Aaron R. Seitz - US grants

Ladan Shams, University of California at Los Angeles
Aaron Seitz, University of California at Riverside

COLLABORATIVE RESEARCH: MULTISENSORY PERCEPTUAL LEARNING

ABSTRACT

In daily life, we frequently experience correlated sensations across our different sensory modalities. For example, as we climb up the stairs, we receive sensations to our auditory, visual, tactile, and vestibular systems that are all related to the experience of stair-climbing. These types of multisensory experiences are a key aspect of how we interact with, and learn about, the world around us. Through our experience with the world, our sensory abilities undergo refinements that allow us to optimize our performance in the tasks that we perform. These sensory refinements involve fine-tuning of processing in each of our sensory modalities, but equally importantly, in how we merge information across modalities. While much research has focused on how learning can take place within each individual sensory system, the learning of how information is combined across the senses has been largely neglected. The PIs will conduct a series of experiments in which they can track visual, auditory, and auditory-visual multisensory learning in parallel, and discriminate among different theories of multisensory processing and learning. Behavioral and neuroimaging methods will be combined to shed light on the roles that different brain areas, and the interactions between brain areas, play in the process of multisensory learning. Altogether these studies will provide fundamental insights into how our sensory systems work together and refine their interactions to best operate in the tasks that we perform.

This project will be the first systematic investigation of multisensory perceptual learning. It will also be the first study of changes in interaction between brain areas that may occur as a result of sensory learning. Altogether, this study promises to provide foundational knowledge regarding the brain mechanisms involved in multisensory learning as well as the mechanisms of learning in general. Understanding multisensory learning can contribute to the development of more effective strategies for learning. These strategies can be utilized to enhance learning for typically-developed children and adults, as well as to facilitate learning and communication for individuals with deprivation in one sense (e.g., individuals with low-vision or low-hearing, patients with cochlear implants or undergoing macular degeneration or cataract surgeries). They can also contribute to devising remedial programs for dyslexia, which appears to involve deficits in combining information across the senses.

DESCRIPTION (provided by applicant): There exists a fundamental gap in understanding of the complex interplay of the integrated processes that determine, induce and regulate plasticity in the perceptual systems. This gap represents an important problem because we can only have a fractured understanding of plasticity in the visual system without knowing how different factors contribute to and interact in learning. This limits our ability to effectively translate basic sciece findings of perceptual plasticity into therapies that could help the over 100 million people worldwide who suffer from low vision; deficits in vision due to disease, injury, stroke or aging that have significant negative impacts on all aspects of individuals' lives. The specific objective to fill the knowledge gap and develop a novel therapeutic approach that integrates, and benefits from, multiple perceptual-learning principles, is driven by the hypothesis that integrating perceptual-learning principles into a coordinated approach, will operate through multiple mechanisms to ameliorate a wider range of visual deficits. We formulated this hypothesis based on research showing that stimulus-reinforcement contingencies, multisensory stimulation, stimulation protocols derived from studies of synaptic plasticity, multi-stimulus training, and video games all enhance the magnitude and quality of learning. However, a key limitation of modern perceptual-learning research is the focus on singular mechanisms, which fail to illuminate the coordinated interactions of multiple learning factors in natural set- tings. Our preliminary data show that a video game that integrates multiple approaches dramatically improves basic visual abilities (e.g., acuity and contrast), and generalizes to untrained stimulus sets. The rationale of the proposed research is that integrated approaches will unravel natural learning mechanisms and improve out- comes for the patients afflicted with low vision. In Aim 1, we will examine how perceptual learning approaches interact and determine the most efficacious integrated therapy, and in Aim 2, we will apply that therapy to low vision to understand mechanisms of action of the therapy to disease mechanisms affecting eye-dominance, spatial distortion to the retinal mosaic, and rapid change in aberrations in the eye. We are well prepared to undertake the proposed research because the investigative team combines veteran video game production executives and developers with an optometrist and a neuro-ophthalmologist who have experience treating low- vision populations. Aaron Seitz (PI), who developed many of the principles upon which this novel integrative approach is based, anchors the team. The proposed research is innovative because it represents a new and substantive departure from the status quo by integrating multiple principles of perceptual learning. This contribution is significant because the development of effective therapies to treat the brain-based aspect of low vision can lead to life-altering benefits for many millions of people worldwide. Our proposed studies should also catalyze a paradigm shift in the field of vision research, and pave the way for designing efficacious treatments of low vision conditions like amblyopia, age-related macular degeneration and cataracts, in the future.

