Theodore Zanto - US grants

DESCRIPTION (provided by applicant): The goal of this project is to elucidate the spatio-temporal properties of neural network components involved in top-down modulation and evaluate how these networks may change due to normal aging. Topdown modulation refers to our ability to focus attention on pertinent sensory information and ignore irrelevant stimuli thereby improving our performance on cognitive tasks such as working memory. It has seen hypothesized that the neural networks underlying top-down modulation are long-range connections between sensory and distal cortices. Moreover, the prefrontal cortex (PFC) and the visual association cortex (VAC) have been identified as components of a distributed network involved in visual working memory and have been suggested to change in functionality during normal aging. Therefore, this project will focus on the interactions within the PFC-VAC network as attentional control influences memory and evaluate what changes may occur after normal aging. Specific Aim 1: Characterize the spatio-temporal properties of the PFC-VAC network during a working memory task. Through the use of an fMRI guided TMS/EEG recording approach, network activity may be localized, recorded and perturbed to study the causal effects of the intrinsic connectivity and functionality. Event-related potential, spectral and bivariate analysis will help characterize the nature of the long-range reciprocal neural influences between the frontal and visual cortices. I hypothesize the PFC yields separable modulatory activity on the VAC through suppression and enhancement of neural activity. Specific Aim 2: Evaluate changes in the PFC-VAC network due to normal aging. The second experiment will utilize the same paradigm and address the same questions as Experiment 1;however, the subject population will consist of older (60-75 years of age) adults as opposed to the younger (18-35 years of age) population in Experiment 1. Thus, generizability of a PFC role in modulating visual working memory may be determined through the observation of age related changes. I hypothesize that older adults will display a more widely distributed processing network due to fewer suppression and more compensatory mechanisms. PUBLIC HEALTH RELEVANCE: Differences in the connectivity and functionality of networks subserving top-down modulation may underlie a wide range of cognitive deficits associated with aging. The exploration of these basic neuralmechanisms is a critical step towards developing interventions that may alleviate this burden.

The International Conference on Music Perception and Cognition (ICMPC) is an interdisciplinary conference devoted to the dissemination of new, unpublished research relating to the neuroscientific, psychological, and computational bases of music perception and cognition. Founded in 1989, ICMPC is an international collective made up of research societies from different parts of the world, including the Society for Music Perception and Cognition in North America, the European Society for the Cognitive Sciences of Music, and the Asia-Pacific Society for the Cognitive Sciences of Music.

This award will provide support for a number of graduate students to attend the International Conference on Music Perception and Cognition (ICMPC), to be held July 5-9, 2016 at the University of California San Francisco (UCSF). Awardees will be enrolled in a Ph.D. program at a U.S. institution and will present their work at the ICMPC. Awardees will be selected to enrich the diversity of the conference in terms of geographical, cultural, and ethnic backgrounds and gender balance. ICMPC will host a lunch for all award recipients to meet and network with the keynote speakers and other award recipients.

Project Summary/Abstract Multi-domain amnestic mild cognitive impairment (aMCI) is a preclinical stage of Alzheimer?s disease that is characterized by declines in attention and working memory, which can negatively impact quality of life. As the population of older adults continues to grow, it becomes more imperative to understand what measures may be taken in order to minimize the concomitant growth of the aMCI and Alzheimer?s disease populations. We have recently demonstrated that transcranial alternating current stimulation (tACS), a painless and well- tolerated form of non-invasive brain stimulation, enhances divided attention abilities in a paradigm that also challenges sustained attention and working memory processes. Given that divided attention, sustained attention and working memory are all detrimentally affected in multi-domain aMCI, the use of tACS to remediate these declines may prove to be an important new therapeutic approach. However, additional research is necessary to understand the efficacy of tACS as a therapeutic for aMCI. This project represents the first attempt to assess efficacy of tACS as a therapeutic in aMCI by implementing a double-blinded, placebo- controlled tACS study. Older adults (aged 60-80 years) with multi-domain aMCI will participate in an experiment that requires six in-lab sessions on separate days. During the first session, participants will be given tests of working memory and sustained attention to evaluate baseline performance. During sessions 2-4, tACS will be applied while participants are engaged in a divided attention paradigm that invokes the use of both sustained attention and working memory. Sessions 5 and 6 will be one day and one month later, respectively, and participants will be presented the same paradigm from sessions 2-4 to assess tACS-related effects on divided attention, as well as the same cognitive tests from session 1 to assess tACS effects on sustained attention and working memory performance in non-divided attention tasks. During all six sessions, electroencephalography data will be collected to characterize the neuroplastic changes associated with tACS- related alterations in these cognitive functions. Participants will be randomly assigned to receive either verum stimulation or control stimulation. It is hypothesized that only the verum stimulation group will exhibit improvements in the divided attention task as well as in non-divided attention tasks that assess sustained attention and working memory abilities. Furthermore, these hypothesized gains in cognition are expected to be retained at the one-month follow-up and all performance improvements are expected to occur with corresponding changes in neural activity akin to healthy young adults. Together, this research will provide an important contribution toward understanding the potential of tACS as a therapeutic for aMCI, help elucidate the neuroplastic changes associated with remediating cognitive declines, and set the stage for future longitudinal research to assess the efficacy of this approach as a preventative measure against dementia from Alzheimer?s disease.

