Full Text MH-93-004

DEVELOPMENTAL STUDIES OF THE CEREBRAL CORTEX IN MENTAL HEALTH

NIH GUIDE, Volume 22, Number 39, October 29, 1993

RFA:  MH-93-004

P.T. 34

Keywords: 
  Brain 
  Nervous System 
  Emotional/Mental Health 
  Mental Disorders 


National Institute of Mental Health

Letter of Intent Receipt Date:  December 22, 1993
Application Receipt Date:  February 22, 1994

PURPOSE

The National Institute of Mental Health (NIMH) invites applications
directed at research toward the understanding of the normal and
abnormal development of components of the central nervous system
involved in mental health.  This research applies most specifically
to the cerebral cortex, but can extend to the thalamus, hippocampus,
striatum, and related areas.

This Request for Applications (RFA) is issued in response to the need
to foster basic and clinical studies that specifically address the
relationship between developmental processes in the brain and the
etiology of mental health disorders.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Developmental Studies of the Cerebral Cortex in Mental Health, is
related to the priority areas of mental health and mental disorders
of children and adolescents.  Potential applicants may obtain a copy
of "Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0) or
"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3228).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by public and private non-profit and
for-profit organizations such as universities, colleges, hospitals,
laboratories, research institutions, units of State or local
governments, and eligible agencies of the Federal government.  Women
and minority investigators are encouraged to apply.  Foreign
institutions are not eligible for First Independent Research Support
and Transition (FIRST) (R29) awards.

MECHANISMS OF SUPPORT

Applications are requested under the traditional research project
grant (R01) mechanism, the FIRST award (R29), or the small grant
(R03).  This RFA is a one-time solicitation.  Future unsolicited
competing continuation applications will compete with all
investigator-initiated applications and be reviewed according to the
customary peer review procedures.

Support may be requested for a period of up to five years with the
exception of the R03 mechanism, which is limited to two years, with a
maximum request of $50,000 per year.

Annual awards will be made subject to continued availability of funds
and progress achieved.  A competing supplemental application may be
submitted during an approved period of support to expand the scope or
protocol of a project during the approved period.  A competing
continuation (i.e., renewal) application may be submitted before the
end of an approved period of support to continue a project (R01s
only).

FUNDS AVAILABLE

It is estimated that approximately $1,350,000 will be available for
this RFA.   This level of support is dependent on the receipt of a
sufficient number of applications of high scientific merit.  Although
this program is provided for in the financial plans of the NIMH,
awards pursuant to this RFA are contingent upon the availability of
funds for this purpose.

RESEARCH OBJECTIVES

Background

The understanding of normal and abnormal development of cortical and
subcortical regions of the brain involved with cognition and behavior
is of fundamental interest to the NIMH ("Approaching the 21st
Century:  Opportunities for NIMH Neuroscience Research.  The National
Advisory Mental Health Council Report to Congress on the Decade of
the Brain".  DHHS Publication No. ADM-88-1580, 1988).  It can be
successfully argued that the cerebral cortex is the organ of human
mentation.  Thus, abnormalities occurring in the cerebrum can mildly
or devastatingly alter many behavioral and cognitive aspects of the
organism.  Many mental disorders afflict significant numbers of
individuals in society, and these disorders may have their root in
abnormal development of the cerebral cortex and closely associated
subcortical regions.  Examples of specific disorders include
affective disorders, anxiety disorders, personality disorders, and
psychotic disorders.  Similarly, many childhood and adolescent mental
disorders such as dysthymic disorders, hyperactivity, anorexia
nervosa, anxiety disorders, and obsessive compulsive disorders can be
linked to abnormal cortical function that may have begun in
embryogenesis.  Despite the importance of the cerebral cortex in
human behavior, a clear understanding of its developmental processes
is largely unknown.  Specific aspects of cortical development that
may play a role in the mental disorders listed above are how nerve
cell types are determined, how many cells are generated, how they are
organized, and how precise connections are established among neurons.

Specific Research Topics

The following are examples of some of the research topics and
conceptual issues in the development of the cerebral cortex and
related brain regions that specifically relate to this RFA:

o  Studies of cognitive and behavioral disorders compared to the
normal condition to identify mechanisms of gene involvement in the
development of the cerebral cortex, thalamus, and hippocampus.
Studies that exploit such identified genes to develop transgenic
animals for examining abnormal cortical development that can be
related to mental and psychiatric disease

o  Studies that correlate mental disorders such as schizophrenia and
depression with factors that may mediate neuronal differentiation in
the cerebral cortex, and the isolation, purification, and elucidation
of the mechanisms of action of such factors as they relate to cell
survival and cortical function

o  Elucidation of the cellular and molecular determinants that
participate in cell phenotype specification in telencephalic and
diencephalic brain regions; of particular interest are brain circuits
implicated in mental disorders (An example is the potential role of
dopamine in the etiology and/or pathophysiology of schizophrenia)

o  Studies that seek to correlate known psychiatric disorders of
children, adolescents, and adults (not including mental retardation)
with specific developmental aberrations of the cerebral cortex by
identifying the processes and mechanisms involved in parcelation of
cerebral cortex into distinct functional regions such as sensory,
motor, and associational domains

o  Studies of post-mortem tissue relevant to deficiencies of cortical
and subcortical development relevant to mental disorders

o  Studies that correlate the etiology and pathophysiology of
schizophrenia, personality disorders, and affective disorders with
the development of specific anatomical and neurochemical pathways.
These include the developmental specification of thalamocortical
connections and their functional relationship to specific cortical
areas, and corticothalamic and corticostriatal pathway development.

o  Studies on sexual dimorphism in the cerebral cortex and the
mechanisms regulating developmental events that lead to such
differences; elucidation of possible sex differences in the brain
that may underlie the differentiation of gender susceptibility to
disorders such as manic depressive illness and anorexia nervosa

Investigators may use any number of technical approaches to address
these research objectives.  These may include pharmacological,
physiological, anatomical, molecular, or genetic techniques.
Further, it is likely that diverse animal models, from insects to
complex vertebrates including nonhuman primates, could be used for
these developmental studies.  Studies that address these topics in
human material are particularly important.