? DESCRIPTION (provided by applicant): Most diagnoses of hearing loss focus on the audiogram, which is not sensitive to dysfunction at many of the additional processing stages associated with auditory perception. For example, recent data from many laboratories, including our own, have shown clear auditory processing deficits both in older listeners and in patients who have suffered traumatic brain injury, despite normal audiograms. Modern auditory neuroscience, computational modeling, and psychoacoustics have provided great insight into the information processing that underlies auditory perception and have identified specific stimuli and tasks for the evaluation of central auditory function, but this information has largely remained in the laboratory. It is the goal of this proposal to develop and evaluate a set of clinicl tests that draw upon modern laboratory tests and theories of auditory system function. These will form the basis of a new clinical test battery for central auditory dysfunction that will suppot the accurate diagnosis of a much wider range of the difficulties that can lead to auditory complaints.

SUMMARY The overall objective is to understand of the factors mediating and moderating transfer of learning in the context of training Working Memory (WM) systems. There is accumulating evidence that WM training impacts performance in a wide variety of tasks, however, to date, knowledge is extremely limited regarding the underlying mechanisms that mediate plasticity in WM systems, and what components of training give rise to transfer to different tasks. This proposal is transformative in how it applies knowledge derived from plasticity in other brain systems (such as perceptual learning, where there is substantial understanding of mechanisms that dtrive transfer) to test their impact in WM systems (Aim 1), in the creation of novel measures to asses transfer to real-world cognition (Aim 2), and in the use of online ?crowd-sourced? studies to characterize individual differences using a large population (Aim 3). These studies are particularly important and timely given current state of the field, which is fraught with controversy, and the lack of understanding of the relevant attributes of training and individual differences factors that give rise to successful training outcomes. Understanding the factors that mediate successful learning, as well as the individual differences moderating these is critical to resolve the current controversies and to move towards a theoretical model of training and transfer. Potential for knowledge gain and translational impact is substantial. Understanding how our memory systems work and the mechanisms that guide learning has great potential to be applied broadly in society. Our acquisition of knowledge in the world intimately relies on WM processes, thus, improvements in WM can benefit almost all aspects of our lives. This has driven a now billion-dollar commercial market that has provided early generation training approaches, which are extremely controversial in the scientific community. The proposed research can shed light on the factors that mediate and moderate these types of cognitive interventions and address the extent to which some procedures may, and others may not, lead to improvements in real world cognition. This can potentially lead to educational, rehabilitative, and technological advancements. For example, WM deficits exist in a wide range of mental health conditions, cases of disease and brain damage, and in cognitive declines with aging, and training approaches that promote better functioning WM systems can promote health and well-being in these groups. Further this research can elucidate approaches that may not work and help people avoid use of infective procedures. The proposed training software will be created on cross-platform game engines to enable dissemination to diverse populations. In this sense, the research output has innovative and broad impacts that can be directly realized from the proposed research. Many individuals are already using ?brain training? products, however, none incorporate the theoretically-driven approaches designed to optimize WM learning with an aim to transfer that training to real world benefit, and that are systematically researched, as proposed here. Programs created in the proposed work will be made publically available.

