2021 Awardees
We had a large number of applications for this award and appreciate the partnership with ICTS in the application review process.
The role of ketones in protecting the brain and heart during ultra-short caloric restriction
550,000 people in the U.S. suffer from cardiac arrest (CA) each year. Only ~175,000 survive CA and only ~17,500 of survivors have good outcomes because survivors often develop severe neurological deficits. While coronary artery disease (CAD) is the most common cause of sudden CA, a multitude of other factors also may cause and/or contribute to such circulatory failure. Non- CAD mechanisms of CA include respiratory failure, hemorrhagic shock, inherited and acquired cardiomyopathies, toxic-metabolic insults, drug overdose, and other causes. Only ~175,000 survive CA and only ~17,500 of survivors have good outcomes because survivors often develop severe neurological deficits. Thus, there is a strong need for development of novel treatments to improve survival and outcome for CA patients, including both cardioprotection and neuroprotection.
For almost a century, caloric restriction (CR) has been shown to have numerous health benefits in humans and animals. CR, defined as reduction in calorie intake, can involve daily, lifelong adherence to strict diet or intermittent fasting. Most CR research has focused on long-term (chronic) CR, adherence to which can be challenging. Thus, there is significant clinical interest in short-term CR, which can last from days to months and has also been shown to have numerous neuroprotective and cardioprotective benefits.
Additionally, there has recently been widespread interest in the ketogenic diet (KD), a high fat, adequate protein, and low carbohydrate diet that utilizes ketone bodies as the primary energy source in the body. There is significant evidence to suggest that KD can provide benefits such as protecting the heart against aging, resistance of the heart to CA, and neuroprotection after CA. However, the effectiveness of KD is still a current topic of debate in the medical literature. Therefore, understanding the mechanisms underlying interventions such as CR and KD is crucial for informing clinical decision making regarding which of these health interventions will be most beneficial to each individual patient.
We have recently discovered that ultra-short CR lasting just 14 hours improves survival and neurological outcome after CA and cardiopulmonary resuscitation. Such acute CR also leads to better brain tissue oxygen saturation, suggesting that metabolism in the brain is more efficient and likely one reason for the neuroprotective benefits. Moreover, this acute CR leads to ketosis, which we hypothesize is one of the mechanisms of its benefits.
Thus, CR and ketosis can alter cerebral blood flow (CBF) and cerebral metabolism. In addition, pulsatility of blood flow can affect tone of blood vessels and uptake and metabolism of oxygen, as well as impact outcome in patients with cardiovascular impairment. Using our highspeed multimodal monitoring platform, we can quantify ketosis-induced changes in CBF, brain oxygenation, metabolism, and cerebral and peripheral pulsatility in vivo. We will also use metabolomics techniques to analyze the blood of CR and KD rats to identify which components of the blood are most significantly modified by these interventions. We hypothesize that ketosis (via ACR, KD, or acute ketone injection) enhances cardioprotection and neuroprotection post-CA, via alteration of perfusion, metabolism, and pulsatility. This proposal has immense potential to provide the groundwork for future clinical-translational studies that may transform the way we treat patients either at-risk of CA or patients who have suffered CA, utilizing affordable and easily implementable approaches revolving around integrative medicine to provide acute metabolic modification for neuroprotection and cardioprotection.
