Adam Gazzaley - US grants

The goal of this project is to precisely characterize the temporal and spatial attributes of distributed neural networks associated with visual working memory (WM) and determine how these networks are influenced by aging. It will focus on two brain regions that are components of the distributed network supporting visual WM; the lateral prefrontal cortex (PFC) and the visual association (VAA). Focus will be on the relationship between the PFC and two stimulus-specific VAAs, the fusiform face area (FFA) and the lingual building area. Both event- related functional MRI (fMRI) and event-related potential (ERP) recording will be utilized in a series of experiments designed to probe the PFC-VAA network and compare the patter of neural activity in these brain regions. Functional imaging will yield superb spatial resolution, but since it measures blood flow coupled to neuronal activity, temporal resolution is limited. In contrast, ERP recordings will provide high- temporal resolution by directly recording electrical activity reflecting neural activity. Aging is associated with deficits in WM that have a large impact on cognitive functioning in the elderly. By identifying the neural mechanisms of WM processes as well as alterations associated with aging, research from this proposal should provide a foundation for diagnostic and therapeutic strategies for memory dysfunction in our aging population.

DESCRIPTION (provided by applicant): The broad objective of this proposal is to support the candidate's development of skills necessary to perform functional magnetic resonance imaging (fMRI) and event-related potential recordings (ERP) to investigate alterations in top-down modulation and neural networks in aging, as well as his continued development as an independent physician-scientist. The research training component includes the mentored development of skills in cognitive experimental design, attaining and processing fMRI and ERP data, multivariate statistical analysis, imaging data - behavioral correlations and the introduction of older participants into the fMRI and ERP environment. The goal of this grant is to identify common neural mechanisms whose impairments underlie a range of age-related cognitive deficits. To accomplish this, experiments will focus on top-down modulation, a process that forms a critical foundation for memory and attention. Both fMRI and ERP will be utilized in counterbalanced studies designed to selectively manipulate and monitor different aspects of top-down modulation in younger and older subjects. The superb spatial resolution of fMRI and high temporal resolution of ERP provide complimentary data to explore the nature and mechanism of this process and its potential alteration in aging. The older age group will be subdivided into different performance groups based on independent neuropsychological testing to facilitate meaningful interpretation of aging findings. A recently developed multivariate method will be applied to investigate age-related changes in neural networks subserving top-down modulation. The University of California at Berkeley provides the perfect training environment as it has a multidisciplinary group of researchers working on advanced fMRI and ERP techniques, as well as many researchers with interest and experience in normal aging research. The proposed research and training plan will provide highly specialized training for the candidate and facilitate the development of an independent cognitive neuroscience research program that will compliment his role as a cognitive neurologist. This training will also serve to support the candidate in his long-term goals of becoming a bridge between large-scale neural network and reductionist approaches to cognitive neuroscience.

DESCRIPTION (provided by applicant): Impairments in cognitive abilities of many older adults are a well-documented phenomenon that impacts multiple domains, such as working memory, episodic memory and attention. These cognitive deficits are a cause of great distress to many older adults who feel that their ability to lead high-quality lives is negatively impacted by this decline, and it is often considered the most debilitating aspect of aging. Our objective is to utilize the tools of human neurophysiology to identify underlying alterations in fundamental neural mechanisms that lead to the wide range of age-related cognitive deficits. Functional MRI (fMRI) and electroencephalography (EEG) will be used in a series of cognitive experiments to evaluate age-related changes in top-down modulation and subserving neural networks. The fine spatial resolution of fMRI and high temporal resolution of EEG provide unique but complementary data, and by simultaneously recording activity from the entire functioning human brain they are ideally suited to study network interactions. Top-down modulation is the neural process that underlies our ability to selectively focus our cognitive resources on sensory information relevant to our goals and ignore irrelevant information, thus serving as a neural basis for selective attention and a critical foundation for successful memory storage. We recently documented an age-related deficit in top-down modulation. Specifically, healthy older adults exhibit an inability to effectively suppress neural activity associated with distracting information, and this suppression deficit correlates with impairments in working memory performance. The specific aims of this project are to: 1) Elucidate the basis of the age-related top down suppression deficit, and 2) Explore the generalizability of age-related top-down modulation changes to different cognitive operations. The experiments proposed will inform us of the underlying neural basis of top-down modulation changes in the aging brain, assess the broader cognitive implications of this deficiency and more effectively guide the development of therapeutic interventions. Cognitive impairment that occurs with aging is a pervasive public health issue that continues to increase in magnitude as the size of the older population in our country continues to grow. The identification of underlying changes in the aging brain is necessary to establish a framework for the development of therapeutic interventions to alleviate cognitive impairments.