Project Summary The overall objective is to develop and test a novel rehabilitative training program for central auditory dysfunction after traumatic brain injury. Solutions designed to enhance auditory processing when hearing thresholds are within normal limits are very limited and none are as recognized or as widely available as are hearing aids and cochlear implants. While there exist some contemporary approaches devised to improve hearing in a variety of populations, these are largely based upon emulating hearing scenarios in the environment. While such programs show some efficacy, three key limitations undermine the overall effectiveness and deployment of these approaches. 1) A lack of alignment of treatments with up-to-date knowledge of how sounds are processed by the brain 2). A lack of alignment of treatments with up-to-date knowledge of perceptual learning research, and 3) Difficulty in getting patients to comply with training procedures that are often frustrating and boring. Here we aim to overcome these limitations by integrating contemporary knowledge of auditory neuroscience, perceptual learning, and modern game design to develop and test novel auditory training therapies. Our primary premise is that 1) Studies of auditory neuroscience and psychoacoustics have advanced our understanding of the function of auditory processes beyond the cochlea. 2) Studies of perceptual learning have advanced our understanding of plasticity in the neural systems underlying hearing, and have refined behavioral procedures that engage these systems. 3) Commercial video games have become ubiquitous, sophisticated, and shaped by competitive market pressures to become both perceptually engaging (rich graphics, sounds, and animations) and cognitively challenging. Combining these elements can lead to behavioral cognitive therapies that are effective and encourage compliance by being compelling, stimulating, and fun. We will test an adaptive training program that involves practice with a ?basis set? of spectral temporal modulated sounds that are modeled after auditory neuron receptive field properties7 combined with interaural localization cues to also train sound source segregation. Efficacy will then be tested in normal hearing participants and in patients with mild traumatic brain injury and auditory processing difficulties (APDs) and compared against active tone training controls. Outcome measures are tests of real world audition including; speech in noise, multiple talker environments and auditory attention and working memory. Potential for knowledge gain and translational impact is substantial. This project will result in techniques and data relevant to rehabilitation of APDs. The data and training will be made available to the clinical and research community. Evidence of efficacy will be followed upon with a R01 proposal to examine how different components of training contribute to observed effects and to examine neural underpinnings. The positive impact whether or not the training program is effective will be new knowledge about what types of training programs are effective, and which are not, and can contribute to development of effective therapies for APDs.

Project Summary Speech in noise tests have traditionally involved 1) unrealistic maskers such as broadband noise presented from the same spatial location as the target speech, and 2) unengaging reward structures. Our overarching hypothesis is that the experience of listeners in their daily lives will be more strongly related to performance if the laboratory tests are enhanced by increasing the realism of the testing environments and introducing game- like interfaces. The main goal of this project is to determine which enhancements have the greatest impact on the relationship with listener complaints, and which listener abilities (auditory and cognitive) mediate and modulate this relationship. Enhanced environments will be tested that 1) simulate real-world experiences by conducting assessments in synthetic environments that include both auditory and visual stimuli and 2) introduce game-like elements that are more rewarding and motivating for the listener. Understanding how different participants respond to a variety of enhancements will provide essential new information about the ways in which realistic experiences differ from traditional laboratory tests and the ways that rewards and motivation influence variability of test results as well as relationships with self-report. Experiments will involve younger listeners with normal hearing, older listeners with a range of hearing abilities from normal to severely impaired, and a group of listeners with a history of mild traumatic brain injury. These participants will provide a wide range of performance on measures of auditory and cognitive abilities, which can then be used to better understand any effects of the enhancements on self-reported ability to function in complex listening environments. Upon completion of this project there will exist, freely available, an extensive set of enhanced auditory assessments that are more engaging and more realistic than what is currently available and that run on inexpensive consumer-grade equipment. This project will establish for these enhanced tests both 1) established ranges of normal performance as a function of age and hearing loss, and 2) known relationships to various established tests of speech in noise. The modeling work associated with this project will reveal which auditory and cognitive abilities are associated with deviations from normal performance and self-reported difficulties hearing in adverse listening environments that are great than would be expected.