Harnessing the power of positive connections to reduce loneliness in college students
Loneliness is the unpleasant feeling that can arise from reduced social connectedness with others. Loneliness has important implications for health and well-being, predicting greater risk for mortality, cognitive decline, depression, and suicidality. Emerging adulthood, the developmental phase spanning the years between 18 and 23, is a crucial developmental and transitional period, during which people explore their identities and grow in autonomy while simultaneously facing challenges in peer relationships, as well as contending with stressors in the domains of career, academics, and finances. This period is also a time in which individuals are most vulnerable for developing psychopathology, such as depression and anxiety disorders. Although the majority of research has focused on understanding and addressing loneliness among older adults, young adults experience greater feelings of loneliness than their middle-aged and older adult counterparts. The COVID-19 pandemic has heightened the psychological and health risks experienced by this population in particular, increasing their experiences of loneliness as their social outlets have been truncated. Thus, identifying ways to ameliorate loneliness within this population, and doing so in a way that fits within COVID-19 guidelines for social distancing, is a public health mandate. Relational Savoring is a brief, strengths-based, psychological intervention grounded in principles of positive psychology, mindfulness, and attachment theory –this intervention involves guiding people to deeply reflect on past, present, or anticipated moments of positive interactions with others and has been found to increase positive emotion, feelings of closeness, and relationship quality among young adults. The goal of the current pilot study is to examine the efficacy of mSavorUs, a mobile-version of relational savoring, delivered as a preventative intervention to reduce loneliness and improve health in college students. Participants will use the mHealth system mSavorUs tool over the course of a 4-week period while monitoring their whole-system health (sleep, physical activity, physiology, psychological well-being, and health behaviors). This integrative approach will use non-invasive smart device wearables, such as a smart ring and smart watch to continuously collect such data in addition to ecological momentary assessments. Through our work, we aim to contribute to our understanding of loneliness and health among emerging adults and establish feasibility and usefulness of a mHealth approach to addressing feelings of loneliness.
Investigation of burnout prevention education and integrative health therapy in Emergency Room nurse wellbeing
Emergency room (ER) nurses experience high levels of occupational distress and have endured tremendous strain during the pandemic. With increased risk of professional burnout, strategies to protect and promote ER nurse wellbeing are needed.
The specific aims of this pilot study are to: 1) Design a burnout prevention course tailored for University of California, Irvine Medical Center (UCIMC) ER registered nurses and test a low respondent burden survey to measure changes in wellbeing. 2) Conduct a pilot study at the UCI Health Susan Samueli Integrative Health Institute (SSIHI) to investigate an integrative health therapy using intravenous nutritional therapy and immune supporting supplements on 90- day changes of ten ER nurses’ wellbeing, burnout, and laboratory biomarkers of stress and immunity.
An important innovation of this pilot project is to provide ER nurses and the UCIMC emergency department a pragmatic approach to measure wellbeing and test strategies to prevent burnout. Another innovation of this pilot study is this will be the first investigation, to our knowledge, of intravenous nutritional therapy and immune supplementation for ER nurse wellbeing. Additionally, the collaboration of this newly formed study team with unique complementary expertise will be an innovative opportunity to address the serious concerns of clinician burnout and occupational fatigue with a focus on wellbeing and integrative health therapies.
Testing the benefits of a novel music-based intervention on auditory processing in older adults: a feasibility study
Hearing loss amongst older adults is a common concern, particularly, speech-in-competition abilities. Auditory processing (including speech-in-competition) and cognitive abilities have been found to be well preserved amongst older adult musicians in comparison to their non-musician counterparts, suggesting that the auditory and attentional demands resulting from musical engagement might strengthen associated cognitive regions. However, underlying mechanisms of how music might benefit these areas remains unknown and there is little investigation of this phenomenon in older adult populations. Our long-term goal is to test for intervention-specific improvements in speech-in-competition abilities in older adults and experimentally determine differential impacts on auditory processing, attention, and working memory, and how these changes in turn may mediate improvements in speech-in-competition. The objective of this pilot proposal is to develop and test the feasibility and acceptability of the materials and assessments of a novel mindful music intervention targeting auditory processing and cognition via tablet technology, and to assess the feasibility of remote testing and training in the target (older adult) population. The rationale underlying the proposed work is that it will lay the groundwork to allow us conduct a larger-scale study to uncover said mechanisms driving the potential benefits observed as a result of mindful music engagement. This proposal utilizes an innovative approach by the development and implementation of a novel, low-cost and easy-to-administer music-based intervention to investigate its potential as a therapeutic tool, and to our knowledge, will be the first music-based investigation cultivating skills typically developed from formal instrumental training. This proposal will produce a convenient and accessible form of training for individuals who may no longer possess the physical capabilities or access that formal instrumental practice demands and that is tested against a solid and broad set of outcome measures that can be used to understand details of how hearing and cognition may change as a function of condition, and as such, differentiate between music and non-music-based interventions. The feasibility of this proposal will be tested in two stages by the target population via remote tablet technology and gather participants’ feedback about various aspects of usability. The proposed research is significant because it will help determine elements of music engagement that may aid in preserved auditory processing abilities and contribute to a body of literature on music’s impact on the aging auditory system. This project has clear translational potential, particularly for older adults, and will provide clinically relevant means of supporting age-related hearing loss and ultimately contributing to the prevention of cognitive decline.
