NIH/NIMH – Novel Mechanism Research on Neuropsychiatric Symptoms (NPS) in Alzheimer’s Dementia (R01, R21 Clinical Trial Optional)

October 1, 2018 by School of Medicine Webmaster

The following description was taken from the R01 version of this FOA.

The goal of this Funding Opportunity Announcement (FOA) is to encourage biomedical, behavioral and social sciences research that will enhance knowledge of mechanisms underlying neuropsychiatric symptoms (NPS) in persons with Alzheimer’s disease (AD) or Alzheimer’s disease-related dementias (ADRD) so as to enable novel treatment development.

NPS, or Behavioral and Psychological Symptoms of Dementia (BPSD), include aggression, psychosis, anxiety, apathy, depression, agitation, sleep disturbances and wandering, and can be significant challenges to the care and treatment of people with dementia. These symptoms lead to accelerated declines in both functional abilities and may lead to earlier nursing home placement. Currently, few pharmacological treatments are available. In addition, there is a need to understand behavioral and environmental targets to further refine and develop promising behavioral treatments for these disorders.

The demand for novel treatment approaches highlights the importance of identifying and dealing with the underlying causes of these symptoms among older adults with dementia. There is thus an urgent need to advance the mechanistic understanding of these problems to identify new treatment targets.  The National Plan to Address Alzheimer’s Disease specifically calls for the development of better treatments for the behavioral and psychiatric complications due to the disease..

In May, 2017, NIMH and  the National Institute on Aging (NIA) held a workshop to assess the current state of research on neuropsychiatric symptoms associated with dementia as well as opportunities and strategies for developing better treatments for NPS NIMH » Novel Approaches to Understanding the Mechanisms of the Neuorpsychiatric Symptoms in Alzheimer’s and Advancing Therapy Development. The workshop participants agreed that, as a heuristic framework, personal, caregiver, and environmental factors should all be examined as potential targets for treatment development in this area.  Particularly crucial to that effort is a better understanding of the neural mechanisms underlying the development of NPS in dementia.  If successful, the research to be conducted will clarify both behavioral and biological mechanisms associated with NPS.  It may provide clues to novel intervention targets for alleviating some of the burden associated with these symptoms, or may suggest which intervention or prevention strategies might be optimal across the intervention spectrum.

Research Objectives

This funding opportunity is intended to support research designed to identify the neurobiological, behavioral, and social mechanisms underlying NPS in AD/ADRD in order to deepen our understanding of the pathways and contextual factors involved. Research that assesses NPS dimensionally, integrating across multiple levels of analysis and employing cutting-edge methodology from such fields as cognitive and affective neuroscience, neuroimaging, neurophysiology, gene expression and epigenetics, and behavioral intervention research is encouraged. Both basic neuroscience work examining models of NPS and translational approaches to understanding neural circuits involved in the expression of NPS are encouraged.

Research that seeks to clarify mechanism of action of evidence-based treatments or proposes to examine potential biomarkers of treatment response is encouraged and will be accepted if it fits under the NIH mechanistic clinical trials framework. The research supported under this FOA is expected to advance mechanistic understanding of neuropsychiatric syndromes in AD/ADRD and underlying neurobiology that will advance the field. Such findings may identify modifiable targets for further intervention development in this area.

Some portion of NPS stem from problems in recognizing and rendering appropriate care for treatable issues in persons with limited cognitive and communicative abilities. Issues, such as medical comorbidities, physical pain/discomfort, hydration, boredom/socialization, etc., can become “unmet needs” that find expression in the form of NPS if not recognized and properly addressed. Research is needed to establish underlying causes for NPS symptoms resulting from these “unmet needs” in order to develop and implement effective methods for screening and handling such issues across the spectrum of typical care settings.

The use of constructs from NIMH’s Research Domain Criteria (RDoC) initiative ( ), or of RDoC-compatible approaches, in assessing NPS or associated factors, such as emotion processing, other component aspects of mental disorders, and/or related domains of brain function, is encouraged.   RDoC has defined a set of  dimensional constructs  that may be useful in this research. These constructs are organized according to five domains of brain functioning (negative valence systems, positive valence systems, cognitive systems, arousal/regulatory systems, and systems for social processes). Research on RDoC constructs should employ assessment methods appropriate for each construct of interest and the assessment methods are expected to converge on the construct from at least two levels of analysis. RDoC units of analysis (potential levels of measurement) include genes, molecules, cells, circuits, physiology, behavior, and self-report. Details about RDoC constructs and units of analysis can be found here . Although the structure of the RDoC matrix suggests boundaries among constructs, given the densely integrated and interconnected nature of the brain’s circuits, it is understood that the constructs function interactively and that promising empirical approaches to an RDoC-based analysis of NPS and/or associated factors may involve examining intersections among constructs. Applicants may propose to examine dimensional constructs that do not appear in the NIMH RDoC matrices as long as there is strong theoretical support for their relevance to a mechanistic understanding of NPS. Applicants should be able to cite substantial evidence for the validity of such constructs, and to indicate strong theoretical support that the construct maps onto a specific biological system, such as a brain circuit or physiological pathway, thought to be involved in specific aspects of NPS.