Project Summary Amnestic mild cognitive impairment (aMCI) is a pre-dementia stage of Alzheimer?s disease that is characterized by declines in episodic memory, and is often accompanied by beta-amyloid load, which plays a role in the pathogenesis of Alzheimer?s disease. As the population of older adults continues to grow, it becomes more imperative to understand what measures may be taken in order to minimize the concomitant growth of the aMCI and Alzheimer?s disease populations. Previous research in 5XFAD mice, a well-established model of Alzheimer?s disease, has demonstrated that 40 Hz (gamma band) neural entrainment can reduce beta-amyloid load in the neural regions where entrainment occurs. Here, we propose to replicate and extend these findings regarding the therapeutic potential of neural entrainment and assess the feasibility of translating this animal-based research to aMCI patients. To achieve this, we propose two experiments. The first experiment will use 40 Hz alternating current stimulation to entrain multiple cortical regions simultaneously in 5XFAD mice to reduce beta-amyloid load more globally than prior research. Furthermore, we will parametrically manipulate stimulation intensity to identify the optimal current that reduces beta-amyloid load. Whereas beta-amyloid load will serve as the primary outcome measure, episodic memory performance will serve as a secondary outcome measure. The second experiment will apply the optimal current intensity from experiment 1 in patients with aMCI via transcranial alternating current stimulation (tACS). Our primary outcome measures are concerned with the safety and tolerability of this method: skin redness under the electrodes, burning sensations, headache, scalp pain, back pain, neck pain, dizziness, tingling, itching, sleepiness, trouble concentrating, acute mood change, phosphenes and seizure. Secondary outcome measures include beta- amyloid load as assessed by positron emission tomography and episodic memory performance. For both experiments, stimulation will be applied for one hour on five consecutive days (Monday through Friday), followed by one hour of stimulation on each of the three following Mondays for a total of eight stimulation sessions over a one month period. Tests of episodic memory as well as beta-amyloid load will be measured pre- and post-stimulation (at the end of one month). Importantly, feasibility of tACS in aMCI patients will be continuously assessed during each stimulation session via observational data and patient feedback. The outcome of this research will advance our knowledge of the therapeutic potential of neural entrainment in a mouse model of Alzheimer?s disease and provide a critical feasibility assessment for the potential to rapidly translate animal research to human therapeutics. If tACS proves to be safe and tolerable in aMCI patients, this will facilitate future research to deploy randomized controlled trials to assess efficacy of this approach.

The overall aim of this project is to understand how the brain enables learned improvements in multitasking ability. Multitasking is a complex cognitive process that is prevalent in everyday life, from texting while walking to driving while reading a street sign. It is well established that during multitasking, both tasks are associated with performance declines, as compared to when the tasks are independently performed. Fortunately, through practice and learning, multitasking costs may be reduced. Yet, how the brain enables us to enhance multitasking performance remains elusive. This project investigates these questions by studying whether training can improve multitasking performance, as well as the changes in brain responses that accompany such improvement. It will also use interventions that impact brain activity and that may themselves produce multitasking improvement. The importance of the current project is in advancing the limited scientific knowledge in this domain, and in enabling multiple activities and outcomes that will be relevant to society more broadly. Apart from the scientific work, this project will offer several volunteer opportunities for high school and college students. For all these positions, women, persons with disabilities and minorities in STEM education will be highly encouraged to apply. Second, the knowledge generated by this research will be disseminated to the public through open-source publications, public lectures, and media outlets. These findings will enhance our understanding of multitasking ability, and developing therapeutics to target populations who suffer from this cognitive decline or learning disorders.