DESCRIPTION (provided by applicant): A major obstacle to high-level performance on a wide variety of goal-directed activities is interference by distractions. This interference can arise from the external environment, in the form of distracting sounds, images and smells, as well as from the internal milieu, as unwanted, intrusive thoughts. In concordance with recent theories on mind-wandering, we propose that all individuals have a tendency to automatically succumb to internal thoughts that are irrelevant to their ongoing goals, and that this is influenced by cognitive and emotional states and their surrounding environment. The degree to which they are capable of self-regulation of these internal distractions mediates the impact of this interference on goal-directed behavior. The objectives of the proposed research project are to evaluate the factors that impact self-regulation of internal distraction and the neural correlates that account for differences in self-regulation abilities across individuals and age groups, as well as the ability to learn to better self-regulate distraction. Specifically, we will explore how regulation of mind-wandering is influenced by task orientation (internal vs. external), and whether the presence of external distraction influences the regulation of internal distraction. We will evaluate if there are differences in executive function and neural networks that explain differences in these self-regulation abilities. Lastly, we assess the neural mechanisms by which self-regulation of internal distraction can be modified via practice. To accomplish these goals, we designed novel cognitive paradigms to evaluate the self-regulation of internal distraction, and the influence of the described factors, in both healthy younger and older adults. Next, using functional MRI, we will study the neural correlates of internal distraction regulation, as well as a failure to adequately suppress distractions. Finally, we utilize a novel distraction-training program, inspired by meditation practices and plasticity-based cognitive training, to study the neural basis of learning to self-regulate internal distraction. In addition, an extensive battery of cognitive tasks and real-life activity measures will be administered to evaluate correlates of these neural and experimentally-assessed distraction measures. We anticipate that the unique methodological approach and experimental design will significantly advance the limited work in this important area of self-regulation. PUBLIC HEALTH RELEVANCE: Internal distractions are a well-recognized impediment to high-level performance on a wide variety of activities. The goal of this project is to understand the factors that influence the self-regulation of internal distraction, as well as the underlying neural mechanisms that govern this regulation and our ability to learn how to better self-regulate with practice. This knowledge will be used to further our understanding of basic principles underlying self-regulation, and to help design future interventions to improve abilities to regulate the impact of distractions in diverse populations.

DESCRIPTION (provided by applicant): Attentional (or top-down) control enables us to focus on task goals and block out interference. Failing to properly engage these top-down mechanisms results in decreased memory performance by overloading our limited memory capacity with irrelevant information. While deficient attentional control periodically occurs in al healthy adults (e.g., distraction, mind wandering), it becomes more prevalent with age and is a prominent factor in those with psychiatric disorders, neurodegenerative disease, and brain injury. Unfortunately, it is unclear exactly how top-down control is implemented in the brain, thereby limiting therapeutic interventions. Remarkably, the brain is naturally resilient to neural decline by recruiting additional neural regions and rewiring neural networks to retain performance abilities. However, little is known about these reorganizational properties and the brain's potential to retain top-down control signals in the presence of dysfunction. The basic science goals of the proposed research project are to characterize where and when top-down signals are communicated and how they pertain to attention and memory processes. From a translational perspective, parallel goals are to assess the potential for neural compensatory mechanisms to retain performance abilities following the perturbation of brain function. To accomplish these goals, young adults will participate in two- session experiments that engage attention and memory processes. The first session will implement functional magnetic resonance imaging (fMRI) to identify putative top-down control regions within the neural networks involved in the task. The second session will utilize transcranial magnetic stimulation (TMS) to perturb neural function within the top-down control regions that were identified from the first session. Following TMS, neural data will be acquired via fMRI or electroencephalography (EEG) while participants are engaged in the same task as the first session. Temporal and spatial measures of cortical function, with an emphasis on network connectivity, will be evaluated. Comparisons between TMS, sham TMS, and TMS to areas not involved in the task will elucidate the role of these control regions from a causal perspective, help characterize the potential for neural reorganization, and offer a basis to understand the mechanistic relationship between attention and memory. In addition to advancing the limited work in this important area, we anticipate that this unique perturb and record methodological approach and experimental design will have a major impact on the field. This knowledge will be used to guide the targeted development of rehabilitation programs directed at the broad range of cognitive abilities and clinical populations that are susceptible to decline in attention and memory function.

