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Sierra Pacific (VISN 21) MIRECC Research

VISN 21 Research
Research Overview

Our research approach is to define risk factors for cognitive decline in older Veterans then to develop and implement novel countermeasures to minimize this to decline. To accomplish this work we have specialized cores that characterize the complexity of older Veterans from the structure and function of their brains to the genetic and neurochemical biology of their sleep and other behavior. Whereas we have divided the research into dementia and PTSD directed programs there are several that overlap. For example the study of health issues related to anxiety and PTSD that put these Veterans at risk for dementia would integrate both domains and is an example of the synergy of studying both disorders in one center. Since the bulk of our clinical work is funded clinical trials and clinical demonstration projects, much of what is described in the education section could be considered applied clinical research.

Research Cores



Research Cores

Neuroimaging Core / Brain Health Registry Core

The goal of the Neuroimaging Core led by Michael Weiner is to use advanced brain imaging technology to study neurodegenerative diseases with the aim of improving diagnosis, progression, and treatment. The MIRECC served to launch what developed in to the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a multisite study of Alzheimer’s Disease and controls and ADNI DOD a study of Veterans with postraumatic stress disorder and traumatic brain injury to study these risk factors for dementia. Additionally the Brain Health Registry Core’s goal is to assist the recruitment of and research reach of veterans who wish to participant in or learn more about brain-related research studies, as well as, assist VA researchers with study recruitment.

Key Personnel: Michael Weiner, M.D., Scott Mackin, Ph.D., Diana Truran-Sacrey, Derek Flenniken.

For more information refer to

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Epidemiology/Risk Factors Core

The focus of epidemiology core led by Kristine Yaffe is the study of cognitive function and dementia in aging populations throughout the United States. The lab aims to improve the outlook of cognitive aging by conducting research focused on identifying risk factors for cognitive impairment, understanding the mechanisms that contribute to cognitive decline, and determining effective strategies to prevent and treat cognitive disorders in older adults. Studies from the lab have led to numerous publications that have increased our understanding of cognitive aging and decline. Results have shown an association between several health and lifestyle related factors and cognitive function, including associations with cardiovascular and metabolic risk factors, kidney function, physical activity, sleep disturbances, depression, and neuropsychological disorders including post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI). Some of the biomarkers that have been studied include inflammatory markers, plasma beta amyloid, markers of cardiovascular health, measures of oxidative stress, structural brain MRI measures, and genetic markers of risk.

Key Personnel: Kristine Yaffe, M.D.

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Precision Medicine Core

The Precision Medicine Core is directly responsive to the priorities of the Veterans Affairs to develop and validate brain and mental health biomarkers among veterans, with specific consideration for depression, anxiety, PTSD and related conditions.  This initiative may be referred to as the “Precision Medicine for Veterans Initiative”, a bipartisan bill passed by the senate in 2019 as the Commander John Scott Hannon Veterans Mental Health Care Improvement Act. Within the Precision Medicine for Veterans Initiative, the methods include brain structure and function measurements such as functional magnetic resonance imaging and electroencephalogram, and their integration with lab-based biomarkers. The Precision Medicine Core serves to integrate, develop and disseminate measurements of functional magnetic resonance imaging, electroencephalogram and demonstrate their utility as biomarkers for making more precise diagnoses and treatment choices.  Biomarkers derived from these measurements show promise for improving the precision with which we can identify subtypes of depression, anxiety and PTSD, and the interventions that will be of most benefit for each subtype. The Precision Medicine Core encompasses multiple types of interventions, including medicines, neuromodulation, novel therapeutics and exploratory approaches such as ketamine and psychedelics. It works closely with the VA Palo Alto Precision Neuromodulation Clinic and the National Clinical TMS program coordinated by the MIRECC at VA Palo Alto. The Precision Medicine Core also has a close academic affiliation with the Stanford Center for Precision Mental Health and Wellness. Precision medicine approaches for mental health are disseminated via webinars and other activities for clinical and educational translation.

Key Personnel: Leanne Williams, Ph.D., Laura Hack, Ph.D.

