SELECTIVE COGNITIVE DEFICITS IN NEURODEVELOPMENTAL DISORDERS

NIH GUIDE, Volume 21, Number 36, October 9, 1992



PA:  PA-93-004



P.T. 34



Keywords:

  Cognitive Development/Process 

  Neurological Disorders 

  Neuroscience 



National Institute of Neurological Disorders and Stroke



PURPOSE



The National Institute of Neurological Disorders and Stroke (NINDS)

encourages the submission of research grant applications to pursue a

promising new approach to cognitive neuroscience that will identify

relations between cognitive function and neurostructure through the

study of specific, atypical patterns of cognitive deficit associated

with neurodevelopmental syndromes of known or suspected biological

origin.  Examples of three clinical entities that can be studied from

this perspective are Williams syndrome, Turner syndrome and autism.

An FY 91 NINDS workshop was devoted to the discussion and

confirmation of the usefulness of in depth, systematic investigation

of patterns or profiles of selective cognitive impairment in these

unusual conditions.



HEALTHY PEOPLE 2000



The Public Health Service (PHS) is committed to achieving the health

promotion and disease prevention goals of "Healthy People 2000," a

PHS-led national activity for setting priorities.  This Program

Announcement, Selective Cognitive Deficits in Neurodevelopmental

Disorders, is related to the priority areas of infant health, chronic

disabling conditions, and the related area of the neurological basis

of cognition.  Potential applicants may obtain a copy of "Healthy

People 2000" (Full Report:  No. 017-001-474-0, or Summary Report:

Stock No. 017-001-00473-1) through the Superintendent of Documents,

Government Printing Office, Washington, DC 20402-9325 (telephone

202-783-3238).



ELIGIBILITY REQUIREMENTS



Applications may be submitted by foreign and domestic, for-profit

organizations, public and private, such as universities, colleges,

hospitals, laboratories, units of State and local governments, and

eligible agencies of the Federal Government.  Foreign institutions

are not eligible for First Independent Research Support and

Transition (FIRST) Awards (R29), program project grants (P01), and

center grants (P50).  Applications from minority individuals and

women are encouraged.



MECHANISMS OF SUPPORT



The support mechanisms for grants in this area will be the

traditional investigator-initiated research project grant (R01), the

FIRST award (R29), the program project grant (P01), and the center

grant (P50). As consistent with the aforementioned mechanisms, the

Principal Investigator or program director, as well as any

participating investigators, will plan, direct, and perform the

research.  Applicants for program project grants should contact the

NINDS representative listed below as early as possible in the

planning stages.



RESEARCH OBJECTIVES



Most of the knowledge about the neurological bases of cognitive

function in humans has been learned from studies of central nervous

system trauma or disease in adults.  Certain experiments of nature

seen in neurodevelopmental syndromes affect the central nervous

system in unique ways by producing specific as opposed to generalized

cognitive deficit.  Studies of these disorders, utilizing

neurobiological and behavioral techniques, can be expected to yield

new insights into the localization of cognitive function and the

developmental course of the syndromic cognitive profiles.



An example of this approach is an ongoing study of the biological

basis of language and other cognitive functions in which behavioral,

neuroanatomic, and neurophysiologic studies are being carried out in

patients with Williams syndrome, a rare metabolic disorder.  Children

with this sporadically occurring condition have distinctive facial

characteristics, low birth weight, digestive disorders in infancy,

mental retardation, mild microcephaly, apparent sensitive hearing and

supravalvular aortic stenosis.  A unique behavioral profile has been

identified in these patients in which there is a striking

fractionation of higher cortical functions with linguistic abilities

selectively preserved in the face of severe cognitive deficits.

Studies of the development of language in Williams syndrome children

are being conducted in conjunction with studies of brain structure

and function to address specific questions about the neural substrate

for this unusual neuropsychological profile.  This research, and

similar investigations, will contribute to our understanding of brain

organization for language, and other cognitive functions, using a

specific neurodevelopmental disorder as a model.  Such an approach

provides an unusual opportunity to investigate central issues of

developmental cognitive neuroscience.



In a parallel and possibly related investigation of autism, a

developmental disorder characterized by a profound deficiency in

social knowledge, affect, and communication, a new finding

demonstrates severe impairment in ability to shift attention, a

necessary developmental precursor to social communication.  Evidence

is presented that relates this deficit to neuroanatomic abnormalities

found in the cerebellum of autistic patients in both autopsy and

magnetic resonance imaging (MRI) studies and  to findings of damage

to the parietal lobe of the cerebrum as well.  There is a clear

contrast between autism and Williams syndrome in both behavioral

deficits and neuroanatomic findings.  Most autistic children have

aberrant language development and marked deficits in social

communication and patients with Williams syndrome have spared

linguistic abilities, but general cognitive impairment, and show an

intensity of affect, especially in social interaction.  The basis for

these behavioral distinctions may be the differences in neocerebellar

structures for which the autistic and Williams syndrome subjects show

divergent morphology.