DESCRIPTION (provided by applicant): A major obstacle to high-level performance on a wide variety of activities is interference by external factors, in the form of distraction and multitaskng. The negative impact of external interference on performance has been shown to worsen with age, and is a prominent factor in cognitive aging. Remarkably, it has been shown that adults of all ages can learn to resolve external interference with practice, largely eliminating performance costs. The basic science goals of the proposed research project are to explore the neural basis of external interference, how we learn to resolve interference with practice and how these mechanisms change with age. From a translational perspective, parallel goals are to assess the transfer of learning to benefit other cognitive abilities and the sustainability of learned skills ver time. To accomplish these goals, younger and older adults will engage in cognitive training regimens, which were specifically developed to train distraction and multitasking abilities. Neural mechanisms of interference effects and learning will be assessed before and after training using simultaneous electroencephalography (EEG) and functional MRI (fMRI) recordings while participants engage in an experimental version of the training tasks. Temporal and spatial measures of cortical function, with an emphasis on network connectivity, will be evaluated. Direct comparisons between age groups will offer a basis to understand alterations in these mechanisms that occur with normal aging. An extensive battery of cognitive tasks and real-life activity measures will also be administered pre- and post-training to evaluate if learning to resolve interference improves other abilities. Participants will be re-tested six months after training on the experimental tasks to assess sustainability of learning. In addition to advancing the limited work in this important area, we anticipate that the unique methodological approach and experimental design of this project will have a major impact on the field. This knowledge will be used to guide the targeted development of rehabilitation programs directed at the broad range of cognitive abilities and clinical populations that are susceptible to negative effects of interference.

DESCRIPTION (provided by applicant): Over two million people in the US download health apps onto their smartphones and tablets, with the intent of improving their quality of life. Despit widespread use of these apps, there is relatively little information regarding app user access (do users download health apps and use them more than once), app user engagement (do users follow the app protocols) and app impact on mood, cognition and daily functioning. Our long-term goal is to conduct a future randomized controlled trial investigating access, engagement and impact of two types of mental health apps, apps based on evidence-based therapeutic principles (i.e.: Problem Solving Therapy) and apps based on cognitive neuroscience principles of depression (i.e.: a cognitive training game called Evolution) and compare both to an information only app. Our intent is to conduct this study entirely on mobile devices, in order to investigate access, engagement, and impact in an ecologically valid manner. The purpose of this pilot study is to test the feasibility of conducting our future randomized controlled trial comparing three mobile mental health apps for the management of depressed mood, improvement of cognitive control, and improvement in activities of daily living in people aged 18 and older. Recruitment, consent, randomization, app use and outcome assessment will be conducted entirely on mobile devices. We will recruit 150 people through four different recruitment avenues to determine which avenue results in the most representative sample of our target population (people 18 and older who have symptoms of depression that are interfering with their quality of life). We will also determine the number we need to recruit to have a final sample of 150 people willing to be randomized between the 3 apps and complete an 12-week study of app impact on mood, cognition and function. This pilot will provide information on the completeness of data from a study conducted in this manner, and uncover any other challenges we may face by using mobile devices for data collection, and if we will find differential drop out between app type (e.g.: will more people stop using of the information only app prematurely?). Although we will not have sufficient statistical power to answer questions about comparative effectiveness between the apps, we plan to explore relationships between sample demographics, app use, and improvement in cognitive control on improvements in mood and function.

