Neuroimaging to Understand Delusions and Hallucinations in Alzheimer's

Ryan Darby, MD
Vanderbilt University (Nashville, TN)


Bradford Dickerson, MD
Massachusetts General Hospital, Harvard Medical School (Boston, MA)
Michael Fox, MD, PhD
Beth Israel Deaconess Medical Center, Harvard Medical School (Boston. MA)
Year Awarded:
Grant Duration:
July 1, 2017 to August 30, 2020
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Postdoctoral Fellowship
Award Region:
US Southern
Ryan Darby, MD

Neurobiology of Psychosis in Alzheimer's Disease


Delusions and hallucinations commonly occur in Alzheimer’s disease (AD) and related dementias, such as Lewy Body Dementia (LBD), causing considerable distress for patients and families.  The goal of this research is to use different types of brain scans and behavioral tests to determine why these symptoms arise.  Our hope is that understanding why delusions and hallucinations occur will help lead to new treatments for these symptoms in the future. 


The goal of this research is to find an explanation for delusions and hallucinations, symptoms which commonly occur in AD and LBD. We are testing the hypothesis that patients who develop these symptoms may have abnormal monitoring of their beliefs and perceptions.  Patients who do not monitor their beliefs appropriately may develop delusions, while patients who do not monitor their perceptions appropriately may be more likely to develop hallucinations.  We plan to test patients with delusions and hallucinations using tasks designed to measure self-monitoring of beliefs and perceptions.  We also plan to get brain scans on patients to determine if abnormalities in specific brain regions occur in patients with hallucinations and delusions, compared to patients without these symptoms.  We think that the monitoring problems, and brain imaging differences, might be different between patients with hallucinations and those with delusions.  This work will hopefully help us to understand why these symptoms occur.  It might also lead to new treatments, which will prove especially helpful if it turns out we need to be treating hallucinations and delusions differently from one another.

About the Researcher

Ryan Darby is an assistant professor of neurology at Vanderbilt University.  He received his undergraduate degree from Princeton University in psychology and neuroscience, and his medical degree from Vanderbilt University.  He trained in neurology at Massachusetts General Hospital and Brigham and Women's Hospital as part of the Partners Neurology/Harvard Medical School program.  He then received the Sidney R. Baer, Jr. Research Fellowship in Clinical Neurosciences at the Beth Israel Deaconess Medical Center.  He simultaneously completed a clinical fellowship in behavioral neurology and neuropsychiatry at Beth Israel Deaconess Medical Center, Massachusetts General Hospital, and McLean Psychiatric Hospital in Boston.  He currently sees patients in the Frontotemporal Dementia Clinic and Neuro-psychosis Clinic in the Department of Neurology at Vanderbilt University Medical Center.

Dr. Darby is interested in patients with symptoms at the border zone between neurology and psychiatry.  Both neurological and psychiatric patients can share similar symptoms, including delusions, hallucinations, social behavioral disorders, and disorders of volition and agency.  This suggests that these symptoms may share a common pathway across different diseases.  He uses a combination of advanced neuroimaging techniques and behavioral testing to understand the underlying neurobiology of these symptoms at the network level.  His work has lent insight into how brain dysfunction can lead to delusions and hallucinations in patients with focal brain lesions, as well as patients with dementia.  His ultimate hope is that this research will translate into new treatment targets for patients with very few therapeutic options.  This includes new types of drugs, as well as the possibility of using noninvasive brain stimulation to alter specific networks in the brain.

Dr. Darby has received numerous awards for his research, including the Stanley Cobb Award from the Boston Society for Neurology and Psychiatry, the Young Investigator Award from the American Neuropsychiatric Association, and the S. Weir Mitchell Award for Outstanding Early Career Investigator from the American Academy of Neurology.  His work is generously funded by the Sidney R. Baer, Jr Foundation, the Alzheimer's Association, and the BrightFocus Foundation.

Personal Story

I first fell in love with behavioral neurology and neuropsychiatry during my cognitive neuroscience course my sophomore year of college.  After reading about the fascinating presentations of patients with alien limb syndrome, neglect, and Capgras syndrome, I knew that I wanted to devote my life to treating these patients.  Throughout my training, I found myself intrigued when patients with neurological diseases presented with complex behavioral or psychiatric symptoms.  These experiences have reinforced my belief that neurology is important not only because of disease processes, but because these processes act on the person--the memories, thoughts, emotions, and personality traits that make us who we are.  These symptoms are often the most debilitating for patients and families. However, I discovered that our understanding of the neurobiology for many complex behavioral syndromes is lacking, limiting treatment options.  I hope that my research can begin to find answers for these important questions.

I am incredibly thankful to the BrightFocus Foundation and their donors for providing me with an opportunity to study dementia patients with hallucinations and delusions.  The grant will provide me with the training and resources to begin my career, which is aimed both at taking care of dementia patients with these symptoms, and pursuing research to understand these symptoms better.  It is only through the generous support of the BrightFocus Foundation that I have the chance to pursue these passions.  I hope that this work will form the foundation for a career in advancing our treatments for patients with dementia.


Tetreault, A.M., Phan, T., Orlando, D., Lyu, I., Kang, H., Landman, B., Darby, R.R. and Alzheimer’s Disease Neuroimaging Initiative, 2020. Network localization of clinical, cognitive, and neuropsychiatric symptoms in Alzheimer’s disease. Brain, 143(4), pp.1249-1260. PubMed Icon Google Scholar Icon

Tetreault AM, Phan T, Orlando D, Lyu I, Kang H, Landman B, Darby RR. Network localization of clinical, cognitive, and neuropsychiatric symptoms in Alzheimer’s disease. Brain. 2020 Mar 16.
PMID: 32176777 PubMed Icon Google Scholar Icon

Darby RR. A network-based response to the two-factor theory of delusion formation. Cogn Neuropsychiatry. 2019 May;24(3):178-182. doi: 10.1080/13546805.2019.1606709. Epub 2019 Apr 16. PubMed PMID: 30987557 PubMed Icon Google Scholar Icon

Padmanabhan JL, Cooke D, Joutsa J, Siddiqi SH, Ferguson M, Darby RR, Soussand L, Horn A, Kim NY, Voss JL, Naidech AM, Brodtmann A, Egorova N, Gozzi S, Phan TG, Corbetta M, Grafman J, Fox MD. A Human Depression Circuit Derived From Focal Brain Lesions. Biol Psychiatry. 2019 Nov 15;86(10):749-758. doi: 10.1016/j.biopsych.2019.07.023. Epub 2019 Aug 2. PubMed PMID: 31561861 PubMed Icon Google Scholar Icon

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