The Scott Hannon Initiative for Precision Mental Health:

For more information on the academic affiliate: Stanford Center for Precision Mental Health and Wellness

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Neurochemistry Core

The goal of the Neurochemistry Core, led by Drs. Joachim Hallmayer and Ruth O'Hara, is to provide the infrastructure to acquire, assay and analyze the biological and genetic markers being implemented as part of our ongoing MIRECC Investigations. Psychiatric research has underscored the importance of biological and genetic factors in the development of psychopathology. Biological and genetic markers can provide key insights into the etiological basis of psychiatric disorders. They may be differentially expressed based on their past or current environmental exposures. In an era of personalized medicine, biological and genetic markers also have the potential to be critical predictors of which patients may be more vulnerable to specific psychiatric disorders, such as PTSD and Dementia and which patients respond better or worse to specific treatments. This information is essential for providing personalized care to our Veterans with these psychiatric disorders. However, biological and genetic studies require specialized sample acquisition, assay development, data management, quality control procedures, nucleic acid extraction, genotyping, DNA and RNA sequencing with a variety of rapidly-evolving technological platforms, and data quality checks and statistical analysis. The MIRECC Neurochemistry Core provides these services to all ongoing MIRECC Investigations, thus facilitating the successful development of studies and grants as well as supporting the development and training of students and fellows.

Key Personnel: Joachim Hallmayer, M.D., Ruth O’Hara, Ph.D., Tamara Beale, Phoebe Liao

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Chronobiology Core

Properly synchronized circadian rhythms are crucial for healthy cognition, immune function, and metabolism, among other aspects of physical and mental health. The Chronobiology Research Core led by Jamie Zeitzer focuses on the impact of circadian rhythms on the physical and mental health of older adults. Circadian rhythm disruptions in a variety of pathologies (e.g., Alzheimers, Parkinsons, traumatic brain injury, cancer, pain) are explored. Novel pharmacologic and non-pharmacologic interventions for the support and enhancement of circadian rhythms are explored in basic laboratory studies, clinical trials, field studies, and computer modeling. The Chronobiology Research Core is dedicated in its support of improving the health of the aging Veteran.

Key Personnel: Jamie Zeitzer, Ph.D.

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Sleep Core

The Sleep Chronobiology Core led by Andrea Goldstein-Piekarski focuses on cognitive impairments and complications produced by sleep disorders such as insomnia and sleep apnea, along with the overall impact on PTSD. The efficacy of various treatment plans, including behavioral and pharmaceutical, are evaluated for implementation.

Key Personnel: Andrea Goldstein-Piekarski, Ph.D.

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Health Services Core

The health services research core led by Craig Rosen aims to improve processes and outcomes of mental health care for people suffering from post-traumatic stress and other mental disorders. The primary focus is improving the processes and outcomes of VA services for Veterans with PTSD and other psychiatric disorders. A second emphasis is using telemedicine technologies to expand access to effective mental health care.

Key Personnel: Craig Rosen, Ph.D., Mark Greenbaum, Ph.D.

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Women's Mental Health & Aging Core

The Women’s Mental Health and Aging Core, led by Dr. Julie Weitlauf, broadly examines the intersection of physical and mental health risk factors on women Veterans’ health and well-being across the lifespan.  We hope to improve late life health of women Veterans by identifying modifiable risk factors of cognitive decline, morbidity and all-cause mortality in aging women Veterans, and creating/evaluating and implementing non-pharmacologic interventions that may improve or preserve their post-menopausal physical health, mental health, physical and cognitive functioning, and quality of life. Four major categories of inquiry are featured in this core:  1) mortality risks and trends among post-menopausal women Veterans, most particularly the Vietnam war/era woman Veteran; 2) identification and characterization of physical (e.g., smoking, sleep, cardiometabolic disorders) and mental health (e.g., PTSD, depression) on physical health and physical and cognitive functioning among post-menopausal women Veterans; 3) prevalence, risk factors (e.g., including dementia, PTSD, depression and MST exposure), and clinical and health utilization correlates of post-menopausal and late life abuse exposure (e.g., elder abuse) in women Veterans; and 4) the intersection of sexual trauma (e.g., MST exposure), PTSD, and sexual dysfunction (e.g., genito pelvic pain and penetration conditions, female sexual arousal disorder) in post-menopausal women Veterans.   To accomplish the Core’s goals, we work collaborate with Stanford School of Medicine (Obstetrics and Gynecology), the Women’s Health Initiative, and Women’s Health, Veterans Affairs Central Office.

Key Personnel: Julie Weitlauf, Ph.D.  Selected Research Collaborators:  Rachel Kimerling, Ph.D., Victoria Davey, M.P.H., Ph.D., Brad Cannell, Ph.D., Michael LaMonte, Ph.D., Yasmin Cypel, Ph.D., Marcia Stefanick, Ph.D., Katherine Williams, M.D., Leah Millheiser, M.D.

