RELEASE DATE:  May 12, 2003


EXPIRATION DATE:  April 30, 2005, unless reissued. 

National Institute of Neurological Disorders and Stroke (NINDS)



o Purpose of the PA
o Research Objectives
o Mechanisms of Support
o Funds Available 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations


The National Institute of Neurological Disorders and Stroke (NINDS) invites 
applications for research programs designed to advance our understanding of 
the neurobiological mechanisms and epidemiology of Complex Regional Pain 
Syndrome (CRPS)/Reflex Sympathetic Dystrophy (RSD). A major goal of this 
initiative is to facilitate the development of novel collaborative research 
programs among physiologists, neuroscientists, behavioral neuroscientists, 
imaging specialists and clinicians in order to develop integrative research 
programs to accelerate progress in CRPS/RSD research. This PA is intended to 
encourage cross-disciplinary research focused on a mechanism-based diagnostic 
classification of CRPS/RSD, which might lead to mechanism-based therapeutic 
strategy for this chronic condition.



Complex Regional Pain Syndrome (CRPS), formerly known as Reflex Sympathetic 
Dystrophy (RSD), is a chronic debilitating condition characterized by severe 
burning pain, pathological changes in bone and skin, excessive sweating, 
tissue swelling, and extreme sensitivity to touch.  It is estimated that 
between 2-5% of individuals with peripheral nerve injury, and up to 20% of 
those with paralysis on one side of the body, will suffer from RSD. Though 
highly debated, the syndrome is thought to evolve through three stages 
(acute, dystrophic, atrophic), each marked by progressive pain and physical 
changes in the skin, muscles, joints and bones. CRPS/RSD can affect both 
genders and all ages (including children), although it is thought to be more 
common between the ages of 40 and 60 and may be more frequent in women. The 
cause of CRPS/RSD is unknown, and most treatments for the symptoms 
experienced by CRPS/RSD patients are not optimal.

Current theories of the potential mechanisms of CRPS/RSD are based on the 
notion that a pathologic sympathetically maintained reflex arc is involved in 
the generation and maintenance of pain. Although there have been many 
anecdotal reports of pain relief after local anesthetic or pharmacological 
sympathetic ganglion blockade, the sympathetic nervous system is not involved 
in every case. Moreover, a reflex arc has not been demonstrated in CRPS/RSD. 
CRPS/RSD has been subdivided into type 1 and type 2. The clinical features 
are similar for both subtypes and the distinguishing feature is the presence 
of a major peripheral nerve injury in patients with type 2. The incidence of 
CRPS/RSD type 1 is high in patients with stroke, spinal cord injury, multiple 
sclerosis and many other neurological disorders. The occurrence of CRPS/RSD 
is related to the intensity of the motor deficit, the spasticity and the 
sensory deficits in these patients. Despite recognition of the comorbidity of 
CRPS/RSD with other neurological disorders and the disabling consequences of 
the condition, a clear understanding of the disorder is still lacking. This 
paucity of information often results in inappropriate treatment modalities 
and delay in treatment affecting long term recovery of CRPS/RSD patients. 


CRPS/RSD is thought to be a form of central hypersensitization in which the 
central nervous system overreacts to the incoming noxious stimuli. Several 
plausible theories have been advanced to explain the CRPS/RSD disorder, 
including the formation of dysfunctional synapses after peripheral nerve 
injury, sensitization of peripheral sensory receptors, abnormal discharges in 
sympathetic and nociceptive afferent nerves after trauma, improper 
communication with the central nervous system through damaged and necrotic 
nerve endings, spontaneous electrical discharges, and increased 
responsiveness to high-threshold and slow conducting C-fibers. The disorder 
could result from peripheral afferent mechanisms, peripheral efferent 
mechanisms, central mechanisms (including psychological mechanisms), or 
combinations of more than one mechanism. While theories abound, there has 
been a paucity of research to elucidate the pathophysiology of CRPS/RSD. 

CRPS/RSD is characterized in the acute stage by symptoms of regional 
inflammation. This inflammatory response is also seen in the rodent chronic 
nerve constriction injury model that is produced by loose ligation of the 
sciatic nerve. Inflammation could be caused by cellular hypoxia and 
diminished oxygen utilization. In the chronic stage, CRPS/RSD is manifested 
as a more neuropathy-like disorder. It has been hypothesized that this 
alteration results from the development of sensitization or plasticity during 
the early inflammation phase of the disorder.