Impact of diet on the gut microbiome in patients with chronic kidney disease
In this pilot/feasibility study, we plan to examine the impact of diet on the gut microbiome in patients with chronic kidney disease (CKD). Gut dysbiosis in CKD generates circulating uremic toxins including p-cresyl sulfate, indoxyl sulfate, trimethylamine N-oxide (TMAO)and lipopolysaccharides (LPS) which promote vascular inflammation and multi-organ dysfunction. These toxins are the result of amino acid proteolysis and correlate with increased cardiovascular events, mortality, and cognitive dysfunction. In Specific Aim 1 we will examine existing serum samples and data from 150 end-stage renal disease patients on chronic dialysis from the NIH-K24 funded “Malnutrition, Diet and Racial Disparities in CKD” (MADRAD) study. The type of food ingested as obtained through validated food frequency questionnaires will be correlated with serum toxin levels, to examine the hypothesis that the source of dietary protein from animal vs. plant-based sources will have an impact on levels of blood uremic toxins. In Specific Aim 2, we will implement a pilot study of a plant-dominant low protein (PLADO) diet in a prospective cohort of 50 pre-dialysis patients with CKD stages 3B to 5 recruited from UCI nephrology ambulatory clinics. Gut microbiome diversity, blood biomarkers and kidney function will be correlated with diet and quality of life questionnaires. Our overall hypothesis is that a PLADO diet is associated with a favorable constellation of microbiome biomarkers. We expect that these studies will lead to important preliminary data for future NIH grant applications that will examine dietary interventions and clinical outcomes via R01/R21/R44 or U01 funding mechanisms.
Impact of community-based Biofeedback program on drug use and mental health among people experiencing homelessness
COVID-19 disproportionately impacts vulnerable populations, including those who are homeless and experiencing significant health disparities. During the COVID-19 pandemic, people experiencing homelessness (PEH) have had increasing rates of anxiety, stress, depression, and substance use, which necessitates urgent, coordinated and culturally-sensitive responses that can be delivered, in part, remotely. Strategies that will target anxiety, stress, depression, and substance use, that is partially delivered remotely, is of timely importance and Biofeedback (BF) is one promising intervention which has been found to reduce these symptoms. This proposal will refine and pilot test a study focused on providing a critical understanding of the impact of Heart Rate Variability – Biofeedback (HRV-BF) on homeless and unstably housed adults who have a history of drug and alcohol use, as well as depression during COVID-19 pandemic. After learning from a community advisory board (CAB) focused on refining the HRV-BF intervention and assessing acceptability and feasibility, we will randomize 50 PEH (N=50), who have been diagnosed as having had COVID-19 (n=25) versus COVID-19 naïve (n=25) to assess anxiety, stress, depression, HRV, and substance use) between baseline and two months. We will be the first to develop a RN/CHW-guided model to deliver HRV-BF to homeless adults, with the goal of reducing anxiety, stress, depressive symptoms, and substance use. Our findings will inform an intervention study that would promote strategies to offset unmet mental health symptoms and worsening substance use among PEH.
