of 
these circuits. Thus, drug addiction affects the very brain areas that 
people need to ``think straight,'' apply good judgment, and make good 
decisions for their lives. The resulting lack of control leads addicted 
people to compulsively pursue drugs, even after the drugs have lost 
their effectiveness in producing pleasure; for now even the memories 
that are linked to the drug motivate behaviors to seek the drug. 
Behavior becomes reflexive and much less amenable to cognitive 
interference. Just as the damaged heart can no longer propel the blood 
to our bodies, the damaged brain can no longer propel the nerve 
impulses to control desires and emotions.
    Like any other medical disorder that impairs the function of vital 
organs, repair and recovery of the addicted brain depends upon targeted 
and effective treatments that address the complexity of the disease. 
Brain imaging shows recovery as well. Research is proving new insights 
on how this can be done. NIDA is engaged in studying new scenarios for 
what constitutes effective treatment: pharmacological treatments to 
mitigate stress and prevent relapse, cognitive treatments that 
strengthen the frontal (thinking) part of the brain, and strategies 
that diminish conditioned responses, promote new learning, inhibit 
stress-induced relapse, and restore the rewarding experiences from 
natural reinforcers.
                           underage drinking
    Question. Dr. Li, how is your institute addressing the growing 
problem of underage drinking? Is progress being made?
    Answer. Although the problem of underage drinking persists progress 
is being made:
    (1) Based on converging evidence from multiple fields we now know 
that underage drinking is best addressed and understood within a 
developmental framework because this behavior is directly related to 
processes that occur during adolescence. Using such a framework will 
make us more effective in preventing and reducing underage alcohol use 
and its associated problems.
    (2) This paradigm shift along with recent advances in the fields of 
epidemiology, developmental psychopathology, human brain development, 
and behavioral genetics provided the scientific foundation for the 
Surgeon General's recently released Call to Action to Prevent and 
Reduce Underage Drinking, the work of the Interagency Coordinating 
Committee on the Prevention of Underage Drinking (ICCPUD) and the work 
of its member federal agencies and departments.
    (3) The release of the first ever Surgeon General's Call to Action 
on underage drinking is a landmark event which will heighten awareness 
of the problem in all sectors of society.
    (4) Federal surveys indicate some modest declines on certain 
measures of underage drinking. While this progress is encouraging, the 
prevalence of underage drinking, and especially binge drinking, remain 
high.
    (5) In order to better characterize trends in underage drinking in 
America, information beyond that previously available from national 
surveys is needed. Based on NIAAA's recommendations, new questions on 
patterns of drinking (e.g. very high level consumption, sources of 
alcohol, and drinking venues) are now being included in national 
surveys.
    (6) A key research question is the extent to which adolescent 
drinking impacts the developing human brain. Research with rodents and 
studies with alcohol dependent youth suggest that alcohol use during 
adolescence, particularly heavy use can have deleterious short- and 
long-term effects on the developing brain. To further address this 
central scientific question, NIAAA has released a Funding Opportunity 
Announcement for two-year pilot studies in this area entitled The 
Impact of Adolescent Drinking on the Developing Brain. Successful 
applications in response to this announcement will be funded in fiscal 
year 2007. These studies are expected to inform a larger longitudinal 
initiative.
                           alcohol and cancer
    Question. Dr. Li, I understand that drinking alcoholic beverages 
has been linked to an increased risk of several types of cancer. Could 
you please tell us if this link has been confirmed, and if so do we 
know what the mechanism for the link might be?
    Answer. Chronic alcohol consumption is a well-established risk 
factor for cancer of the oral cavity, pharynx, esophagus, and larynx. 
For example, for those individuals who average 100 grams of alcohol 
consumed per day (about 7 standard drinks) the relative risk for cancer 
of the oral cavity and pharynx increases 6.5 times compared to non-
drinkers. Consuming this same level of alcohol increases the relative 
risk for cancers of the larynx, esophagus, breast and liver 3.9, 3.6, 
2.4, 1.8 fold respectively. While not as high, there are also 
significant elevated risks for each of these cancers associated with 
consumption of 25 grams of alcohol per day (about 2 standard drinks). 
Concurrent smoking and drinking, which is common, synergistically 
increases the risk of cancer. For example, one study reported an 18-
fold increase in the relative risk for esophageal cancer due to the 
consumption of more than 6 drinks/day, a 5-fold increase due to smoking 
more than 20 cigarettes/day, and 44-fold greater risk for combined 
heavy alcohol consumption and cigarette smoking.
    Alcohol is metabolized primarily by alcohol dehydrogenase in the 
liver to form acetaldehyde, a highly reactive and carcinogenic compound 
which is further metabolized by aldehyde dehydrogenase (ALDH2) to 
acetate. A variant of this enzyme (ALDH2*2) is virtually inactive 
(leading to higher concentrations of acetaldehyde) and occurs in 28-45 
percent of Asian populations. As a result of the accumulation of 
acetaldehyde, homozygous carriers of this allele (ALDH2*2/*2) 
experience aversive reactions to alcohol including strong facial 
flushing and toxic reactions. Therefore most homozygous individuals 
either abstain or drink infrequently. In contrast, heterozygous 
carriers (ALDH2*1/*2, which has about 10 percent residual ALDH2 
activity) who consume alcohol are at a high risk for developing 
esophageal cancer. Thus, acetaldehyde is implicated as a carcinogen, 
and is included in the list of ``IARC Group 2B Carcinogens.'' Several 
mechanisms have been implicated in alcohol-induced cancer, including: 
(1) formation of acetaldehyde which forms adducts with DNA; (2) 
production of reactive oxygen species (ROS) and lipid peroxidation 
products; (3) changes in folate and methionine metabolism; (4) alcohol-
induced increase in estrogen formation in breast cancer; (5) suppressed 
immune function; and (6) alcohol's solvent action enhancing the 
bioavailability of carcinogens from tobacco and other sources. The 
induction of microsomal cytochrome P450 enzymes by alcohol increases 
the metabolism of procarcinogens, such as nitrosamines, present in 
tobacco smoke, and likely plays an important role in the greater risk 
for cancer due to heavy alcohol consumption and smoking.

                          SUBCOMMITTEE RECESS

    Senator Harkin. So with that, thank you very much.
    The subcommittee will stand in recess to reconvene at 9:30 
a.m., Wednesday, March 28, in room SD-124. At that time we will 
hear testimony from the Honorable Elaine L. Chao, Secretary, 
Department of Labor.
    [Whereupon, at 5:24 p.m., Monday, March 26, the 
subcommittee was recessed, to reconvene at 9:30 a.m., 
Wednesday, March 28.]