Impairments of sympathetic vasoconstrictor activity and other autonomic 
functions have been observed in CRPS patients. Pain is maintained by 
sympathetic efferent innervation or by supersensitivity to circulating 
catecholamines and can be relieved by a sympatholytic procedure such as 
ganglionic nerve blockade or pharmacological intervention. It is not yet 
known how direct and indirect effects in the manifestation of pain are 

Clinical examination and quantitative assessment of neurologic function in 
CRPS/RSD reveal abnormalities of spinothalamic, trigemino-thalamic, and 
corticospinal function, suggesting medullary dysfunction in RSD/CPRS. 
Moreover, recent imaging studies have suggested that prefrontal abnormalities 
may alter pain consciousness in CRPS/RSD patients. The development and 
maintenance of the disorder may be influenced by psychological factors such 
as anxiety, depression and life stressors.  

The clinical manifestations of CRPS/RSD are widespread throughout the body 
with inflammation associated with increased temperature, edema, redness, pain 
and loss of function. The mediators of one or more of these manifestations 
including various neuropeptides, cytokines, eicosanoids, substance P, and 
steroids offer various classes of pharmaceutical compounds as potential 
therapeutic agents for development and clinical testing in this disease. 

Future research on the mechanisms of CRPS/RSD must be much better integrated 
with clinical observations in human patients. Design of both animal and human 
models must be more closely integrated with each other and with the clinic in 
order to focus the scientific questions, the formulation of hypotheses and 
the experimental approaches. Interdisciplinary and multidisciplinary 
approaches could help uncover the pathophysiology of CRPS/RSD and improve 
treatment of this disorder. The present PA seeks to achieve this overall goal 
by creating basic research programs in association with the clinic in which 
the CRPS/RSD patients are diagnosed and treated. These research programs 
would require the involvement of experts from a wide variety of clinical and 
basic research areas, including neuroimaging, pain, neural plasticity, the 
sympathetic nervous system and the immune system. Examples of potential 
research questions would include but not be limited to issues such as: 

o Development and validation of animal models that recapitulate the unique 
features of CRPS/RSD 

o Characterization of neurobiological mechanisms of CRPS/RSD including 
peripheral afferent and efferent mechanisms, central mechanisms and factors 
that influence these processes

o Studies of neurotransmitter systems and neuropeptides involved in CRPS/RSD

o Studies of signaling mechanisms in CRPS/RSD

o Research on the immune system mechanisms and autoimmune inflammatory 
processes in CRPS/RSD (for example, role of glial cell activation and 
cytokine release in central and peripheral pathophysiology of CRPS/RSD)

o Studies of the role of estrogen (genomic and non-genomic effects) in the 
pathophysiology of CRPS/RSD
o Studies that investigate the correlation between the clinical 
manifestations of CRPS and the underlying neurobiological and neurochemical 
mechanisms that will provide the means to measure the effect of therapeutic 
interventions on specific targets in clinical trials

o Translational studies that integrate the research paradigms validated in 
animal and human models with clinical research on patients (development and 
application of clinically relevant assays of nociception in human studies) 

o Studies of gene and protein expression profiling in models of CRPS/RSD

o Development of new CRPS/RSD therapies for prospective clinical trials

o Neuroimaging studies of nervous system activation in CRPS/RSD 

o Comparison of brain activation studies between normal pain as compared to 
pain experienced by RSD/CRPS patients (allodynia, hyperalgesia) in order to 
identify which regions of the nervous system are abnormally activated in this 
disease state 

o Studies of the effect of psychological stress on CRPS/RSD in the context of 
disease progression and treatment response

o Development of standardized diagnostic criteria for CRPS/RSD

o Assessment of risk factors and incidence of CRPS/RSD through 
epidemiological studies 

o Studies of disease mechanisms that give rise to CRPS/RSD in susceptible 

o Studies that assess the effect of gender, age and co-morbid neurological 
conditions on the development and maintenance of CRPS/RSD


Though this solicitation, the NINDS encourages a broad analysis of the 
experience of pain and recommend that an integrated approach be adopted 
toward the development of new treatment modalities. Research programs that 
combine anatomical, physiological, psychological, or molecular approaches are 
needed to accelerate progress in Complex Regional Pain Syndrome (CPRS)/Reflex 
Sympathetic Dystrophy (RSD) research. This PA initiative will encourage 
applications to study CRPS/RSD in the context of 1) disease mechanisms, 2) 
CRPS/RSD model systems, 3) epidemiology, 4) diagnostic criteria, 5) 
integration between basic research and clinical research, and 6) therapy.