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Biostatistics & Data Management Core

The Biostatistics & Data Management Core provides a comprehensive analytical and computational infrastructure to support the clinical, educational and research missions of the VISN 21 MIRECC. In research program development and implementation, the Core provides study design, operational, and analytical expertise in a wide range of topics including randomized controlled trials (randomization, non-inferiority trials, moderator/mediator analyses, mechanistic trials) and cross-sectional and long-term longitudinal observational studies. The Core possesses a high level of expertise for data in the neurocognitive and genomic domains. The Core is also responsible for maintaining best practices for data management throughout the MIRECC. 

Key Personnel: Laura Lazzeroni, Ph.D., Art Noda, Beatriz Hernandez

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Dementia Research

Neuroimaging of Aging and Dementia

Neuroimaging of dementia is a major focus for the center and is led by Michael Weiner at the San Francisco VAHCS Center for Imaging of Neurodegenerative Diseases (CIND). MIRECC launched what became the Alzheimer’s Disease Neuroimaging Initiative (ADNI), The early vision for the center was that imaging would guide therapy. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) now in its third renewal made feasible multisite imaging and is a standard for therapeutic trials. With the advent of amyloid scans, imaging is now part of standard clinical care and a criterion for entry in certain clinical trials. Essentially people receive treatment before cognitive impairment develops. The problem with this approach is that healthy people must learn they have brain pathology that may lead to dementia. To address this and similar ethical issues related to innovation we now lead a feature in the Journal of Alzheimer’s Disease. A serious problem for clinical trials is recruiting patients and controls so that the Brain Health Registry recruits people willing to be contacted to participate. To explain why imaging is important in AD we have a book on the topic that is summarized here.

Dr. Weiner and his team are also conducting a DoD-funded project that examines the effects of TBI and PTSD on development of Alzheimer’s disease in Vietnam-era Veterans (ADNI DOD). Thus far, this project has enrolled two hundred older Veterans who are studied with clinical/cognitive tests, MRI, and amyloid and tau PET scans. Preliminary results show no effect of prior TBI on cognition or AD biomarkers, raising questions concerning TBI as a risk factor for AD. In addition, participants with PTSD have impaired cognition and more MCI, but lower brain amyloid levels suggesting that PTSD-related cognitive decline is mediated by non-AD mechanisms.

Risk Factors for Dementia and Cognitive Impairment

The evolution of our MIRECC over the past decade reflects improved understanding of factors associated with premature cognitive decline in older Veterans. For example, research by VISN 21 MIRECC investigator Kristine Yaffe and other MIRECC investigators have demonstrated that traumatic brain injury, PTSD, depression, and sleep disturbances, especially sleep apnea, hasten cognitive decline in older adults and Veterans. This knowledge has led to the development of countermeasures to target each risk factor.

  1. PTSD. Using the VA National Patient Care Database, the team found, in a predominately male Veteran cohort, that those diagnosed with PTSD had a nearly two-fold risk of developing dementia compared to those without PTSD. Further investigation will examine if successful treatment of PTSD reduces risk of adverse health outcomes, including dementia.
  2. Traumatic Brain Injury (TBI). As with PTSD, TBI is associated with 60% increase in the risk of developing dementia. Dr. Yaffe also leads the main epidemiology project in the Chronic Effects of Neurotrauma Consortium (CENC) (co-funded by VA and DOD) on mTBI and neurosensory outcomes. The primary objective of this project is to integrate and analyze existing VA healthcare data to study the chronic effects of mild traumatic brain injury (mTBI) on neurodegenerative disease and other comorbidities, and the methods to treat and rehabilitate adverse effects of mTBI, in Veterans over time. Although prior studies have found that moderate and severe TBI are associated with a variety of adverse clinical outcomes, the effects of mTBI are less well understood. This study aims to evaluate the association between mTBI and clinical outcomes focusing on identifying factors associated with resilience and the potential benefits of adequate treatment.
  3. Mood Disorders. While mood disorders are common in Veterans, particularly in those with PTSD, it was not well known how they relate to risk for dementia in patients with PTSD. Dr. Yaffe’s group found that male Veterans with PTSD, dysthymia and depression had an increased dementia risk. Risk of death was also over 40% higher for patients with dysthymia or depression compared to those without either, underscoring the potency of mood disorders for risk in older Veterans with PTSD.
  4. Sleep Disturbance. Sleep disturbance, including insomnia, increased daytime sleepiness and sleep apnea, is increasingly being recognized as a risk factor for cognitive decline. These findings are particularly concerning given that Dr. Yesavage’s recently completed VA MERIT award discovered a higher than expected prevalence of undiagnosed sleep apnea (>50%) in over 200 Vietnam-era Veterans. This high prevalence of sleep apnea is perhaps not surprising given the high rate of obesity among study participants (average BMI was 31).