With respect to assessing psychopathology or mental disorder, an RDoC approach encourages taking a dimensional perspective, and concentrating on aspects of behavior and brain function that span a range from intact to gradations of impairment, independent of diagnosis. Thus, in such an approach, recruitment and eligibility of study participants need not be determined on the basis of traditional diagnostic categories, but should instead be based on criteria that result in a sample that is optimized to study the clinical phenomena of interest over their full range of variability. Such an emphasis on understanding the full dimensionality of neurobehavioral functioning generally precludes simple, dichotomous designs comparing patients versus controls. Under this FOA, if an RDoC or other dimensional construct is proposed to serve as the primary variable representing psychopathology (as opposed to using a diagnostic characterization), the study design and sampling plan must be such as to assure that an adequate number of individuals assessed as falling within the more severely impaired ranges of that dimension will be included in the study.

Areas of research interest for this funding opportunity announcement include, but are not limited to:

  • Improved understanding of the neurobiological and behavioral mechanisms underlying NPS syndromes in AD and related dementias;
  • Assessments of neural circuits involved in apathy or other NPS in AD/ADRD, as compared to other neuropsychiatric diseases;
  • Examination of circadian rhythm disruptions as related to the manifestation of agitation and other disruptive behaviors;
  • Defining and clarifying specific irregularities of perception, cognition, emotion processing or other basic psychological functions, and their neurobiological correlates, that are associated with particular forms of NPS in persons with AD/ADRD;
  • Evaluation of differences in the brain circuits or cortical areas recruited during emotional challenge or cognitive task performance in individuals with MCI or AD/ADRD, and whether such differences predict vulnerability to or resilience against onset of NPS;
  • Examination of the role of prior psychiatric disorder or other historical factors as influences on the development or expression of NPS syndromes in AD/ADRD;
  • Utility of passive sensing technology to more precisely and comprehensively characterize the behavioral patterns, circadian and other neurophysiological fluctuations, environmental exposures, and like factors associated with NPS in persons with AD/ADRD;
  • Identification and regulation of clinically relevant brain circuits and/or neurobiological systems that may be targets for treatment development or mechanisms of NPS pathophysiology;
  • Development of outcome measures that are clinically meaningful to AD/ADRD patients and caregivers;
  • Development of clinically useful biomarkers to predict NPS onset and/or treatment outcome;
  • Utility of computational approaches to identify predictive and/or explanatory patterns of factors associated with NPS in available extensive datasets;
  • Elucidation, refinement and implementation of criteria for distinguishing subjects with NPS syndromes that are not resolvable via appropriate attention to their unmet needs.

Examples of studies that are not responsive to this FOA and will not be reviewed include the following:

  • Applications that assess potential NPS mechanisms at only a single level of observation and analysis (i.e., without combining multiple levels/methods such as genetic, cellular, brain circuit, physiological, behavioral, self-report);
  • Applications that propose clinical trials of the safety, efficacy, effectiveness, management or implementation of potential therapies for NPS.

This FOA will support mechanistic clinical trials, defined by the NIH to include studies designed to understand a biological or behavioral process, or the pathophysiology of a disease process, through a manipulation of that process, or to understand the mechanism of action of an intervention (see NOT-OD-15-015).

This funding opportunity announcement will not accept studies whose purpose is to evaluate safety; clinical efficacy, effectiveness, and management; and/or implementation of new interventions. See the NIMH Clinical Trials website (link to for a listing of current NIMH CT FOAs that will support such studies. Also see in particular, the section of that website titled “Limited NIMH Participation on Parent Research Grant FOAs for Clinical Trials” for further details about submission of mechanistic clinical trials to NIMH.

If the proposed research involves neuroimaging methods, applicants are encouraged to incorporate use of protocols from the Human Connectome Project, assuming that the research addresses constructs that have been previously examined in the Human Connectome Project and that such protocols are available to the investigator.

Applicants are strongly encouraged to review the Notice on enhancing the reproducibility of NIH-supported research through rigor and transparency (NOT-OD-15-103), and to incorporate appropriate features into the proposed research plans. NIMH has published guidelines for reporting elements of rigor in experimental design in applications (NOT-MH-14-004), and examples of critical elements for a well-designed study are summarized on the NIMH website (

Deadlines:  October 19, 2018 (letters of intent); November 19, 2018 and March 19, 2019 (full proposals)


Filed Under: Funding Opportunities