This PA will use the National Institute of Health (R01) award mechanism.  As 
an applicant, you will be solely responsible for planning, directing, and 
executing the proposed project. This PA uses just-in-time concepts.  It also 
uses the modular as well as the non-modular budgeting formats (see  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications. Relevant applications and amended 
applications are welcome throughout the duration of this PA (2 years).


NINDS has set aside one million dollars (total costs), in addition to funds 
available for applications sent in response to this program announcement that 
score within the NINDS payline (see NINDS Funding Strategy, depending on the 
overall scientific merit of the application and the availability of funds 
throughout the duration of this solicitation (2 years).

Within the context of this PA, the National Center for Medical Rehabilitation 
Research in NICHD would welcome applications that address the biomedical and 
sociobehavioral consequences of chronic conditions, especially in the area of 
rehabilitative treatments for pain, sensory dysfunction, and motor 


You may submit (an) application(s) if your institution has any of the 
following characteristics:

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign


Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.


We encourage your inquiries concerning this PA and welcome the opportunity 
answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Emmeline Edwards, Ph.D.
Systems and Cognitive Neuroscience
National Institute of Neurological Disorders and Stroke 
6001 Executive Blvd., Room 2109
Bethesda, MD  20892-9521
Telephone:  (301) 496-9964
FAX: (301) 402-2060 

Linda Porter, Ph.D.
Systems and Cognitive Neuroscience
National Institute of Neurological Disorders and Stroke 
6001 Executive Blvd., Room 2113
Bethesda, MD  20892-9521
Telephone:  (301) 496-9964
FAX:  (301) 402-2060 

o Direct your questions about financial or grants management matters to:

Aaron Kinchen
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd., Room 3271
Bethesda, MD  20892
Telephone:  (301) 496-7386
FAX:  (301) 402-0219 


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at  Application 
deadlines are also indicated in the PHS 398 application kit.

up to $250,000 per year in direct costs must be submitted in a modular grant 
format.  The modular grant format simplifies the preparation of the budget in 
these applications by limiting the level of budgetary detail.  Applicants 
request direct costs in $25,000 modules.  Section C of the research grant 
application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at

Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:

1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
3) Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five signed photocopies in one 
package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

APPLICATION PROCESSING: Applications must be received by or mailed before the 
receipt dates described at  The CSR will 
not accept any application in response to this PA that is essentially the 
same as one currently pending initial review unless the applicant withdraws 
the pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude the 
submission of a substantial revision of an application already reviewed, but 
such application must include an Introduction addressing the previous 

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.


Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
( will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the appropriate national advisory council 
or board


The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to discuss the following 
aspects of your application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score.  For example, you may propose to carry out 
important work that by its nature is not innovative but is essential to move 
a field forward.

(1) SIGNIFICANCE:  Does your study address an important problem? If the aims 
of your application are achieved, how do they advance scientific knowledge?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

(2) APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Do you acknowledge potential problem areas and consider alternative 

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project challenge 
existing paradigms or develop new methodologies or technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

PROTECTIONS:  The adequacy of the proposed protection for humans, animals, or 
the environment, to the extent they may be adversely affected by the project 
proposed in the application.

INCLUSION:  The adequacy of plans to include subjects from both genders, all 
racial and ethnic groups (and subgroups), and children as appropriate for the 
scientific goals of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria included in the 
section on Federal Citations, below)

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.


Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities


HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained.

the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of 
the research. This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts 
on October 9, 2001 (
02-001.html); a complete copy of the updated Guidelines are available at
.htm.  The amended policy incorporates: the use of an NIH definition of 
clinical research; updated racial and ethnic categories in compliance with 
the new OMB standards; clarification of language governing NIH-defined Phase 
III clinical trials consistent with the new PHS Form 398; and updated roles 
and responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; 
and b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 

The NIH maintains a policy that children (i.e., individuals under the age of 
21) must be included in all human subjects research, conducted or supported 
by the NIH, unless there are scientific and ethical reasons not to include 
them. This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at

policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at

Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application.  In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

Department of Health and Human Services (DHHS) issued final modification to 
the "Standards for Privacy of Individually Identifiable Health Information", 
the "Privacy Rule," on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR).  Those who must comply with the Privacy Rule (classified 
under the Rule as "covered entities") must do so by April 14, 2003 (with the 
exception of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution.  The OCR website 
( provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on "Am I a covered 
entity?"  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of "Healthy 
People 2010," a PHS-led national activity for setting priority areas.  This 
RFA is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.  

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