Traditional Clinical Trials

The MIRECC is a member of the Alzheimer’s Disease Cooperative Studies funded by NIA and contributes by providing Veteran participants for these clinical trials. These include the A4 study mentioned above [18] and the NIMH-funded CITAD study that documented a beneficial effect of citalopram on agitation in AD patients.

Innovative Clinical Trials

Transcranial Magnetic Stimulation (TMS) and Image Guidance

TMS is a method of changing brain functioning without drugs. The first FDA application was for treatment resistant major depression and our center is completing a nine site clinical trial in Veterans with comorbid PTSD and traumatic brain injury. This study (PI Jerome Yesavage) is funded by the cooperative studies program (CSP556). Our center has a pilot study (PI Joseph Cheng) of rTMS in dementia patients. These studies used the standard clinical practice of directing the stimulation using landmarks on the scalp. We are also studying what brain areas are actually stimulated using functional and structural MRI (PI Allyson Rosen).

Exercise in Aging, MCI and Dementia

There are a series of studies in which exercise is used to treat cognitive dysfunction (PI Jennifer Kaci Fairchild). One study combines aerobic exercise and cognitive training to improve cognitive function in Veterans with an increased risk of dementia. Another DOD-funded trial involved 75 Veterans with MCI randomized to either a combined aerobic and resistance + cognitive training or a balance and flexibility + cognitive training intervention. There is now a third study of patients with amnestic MCI using water-based physical activity + cognitive training to determine if similar cognitive effects can be evidenced in those with greater frailty or physical limitations. Additional studies explore genetic and cellular mechanisms underlying the impact of physical exercise on cognitive function (Alzheimer’s Association, Department of Neurology. Additional DoD-funded studies will explore other biological factors such as BDNF as potential predictors of response to exercise therapy.

Telemedicine and Tele-Mental Health

Telemedicine is emerging as an effective means of providing consultation and care to rural residents without access to specialty services. Dr. Yaffe is using this technology to provide access to Veterans in rural areas of California. All patients receive evaluations, diagnoses and treatment recommendations, including antidepressant therapy, cholinesterase inhibitors and counseling about vascular risk factor reduction and behavioral management strategies. Dr. Fairchild has developed a physical exercise + caregiver skills training intervention that is fully deployed through mobile technology. The DOD has funded this RCT of a tablet-based intervention for caregivers of Veterans diagnosed with significant cognitive impairment due to dementia or TBI. Blake Scanlon, a former MIRECC Fellow currently on a CDA, has developed several telemedicine and mobile health interventions for Veteran AD patients and caregivers. He developed these in partnership with the State of California’s Alzheimer’s Center on site at VAPA, directed by MIRECC investigator Jauhtai Joseph Cheng. Dr. Scanlon’s projects use IPads to provide skills training and education to caregivers of dementia patients. Dr. Scanlon and Dr. Yesavage have moved the Geriatric Depression Scale and Dementia Warning Signs to mobile applications.

PTSD Research

Science of Behavior Change Initiative.

The Science of Behavior Change initiative, an accelerated program (administered by NIH Director’s office), led by Lea Williams, is using the personalized medicine approach within a dissemination and team science context. The project aims to determine which brain circuits and behavior are related to emotion regulation and cognitive control and best predict who will adhere to interventions combining problem solving with pharmacotherapy to improve depressed mood and accompanying cognitive and weight management problems. Dr. Williams has been the first (2016) MIRECC investigator to receive this award.

Neuroimaging Directed Therapy in PTSD.

The BRAINS research project, led by Amit Etkin, is a neurobiological investigation, using neuroimaging, of how psychotherapy (Prolonged Exposure) works to treat PTSD. Based on the results of this work, he has received a large grant from Cohen Veterans Bioscience to expand functional MRI experiments to identify pre-treatment predictors of outcome with either Prolonged Exposure or Cognitive Processing Therapy in Veterans receiving treatment in the VA Mental Health Clinic, translate sophisticated circuit models in functional MRI to easy-to-use electroencephalography (EEG) measures, which could be obtained on-site in the clinic, develop tools for directly assessing brain circuit functioning in Veterans by combining non-invasive brain transcranial magnetic stimulation with EEG (TMS/EEG). This allows determination of causal brain circuit deficits in Veterans that track with PTSD and predict psychotherapy outcome. Critically, this also identifies novel rTMS treatment targets for PTSD, and in particular for the specific imaging/EEG-identified likely psychotherapy non-responders (or augmenting the impact of PE and CPT). Through this project, as additional Cohen Veterans Bioscience and NIMH-funded work, Dr. Etkin is identifying multi-modal brain imaging, genetic and blood measure diagnostic markers for PTSD and TBI. This work has been conducted with former VISN 21 MIRECC investigator Dr. Charles Marmar (now Chair of Psychiatry at NYU).