This supplement seeks to advance understanding of Alzheimer's disease (AD) and Alzheimer's disease related dementias (ADRD) by clarifying relationships between measures of visual processing, cognitive functioning, and perceptual learning in a diverse older adult population, including those with prodromal AD/ADRD and MCI. The proposed supplement is within the scope of the funded project, entitled ?Mediators and Moderators of Perceptual Learning? which already aims to examine such relationships in older adults without dementia. Here we propose to expand inclusions to better target older adults with possible prodromal AD/ADRD and to add new measures to better characterize cognitive function in this population. Indeed, the well-documented age-related declines that occur in vision and in cognition as a result of normal aging are considered major issues in regard to individuals' health and well-being as well as with respect to more global economic and social policies, with these issues being more severe, and thus taking on even greater relevance, in the context of AD/ADRD. The proposed supplement is premised on the observation that age-related declines in centrally mediated visual processes may explain unaccounted for variance in estimates of higher-cognitive function and that likewise cognitive factors may explain unaccounted for variance in estimates of visual functions. As such, whether in the context of understanding outcome measures of perceptual learning (such as in the current proposal), or whether testing vision in the clinic, it is essential to consider measures of cognition, and how they change, as a moderating factor in estimating visual processes. Further, measures of central visual processes may help identify individuals with prodromal AD/ADRD. In this manner we can gain new insights into the reciprocal role that vision and cognitive processes play in the aging process from both a mechanistic and a practical perspective. This is likely to stimulate additional activity by giving rise to a unique data-set that can be used as a foundation for new lines of research that can potentially lead to new behavioral biomarkers of prodromal AD/ADRD. Thus, the supplement can also promote development of new procedures to more accurately measure vision and cognitive function in older adults suffering from cognitive impairments.

Effective measurement of cognitive abilities is fundamental to effective diagnostics, risk assessment and evaluation of interventions targeted towards older adults (OA) and in particular those with Alzheimer's Disease and related dementias (ADRD). With the ubiquitous availability of smartphone/tablet technology in modern society a proliferation of mobile cognitive assessments from companies, healthcare providers, and researchers are being developed. However, a difficulty in evaluating such interventions, and in particular making comparison between them is the lack of standardization/interoperability of assessment tools. This is especially the case for early stage/mechanistic studies where it is common for investigators to each use their own labs' toolset to evaluate intervention outcomes. Here we address particular needs in the field of cognitive training, as well as for other longitudinal assessments focused on OA, where the limited standardization and accessibility of cognitive outcome measures makes it difficult to evaluate effectiveness of interventions. This R21/R33 infrastructure proposal seeks to develop shared tools to facilitate effective translation and sharing of cognitive assessment and training procedures. We accomplish this by leveraging technologies, existing assessment batteries, and know- how from 3 groups that have each independently developed robust systems for cognitive assessment and training that can run on mobile devices (UCR Brain Game Center, UCSF Neuroscape Center, and UCI Working Memory and Plasticity Lab). We target development of systems that allow for interoperability of assessments, enrollment/participant tracking systems, data visualization, and participant compliance systems. In the R21 phase, we aim to develop such systems and demonstrate that they can be effectively shared across labs, and in the R33 phase, these systems will be both tested for robustness in large scale-research projects that will now be able to share outcome measures, and for developing personalized, precision training approaches for participants based upon these assessments. Further, these systems will be documented and will be shared with other scientists groups to reduce the barrier of entry for other groups. The long-term impact of this work will be an infrastructure that will support better comparison across studies of cognitive training, as well as other interventions that are increasingly being used to ameliorate cognitive declines in older adults such as those related to ADRD. The key value of this system compared to others is that it will simultaneously support the flexibility required for basic research, by facilitating groups to continue to use their own lab's software systems, while at the same time providing them with a powerful infrastructure for sharing that allows them to incorporate assessments, server infrastructure and compliance tools into their own studies. This will facilitate comparisons across studies using common outcome measures as well as the ability to use the same assessments in numerous other domains including risk-assessment and longitudinal testing in older adults at risk for ADRD.