DESCRIPTION (provided by applicant): Over two million people in the US download health apps onto their smartphones and tablets, with the intent of improving their quality of life. Despit widespread use of these apps, there is relatively little information regarding app user access (do users download health apps and use them more than once), app user engagement (do users follow the app protocols) and app impact on mood, cognition and daily functioning. Our long-term goal is to conduct a future randomized controlled trial investigating access, engagement and impact of two types of mental health apps, apps based on evidence-based therapeutic principles (i.e.: Problem Solving Therapy) and apps based on cognitive neuroscience principles of depression (i.e.: a cognitive training game called Evolution) and compare both to an information only app. Our intent is to conduct this study entirely on mobile devices, in order to investigate access, engagement, and impact in an ecologically valid manner. The purpose of this pilot study is to test the feasibility of conducting our future randomized controlled trial comparing three mobile mental health apps for the management of depressed mood, improvement of cognitive control, and improvement in activities of daily living in people aged 18 and older. Recruitment, consent, randomization, app use and outcome assessment will be conducted entirely on mobile devices. We will recruit 150 people through four different recruitment avenues to determine which avenue results in the most representative sample of our target population (people 18 and older who have symptoms of depression that are interfering with their quality of life). We will also determine the number we need to recruit to have a final sample of 150 people willing to be randomized between the 3 apps and complete an 12-week study of app impact on mood, cognition and function. This pilot will provide information on the completeness of data from a study conducted in this manner, and uncover any other challenges we may face by using mobile devices for data collection, and if we will find differential drop out between app type (e.g.: will more people stop using of the information only app prematurely?). Although we will not have sufficient statistical power to answer questions about comparative effectiveness between the apps, we plan to explore relationships between sample demographics, app use, and improvement in cognitive control on improvements in mood and function.

? DESCRIPTION (provided by applicant): Deficits in cognitive control are at the core of many functional declines in healthy older adults. A fundamental contributor to these deficits is compromised regulation of both external and internal attention processes, which leads to a decreased ability to effectively engage in complex, goal-directed behavior. As a result, there is a critical need to develop targeted interventions to reverse or prevent declines in regulation of attention processes in healthy older adults. Targeted cognitive training and focused-attention meditation are two interventions that hold great promise for boosting attention and cognitive control abilities in healthy older adults, but we lack a firm understanding of the neural and physiological mechanisms that underlie this positive neuroplasticity. We also know little about whether such interventions might have multiplicative effects on cognition when administered in a combinatorial manner. The goals of the proposed research are threefold. First, we will determine the unique and synergistic effects of an externally-oriented attention training paradigm and an internally-oriental meditation paradigm on enhancing regulation of external and internal attention in healthy older adults, leading to improvements in functional outcomes. Second, we will examine the impact of potential genetic, physiological, and social moderators of the treatment effects in individuals and subgroups who show variability in their response to the interventions. Third, we will document the neural and physiological mechanisms underlying the unique and synergistic plasticity associated with each individual or combined intervention. To accomplish these aims, we will conduct a randomized clinical trial in healthy older adults of two novel cognitive training paradigms that are deployed on wireless mobile devices. We will collect data from two samples: a large (N = 1650) sample that will be recruited nationally who will complete the study entirely on mobile devices and a smaller (N = 225) local sample who will also complete more in-depth lab-based cognitive assessments, EEG, structural MRI, and functional MRI. The national sample will provide the numbers needed to examine individual and subgroup differences in treatment response in an extremely diverse sampling of the general population. The local sample will allow us to dive deeper into the underlying neural and physiological mechanisms that give rise to training effects. Both groups will complete baseline, immediate follow-up, and one-year follow-up assessments of cognitive and functional outcomes, while the local group will undergo neuroimaging at all three time points. We anticipate that the unique methodological approach and experimental design will significantly advance the development of rehabilitation programs directed at the broad range of cognitive abilities and functional outcomes in both healthy and clinical populations that suffer from problematic regulation of attention and cognitive control.