The overall aim of this project is to address the hypothesis that regions within prefrontal cortex rely on theta band (4-7 Hz) oscillations to enhance and optimize multitasking ability. To achieve this, transcranial alternating current stimulation (tACS) will be applied in the theta band above prefrontal cortex while participants are engaged in multitasking: visual discrimination with a concurrent visuomotor tracking task. Transcranial stimulation will be applied on three consecutive days while participants are engaged in multitasking. Participants will be assessed one day and one month after tACS to assess whether theta stimulation above the prefrontal cortex facilitates learned improvements in multitasking. Additionally, electroencephalography (EEG) data will be used to assess changes in oscillatory activity that supports learned multitasking improvements. It is hypothesized that tACS stimulations that impact theta oscillations will be particularly effective in improving multitasking performance, potentially impacting frontal theta EEG oscillatory power. To evaluate whether these learned multitasking improvements arise from alterations within the prefrontal cortex, magnetic resonance imaging (MRI) data will be collected from each participant and used to form individualized models of the tACS-induced electric fields in the brain. It is hypothesized that due to anatomical differences that impede tACS current flow to the brain, participants with greater modeled electric fields in the medial prefrontal cortex will exhibit the greatest increases in prefrontal theta oscillations and the largest improvements in multitasking ability. The proposed research will provide a direct assessment of mechanisms by which brain networks give rise to learned improvements in multitasking ability.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PROJECT ABSTRACT The neural mechanisms underlying successful cognitive performance are not well understood. In this R03 project, we will thoroughly investigate the ability to predict behavioral improvements through changes in shared underlying neural mechanisms. Identifying neural metrics that predict individual performance gains will ensure more reliable behavioral outcomes across diverse populations with varying cognitive capabilities and age ranges. Additionally, understanding the neural mechanisms underlying successful cognition will allow for rescuing of lost cognitive abilities and prophylaxis of cognitive decline in aging and other vulnerable populations such as in mild cognitive impairment (MCI). We recently identified several signals in the electroencephalogram (EEG) that correlated with cognitive performance improvements following and intervention with cognitive training and/or noninvasive neurostimulation. Specifically, frontal midline power in the theta band (4-8 Hz) correlates with improved divided attention ability and transfer to improved sustained attention ability in older adults (Anguera et al., 2013), and frontoparietal connectivity in the theta band is linked to improved attention (Anguera et al., 2013) and working memory (Jones et al., 2017). In addition to band- limited theta, we found that cross-frequency coupling between frontal theta oscillations and temporo-parietal gamma (>30 Hz) activity tracked individual performance gains in working memory following intervention with training and neurostimulation (Jones et al., 2020). These findings suggest that theta oscillations, as measured by power, connectivity, and cross-frequency coupling in task-relevant regions, underlie individual differences in cognitive performance. Indeed, the application of noninvasive neurostimulation confirmed the critical role of theta oscillations in divided attention by showing that direct entrainment of frontal theta oscillations further enhanced performance (Hsu et al., 2017, 2018). The proposed research will determine the mechanisms by which theta oscillations, assessed at baseline, predict subsequent cognitive performance outcomes in aging and vulnerable populations. Critically, we identified preliminary evidence that an individual's intrinsic peak theta frequency predicted the efficacy of theta entrainment with neurostimulation on divided attention ability. This important preliminary result demonstrates that a nuanced approach to tailoring an intervention to the individual is feasible. Here, our analyses seek to predict subsequent performance during divided attention prior to intervention (Aim 1) and before trial onset in a range of cognitive tasks (Aim 2). We will conduct comprehensive regularized multiple regression and deep learning analyses on 13 existing EEG datasets, several of which share the same divided attention task, yet vary in participant demographics, including age and cognitive capability (healthy older and younger adults, multi-domain amnestic MCI patients), to develop a predictive model for an individually-tailored cognitive intervention. The results will inform future research that seeks to maximize the reliability of intervention protocols across demographics at any age or cognitive capability.