Project Summary Research on perceptual learning (PL) has been dominated by studies that seek to isolate and improve individual visual processes. However, an important translational outcome of PL research is to address the needs of patients with vision loss, who seek to improve performance on daily tasks such as reading, navigation, and face recognition. These more ecological cases of behavioral change and cortical plasticity, which are inherently complex and integrative, have revealed significant gaps in a more holistic understanding of how multiple visual processes and their associated brain systems jointly contribute to durable and generalizable PL. To address these gaps, here we study simulated and natural central vision loss. We focus on macular degeneration (MD), one of the most common causes of vision loss (projected to affect 248 million people worldwide by 2040), which results from damage to photoreceptors in the macula that disrupts central vision. Such central vision loss is a superb lens through which study to how ecologically relevant changes in the use of vision relate to changing brain activity and connectivity because it represents a massive alteration in visual experience requiring reliance on peripheral vision for daily tasks. With the use of eye-trackers and gaze-contingent displays that induce central scotomas, central vision loss can be simulated in normally seeing individuals, who then develop peripheral looking patterns that resemble compensatory vision strategies seen in MD patients. Ideal use of peripheral vision requires improvement in multiple vision domains, three of the most important being: early visual processing (e.g., visual sensitivity), mid-level visual processing (e.g., spatial integration), and attention and eye-movements. To date, no study has systematically investigated these three domains of PL and their neural underpinnings. The proposed research plan rests on rigorous prior work showing that PL influences multiple brain structures and functions related to these three domains. We propose a novel approach of systematically measuring how different training regimes related to the three domains influence a broad range of psychophysical and ecological behaviors (Aim 1), how these changes arise from plasticity in brain structure and function (Aim 2), and how PL after simulated central vision loss compares to PL in MD (Aim 3). This work is significant and innovative as it will be the first integrated study of PL characterizing multiple trainable factors and their impact on diverse behavioral outcomes and on cutting-edge assessments of neural representations and dynamics. It is also the first study to directly compare PL in MD patients with PL in a controlled model system of central visual field loss with simulated scotomas, which if validated will allow the use of this model system to interrogate MD in larger samples of healthy individuals. We will also share a unique dataset that will help the field to understand behavioral and neural plasticity after central vision loss and individual differences in responsiveness to training. Finally, this work will illuminate basic mechanisms of brain plasticity after sensory loss that may generalize to other forms of rehabilitation after peripheral or central damage.

PROJECT SUMMARY The overall objective of the proposed work is to test the benefits of a music-based intervention on speech-in- competition abilities in an older adult population that includes individuals that may be at risk of Alzheimer's disease and related dementias (ADRD). Age-related hearing difficulties are prevalent, with speech-in- competition difficulties being a common challenge amongst older adults. Critically, these difficulties and frustrations often lead to social isolation and decreased cognitive engagement, and they are associated with an increased risk of developing ADRD. There is evidence suggesting that musical training is associated with cognitive advantages in older adults, including preserved ability for speech-in-competition. However, to date, there is extremely limited knowledge and lack of experimental evidence explaining how music might benefit speech-in-competition abilities, along with more basic auditory processes and/or cognitive functions. We aim to contribute to uncovering the underlying mechanisms driving the potential effects of music and attention through an innovative, attention-based music listening intervention that cultivates auditory and attentional skills akin to those developed during formal instrumental training. To disentangle potential effects of music and attention and to get at the underlying mechanisms of music effects, we will compare outcomes of this attention-based music intervention with those of two active control interventions that consist of either passive music listening or active listening to non-music sounds. Specific aims are to develop and test the feasibility of music and control interventions and assessments targeting auditory processing and cognition (R61; Aim 1); test for intervention- specific improvements in speech-in-competition using a randomized-controlled trial (R33; Aim 2); and determine whether experimental and control interventions differentially impact measures of auditory processing, memory, and attention, and test how these may mediate performance on measures of speech-in-competition (R33; Aim 3). Long-term objectives are to understand the key mechanisms underlying the benefits of music with the overall goal to inform interventions aimed at mitigating the effects of ADRD. This proposal is transformative in that it utilizes an innovative approach to uncover potential benefits and underlying mechanisms of music by testing the added benefits of interventions and testing their benefits against a broad set of outcomes measures that can be used to further understand the malleability of auditory processes and cognition in aging. In addition, the intervention is cost-effective, easily administrable, and accessible to individuals who may not possess the physical capabilities or resources that formal instrumental practice demands. In addition, music has been shown to provide other benefits including mood regulation and psychological well-being, and as such, the intervention may have benefits that go beyond the auditory or cognitive domain. Overall, the proposed work aims to contribute to the amelioration and/or prevention of cognitive decline in individuals that may be at risk for developing ADRD.