Cognitive Behavioral Treatment of Insomnia in Posttraumatic Stress Disorder.

A VISN 21 MIRECC pilot project by Dr. Neylan led to a successful NIH R34 Grant examining whether CBT-I improves sleep quality in men and women up to age 65 with chronic PTSD. The results show strong efficacy of CBT-I in Veterans with PTSD.

Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance.

This study by Dr. Neylan tests the hypothesis that a hypocretin antagonist (almorexant) is associated with fewer neurocognitive side-effects, as compared to a commonly prescribed hypnotic, zolpidem, and therefore more suitable for use in adults with dementia.

A transdiagnostic research domain criteria study of stress, mood and anxiety.

MIRECC Investigator Dr. Williams was awarded in 2013 an NIMH RFA under the Research Domain Criteria (RDoC), in collaboration with Drs. Yesavage, O’Hara and Etkin. This study focuses on disruptions to brain circuits involved in fear processes relevant to PTSD, and that are also present in overlapping anxiety and mood disorders. This project uses functional neuroimaging, cognitive behavioral measures and individual symptom ratings to develop a new taxonomic model based on natural variation in brain circuits supporting fear processing, and related aspects of cognitive processing, without initial reference to their traditional diagnosis. This project provides a foundation for a new growth area focused around translational precision medicine for veteran mental health.

Trial of mobile and online apps for PTSD and related mood and anxiety disorders.

In this study, Dr. Williams draws on a precision medicine and RDoC. Patients with PTSD and related mood and anxiety disorders are randomized to receive an online intervention known as “Good Days Ahead”, versus waitlist, for 12 weeks. After this interval they are offered intervention with multiple online apps according to individualized preference and symptom profile. These apps include PTSD Coach. Outcomes are assessed using both symptom and daily function criteria.

Health Services

Services Challenges for Effective Care Delivery to PTSD Patients (Drs. C. Rosen and Weitlauf)

Among several studies conducted by the Health Services Core, the following highlight factors associated with functional outcomes and barriers to treatment.

More PTSD care is not better if the care is ineffective. A recent trial led by Dr. C. Rosen tested whether telephone care management (TCM) improved Veterans’ retention in outpatient PTSD care. As expected TCM increased the number of visits during the three months of intervention from 4.2 in usual care to 6.0 in TCM. However, this did not translate into increased improvement in clinical outcomes over the 12 months of the study. The investigators noted that few participants received an evidence-based treatment for PTSD. This group previously showed that the dose of psychotherapy that Veterans receive (without determining the type of psychotherapy delivered) is a poor indicator of quality of care for PTSD.

Clinic organization impacts use of evidence-based psychotherapies (EBPs) for PTSD. VHA has trained over 6,000 clinicians in EBPS for PTSD, but reach of these treatments remains low. Dr. C. Rosen and colleagues conducted 96 staff interviews to compare organizational characteristics of ten PTSD specialty clinics with high, medium, and low use of EBPs. Results of these interviews showed that all high-reach clinics were organized around a primary mission of delivering time-limited EBPs for PTSD. In these clinics, leaders and staff established operational policies and team cultures that supported EBP delivery. In contrast, low reach teams provided a wide range of services for diverse care needs of Veterans with PTSD, and clinic processes and norms did not necessarily facilitate EBP provision. Dr. Rosen also led a workgroup that synthesized results of 19 studies on implementation of EBPs for PTSD in VA.

PTSD as a Barrier to Women’s Preventive Health Care. Dr. Weitlauf has addressed ways in which PTSD and related mental health conditions may interfere with women Veterans’ timely receipt of preventive healthcare. Studies conducted by this group [35-37] suggest that active symptoms of PTSD, particularly symptoms of hyperarousal, were associated with traumatic reactions to the pelvic examination for cervical cancer. These studies have provided a strong empirical foundation for trauma-informed women’s health care in VA, and was used extensively by the American Congress of Obstetrics and Gynecology’s guiding documents (Committee Opinion of the Committee on Underserved Populations) related to evidence-based women’s health care for Veterans.

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