Shared medical appointments using integrative techniques for patients with Inflammatory Bowel Disease
The management of the chronically ill continues to rise and place a significant financial burden on healthcare costs in this country. These patients demand a moderate amount of time and attention by healthcare providers. Despite the amount of money and time spent on these patients with high health services utilization, it does not necessarily translate into decreased morbidity and mortality in the US. The healthcare system realizes that we must take a proactive rather reactive approach to the management of these patients. The US is recognizing that there needs to be shift in the delivery of healthcare model to provide optimal long-term care for patients. As such, it is embracing the idea of Integrative Medicine and the beneficial complement that it adds to patients’ comprehensive treatment and satisfaction. It is also beginning to study the benefits of the Shared Medical Appointment Group Visit model as a potential means of providing more cost and time efficient care to patients and improve their mental as well as physical well-being.
Prevention of chronic pain by activating metabolism with a medical food
Chronic pain affects more than 70 million Americans and is inadequately managed by conventional therapies. Surgical tissue trauma is a frequent cause of this condition, which is common among persons who undergo invasive surgery or experience accidental tissue damage. In recent experiments, we generated compelling evidence indicating that end-organ injury causes a transient metabolic reprograming in spinal cord from mitochondrial respiration to aerobic glycolysis, which is crucial for pain chronification. Importantly, stimulating local mitochondrial respiration during this critical period completely blocks the transition to pain chronicity. Here we propose to conduct studies aimed at developing a medical plant-derived food that could effectively block the emergence of chronic pain after surgical or accidental trauma.
Neural circuit mechanisms of acupuncture-mediated pain management
Acupuncture is an effective treatment option for patients with chronic pain conditions, including back and neck pain, osteoarthritis, chronic headache, and shoulder pain. While acupuncture’s mechanism is not well understood, it is appealing as an inexpensive, non-addictive medical alternative with a prolonged action. Acupuncture mechanistic studies in humans are complicated by the issue of patient expectations and placebo effects. Rodent models however, allow for objective evaluations for acupuncture effects and underlying mechanisms. Building on the strong premise from the literature and our previous studies, we propose to use state-of-the-art molecular, genetic and functional imaging approaches established in our laboratories to elucidate neural mechanisms underlying acupuncture-mediated pain management using the mouse model. We choose to study the effects of acupuncture on chronic pain when it is applied in the acupoint Zusanli (ST36), one of the most effective acupoints to induce anti-nociceptive effects in mouse models of chronic pain. Given that chronic pain is a complex condition with different causes, we will use two mouse models of chronic pain: inflammatory pain evoked by injection of complete Freund’s adjuvant (CFA) into the mouse paw, and neuropathic pain evoked by spinal nerve ligation. We hypothesize that sensory nerve stimulation at the ST36 acupoint projects to central brain regions, and that ST36 acupuncture results in modulation of neural circuit excitation and inhibition balance in higher-order pain perception regions to alleviate chronic pain conditions evoked by inflammation or peripheral nerve injury. To test the hypothesis, in Specific Aim 1, we will optimize acupuncture stimulation parameters and study ST36 acupuncture-specific effects on neural activation in the mouse central nervous system (CNS). We will genetically identify and visualize neurons activated by electro-acupuncture applied at the ST36 relative to controls. We will determine the effects of pain reduction by ST36 electro-acupuncture in mouse models of chronic pain. Focusing on cortical physiological mechanisms for modulation of pain perception, in Specific Aim 2, we will use in vivo two-photon calcium imaging to examine the ST36 acupuncture effects on neural population activities with single cell resolution in the anterior cingulate cortex (ACC, a cortical area identified as a higher brain site for processing pain perception) of mice with chronic pain. While activation of specific cortical interneurons prevents the development of neuropathic pain, it remains to be understood how acupuncture modulates specific excitatory and inhibitory neural activities in ACC and its associated brain regions to exert effects. Successful completion of this project will establish a mechanistic framework to account for acupuncture-mediated pain management, and will further establish the evidence base for acupuncture practices.