Understanding how the brain of a student learns new information and flexibly applies that information in real-world settings is critical for guiding efforts to improve the U.S. education system. How a student learns is fundamentally related to core aspects of cognition, termed executive functions (EFs). EFs are known predictors of academic achievement across multiple content areas (e.g., math and reading); however, there remain many unanswered questions regarding exactly how EFs contribute to academic performance and whether weak EFs can be enhanced with cognitive training. It is important to build a precise understanding of how these abilities develop over childhood and how they can be improved in order to supply educators with precise tools and insights about whether, when, and how to intervene when a student is struggling.

The study of how EFs contribute to academic achievement has advanced rapidly in recent years, but has not typically included the investigation of EFs in middle childhood. Because middle childhood is a period of high neural plasticity, it promises great opportunity to intervene when EFs are weak. This research program develops an innovative approach that improves both diagnostic and intervention methodology for detecting and remediating EF weaknesses in educational settings. The program leverages a novel, precision EF assessment tool in order to rapidly assess and longitudinally track the multidimensional profile of EFs in children over time. The critical advancement is the adaptive nature of the assessment tool, which increases in difficulty as the learner improves. This adaptivity allows multiple, precise assessments over time and thus enables unprecedented understanding of how different EF profiles develop across middle childhood and, critically, how these profiles contribute to math and reading achievement. Additionally, by utilizing a novel intervention that uses each student's multidimensional EF profile to selectively challenge subdomains of EF during physical fitness training, the research will inform us if personalized, multi-factor EF training can improve math and reading outcomes. Specifically, the research will: (1) fill gaps in existing knowledge about the relationship between EF profiles and academic skills beyond early childhood, (2) characterize how these relationships evolve across age, (3) determine whether EFs are more critical to certain content areas (subdomains of math and reading), and (4) advance the field's understanding of the feasibility and timeline of personalized EF interventions. Importantly, this research will serve to lay a definitive foundation for future science of learning research to build upon. In particular, the proposed investigations of the typically developing mind will inform efforts to understand disorders of development such as ADHD and autism. Finally, the EFs assessment tool will be made publicly available, to promote widescale investigations of EFs across the diverse range of student learners. A precise understanding of how the multidimensional profile of EFs contributes to academic achievement promises tremendous societal impact by guiding efforts to intervene when students are struggling academically.

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.

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 Summary Deficits in cognitive control, those abilities that allows one to engage in complex, goal-directed behavior, factor prominently in the functional declines experienced by older adults (OAs). Given that the older human brain still has the capacity to adapt, there is a critical need put into practice evidence-based approaches to help keep these individuals cognitive healthy, productive, and independent. Achieving this goal requires the development of targeted, accessible interventions to slow or reverse declines in these cognitive control processes. However, while telemedicine and internet-based approaches have been shown to be as effective as in-person treatment, there is virtually no known information about the optimal protocols for implementing self-administered mobile cognitive assessments or interventions in community settings like a senior center, or the feasibility of even attempting such efforts. The goal of this R21 is to test the feasibility of a targeted digital health remediation program for the older adults in senior living communities to enhance cognitive control abilities based upon an initial characterization of these abilities. To test this approach, we will use both custom assessments and interventions that are designed to be 100% self-administered via mobile devices. We will collect data from 120 OAs from the Brookline Senior Living communities, the largest owner and operator of senior living communities across the United States (1000+ communities, 100,000+ residents) where the average age of residents are 85 years old. Participating individuals will complete cognitive assessments and be randomly assigned to one of three training groups: directed training (DT), non-directed training (NDT), or an expectancy-matched placebo control group (PC). The total training experience will encompass 6 weeks of training (3 days/week), with each training session lasting ~30 minutes. All groups will complete baseline and immediate follow-up assessments of cognitive and functional outcomes. Evidence of feasibility here using these unique methodological approaches would provide empirical evidence supporting the basis for a larger-scale implementation of such digital health technologies into senior community settings.