Turner syndrome is a genetic disorder associated with monosomy X that

is characterized by a variety of somatic and cognitive deficiencies.

The classical features of the syndrome include short stature, webbed

neck, a broad chest, cubitus valgus, and failure of gonadal

development.  While females with Turner syndrome typically have

normal verbal IQ scores, they consistently show selective impairments

in tasks that are included in tests of performance IQ.  The results

of most studies present clear impairment in performance in spatial

rotation and left-right discrimination tasks.  Other studies report

deficits in visual-spatial memory, visual-motor coordination, and

motor learning.  Slower motor responses have also been demonstrated

in females with Turner syndrome.  The etiology of these cognitive

deficits is still unknown and there is considerable inter-individual

variation in the neurocognitive phenotype of Turner syndrome.

However, right hemisphere involvement is certainly indicated.

Current studies are addressing the problems of variations in patterns

of cognitive abilities with variations in karyotype in Turner

syndrome, changes in patterns of cognitive abilities in response to

hormone therapies, sources of deficits in social cognition, and

neurophysiological indications (event-related potentials) of altered

brain development in Turner syndrome.



More extensive investigations of the etiologies and effects of these

syndromes and carefully designed studies of other syndromes and

conditions that result in atypical patterns of cognitive deficit are

encouraged.  Examples are various types of hydrocephaly and the

fragile X syndrome.  Because of the multi-leveled

approach--behavioral, neurophysiological, and neuroanatomic--and the

likelihood of small samples,  multidisciplinary and collaborative

studies will be most appropriate.



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 must 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 must 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 must be included in the form PHS 398 in

Section 1-4 of the research plan AND summarized in Section 5, Human

Subjects.  Applicants/offerors 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 must be provided.



For the purpose of this policy, clinical research is defined as 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 review will be deferred until the information is provided.



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.



APPLICATION PROCEDURES



Applications are to be submitted on the grant application form PHS

398 (rev. 9/91) according to instructions contained in the

application kit.  Application kits are available from most

institutional offices of sponsored research and may be obtained from

the Office of Grants Inquiries, Division of Research Grants, National

Institutes of Health, Westwood Building, Room 449, Bethesda, MD

20892, telephone 301-496-7441.



Check "yes" in item 2a on the face sheet of the application and type

"Selective Cognitive Deficits in Neurodevelopmental Disorders."

FIRST 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.  Applicants for the P01 or P50 must use the

application format described in the NINDS pamphlet, NINDS GUIDELINES:

PROGRAM PROJECT AND RESEARCH CENTER GRANTS (Revised June 1992).

Deadlines for the receipt of applications are February 1, June 1, and

October 1.  The completed original application and five exact copies

must be sent or delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



If the application is for a program project or center grant, please

send the original and three copies to the Division of Research

Grants.  An additional two copies sent to the address below would be

useful for expediting the processing of applications for

multidisciplinary efforts.



Applications will be assigned on the basis of established Public

Health Service referral guidelines.  Applications will be judged on

scientific merit and program relevance in accordance with NIH policy

and procedures involving peer review.  An initial review will be made

by an appropriate study section of the Division of Research Grants

for research grants (R01) and FIRST awards (R29), and by an

appropriate institute committee for program projects (P01) and

centers (P50).  A second level of review will be made by an

appropriate national advisory council.



AWARD CRITERIA



Applications assigned to the NINDS will compete for available funds

with all other approved applications assigned to the NINDS.  The

following will be used in making funding decisions:



o  Quality of the proposed project as determined by peer review

o  Availability of funds

o  Program balance among research areas of the announcement



INQUIRIES



For further information regarding this announcement, potential

applicants may write or call:



Sarah H. Broman, Ph.D.

Developmental Neurology Branch

National Institute of Neurological Disorders and Stroke

Federal Building, Room 8C-06

Bethesda, MD  20892

Telephone:  (301) 496-5821



For fiscal and administrative inquiries regarding this announcement,

potential applicants may write or call:



Dwight Mowery

Grants Management Branch

National Institute of Neurological Disorders and Stroke

Federal Building, Room 1004

Bethesda, MD  20892

Telephone:  (301) 496-9231



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic

Assistance Nos. 93.853 and 93.854.  Awards are made under

authorization of the Public Health Service Act, Title IV, Part A

(Public Law 78-410, as amended by Public Law 99-150, 42 USC 241 and

285) and administered under PHS grants policies 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 or Health Systems Agency review.



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