SPECIAL REQUIREMENTS

Grant funds may be used for expenses clearly related and necessary to
conduct research projects, including both direct costs that can be
specifically identified with the project and allowable indirect costs
of the institution.  Funds may not be used to establish, add a
component to, or operate a treatment, rehabilitation, or prevention
intervention service program.  Support for research-related
treatment, rehabilitation, or prevention services and programs may be
requested only for costs required by the research.  These costs must
be justified in terms of research objectives, methods, and designs
that promise to yield generalizable knowledge and/or make a
significant contribution to theoretical concepts.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
women in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information should be included in the form PHS 398
in Sections 1-4 of the Research Plan AND summarized in Section 5,
Human Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However,
NIH recognizes that it may not be feasible or appropriate in all
research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native
Americans (including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by December 22, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of this RFA.

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains is helpful in planning for the review of
applications.  It allows NIMH staff to estimate the potential review
workload and to avoid conflict of interest in the review.

The letter of intent is to be sent to Dr. Cianci at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

Applicants are to use the grant application form PHS 398 (rev. 9/91).
Application kits containing the necessary forms and instructions for
regular research grants may be obtained from the office of sponsored
research at most universities, colleges, medical schools, and other
major research facilities; from the Office of Grants Information,
Division of Research Grants, National Institutes of Health, Westwood
Building, Room 449, Bethesda, MD 20892, telephone 301/710-0267; and
from the program staff listed under INQUIRIES.

The RFA label available in the PHS 398 application form must be
affixed to the bottom of the face page of the application.  Failure
to use this label could result in delayed processing of the
application such that it may not reach the review committee in time
for time for review.  In addition, the number and title of the RFA
"MH-93-004: DEVELOPMENTAL STUDIES OF THE CEREBRAL CORTEX IN MENTAL
HEALTH," must be typed in item number 2a on the face page of the PHS
398 application form.

Grants must be administered in accordance with the PHS Grants Policy
Statement (rev. 10/90), which is available from the office of
sponsored research at most institutions.

FIRST (R29) award applications must include at least three sealed
letters of reference attached to the face page of the original
application.  FIRST award applications submitted without the required
number of reference letters will be considered incomplete and will be
returned without review.

The signed original and four legible copies of the completed
application must be sent to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, one additional copy of the application
must also be sent to:

Salvatore N. Cianci, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
Parklawn Building, Room 9-95
5600 Fishers Lane
Rockville, MD  20857

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the
Division of Research Grants (DRG) and for responsiveness by the NIMH.
Incomplete applications will be returned to the applicant without
further consideration.  If the application is not responsive to the
RFA, NIMH staff will contact the applicant to determine whether to
return the application to the applicant or submit it for review in
competition with unsolicited applications, at the next review cycle.

Applications may be triaged by an NIMH peer review group on the basis
of relative competitiveness.  The NIH will withdraw from further
competition those application judged to be non-competitive for award
and notify the applicant Principal Investigator and institutional
official.  Those applications judged to be competitive will undergo
further scientific merit review.  Those applications that are
complete and responsive will be evaluated in accordance with the
criteria below for scientific/technical merit by an appropriate peer
review group convened by the NIMH.  The second level of review will
be provided by the National Advisory Mental Health Council, except
for R03 applications.

Criteria for scientific/technical merit review of applications will
include the following:  significance and originality, from a
scientific or technical standpoint, of the goals for the proposed
research; evidence of familiarity with relevant research literature;
adequacy of the conceptual and theoretical framework for the
research; adequacy of the methodology proposed to carry out the
research; feasibility of the proposed research; qualifications and
research experience of the principal investigator and other key
research personnel; availability of adequate facilities, other
resources, and collaborative arrangements necessary for the research;
appropriateness of budget estimates for the proposed research
activities; adequacy of plans to include women and minorities in
study populations; and adequacy of provisions for the protection of
human subjects and the welfare of animal subjects, as applicable.

AWARD CRITERIA

The anticipated date of award for funding is September 1994.
Applications recommended for approval by the National Advisory Mental
Health Council will be considered for funding on the basis of overall
scientific and technical merit of the research as determined by peer
review.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries regarding programmatic issues to:

Douglas L. Meinecke, Ph.D.
Division of Neuroscience and Behavioral Science
National Institute of Mental Health
5600 Fishers Lane, Room 11C-06
Rockville, MD  20857
Telephone:  (301) 443-5288
FAX:  (301) 443-4822

Direct inquiries regarding fiscal matters to:

Diana Trunnell
Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C-23
Rockville, MD  20857
Telephone:  (301) 443-3065
FAX:  (301) 443-6885

AUTHORITY AND REGULATION

This program is described in the Catalog of Federal Domestic
Assistance No. 93.242.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410, as
amended by Public Law 99-158, 42 USC 241 and 285) and administered
under PHS grants and Federal Regulations 42 CFR 52 and 45 CFR Part
74.  This program is not subject to the intergovernmental review
requirements of Executive Order 12372.

.

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