Project Summary The overarching goal of the present proposal is to understand how individual differences in the structure and function of Locus Coeruleus (LC) moderate perception and memory in an older adult population. There is substantial evidence that the LC circuit plays a central role in cognitive processes and neuronal loss in LC is known to occur in neurodegenerative disorders such as ADRD and PD. Integrity of LC neurons is hypothesized to mediate the preservation of cognitive abilities during normal aging as well. To date, however, there exists a dearth of research that either characterizes differential effects of LC integrity or details relationships between LC integrity and cognitive function in older adult humans. More generally, the link between LC activity and cognitive processes has not been well characterized in humans. Historical reasons for this is that the LC has been difficult to image due to its small size and thus most human research makes inferences about LC function by using pupil dilation as a surrogate measure. To overcome existing limitations in the field, we propose a series of detailed psychophysical and MRI-based studies in older adults aimed to characterize how LC structure and function moderates behavior and in turn how this is mediated by activity in intermediate brain regions known to be involved in perceptual and memory processes. We further propose computational approaches to characterize individual differences in how LC circuit integrity relates to different patterns of cognitive performance across tasks, and advanced neuroimaging methods to localize and image the LC, which have been pioneered by our group. Using MRI-based methods, we will examine LC integrity using high-resolution neuromelanin-sensitive structural imaging, tractography and functional connectivity. This approach will allow us to identify candidate biomarkers of LC circuit integrity. We will use a series of within-subject designs where we manipulate LC activity and examine whether relationships between LC and behavior and brain regions thought to mediate those behaviors are consistent or not between different perceptual modalities and memory tasks. Overall this study will provide an important and much needed understanding of how LC integrity underlies cognitive declines in older adults. By combining advanced neuroimaging, well-controlled behavioral assessment, and computational analysis, we expect to uncover previously inaccessible in vivo mechanisms of LC modulation and generate a unique dataset to address fundamental mechanistic questions of how the LC integrity moderates cognition, how this varies across older adults and the extent to which relationships between LC and cognition are generalized or individualized to particular domains. The resulting understanding of LC circuit can help explain how dysfunctional modulatory circuits may generate cognitive declines or be implicated in normal aging and age- related disorders such as Alzheimer's and Alzheimer's related disorders. This, in turn, has potential to support non-invasive methods for diagnosing pathologies associated with LC decline and developing new treatments.

PROJECT SUMMARY The overall objective of the proposed work is to understand factors mediating and moderating transfer of learning in the context of training Working Memory (WM) systems in a diverse older adult population that is inclusive of individuals that may be at risk of Alzheimer?s disease and related dementias (AD/ADRD). There is accumulating evidence that WM training can be effective in older adults, however, to date, knowledge is extremely limited regarding the underlying mechanisms that mediate and moderate plasticity in WM systems, and what components of training give rise to transfer. Specifically, we will investigate whether there is an inhibitory control (IC) phenotype in older adults at risk of dementia that may explain some of the disparate results observed in the literature in terms of WM training outcome. Specific aims are to test an Inhibitory Control (IC) model that predicts individual differences in how gamification of training using an n-back task differentially affects learning and transfer and contrast this with a General Cognitive Ability (GCA) model (Aim 1). We will further test the generalizability of the models using a complex span training (Aim 2), and furthermore, investigate applicability to Multisensory Facilitation (MF) where sounds supporting visual processing of task targets can promote learning and transfer (Aim 3). This proposal is transformative in that it seeks to understand how individual cognitive strengths and needs in older adults may have different requirements for training interventions. These studies are particularly important and timely given the current state of the field, which is fraught with controversy, and the lack of understanding of the relevant attributes of training and individual differences factors that give rise to successful training outcomes. Understanding the factors is critical to resolve the current controversies and to move towards a theoretical model of training and transfer. Performance in everyday life intimately relies on WM processes, thus, improvements in WM can benefit almost all aspects of our lives. This has driven a now multi- billion-dollar commercial market that has provided early generation training approaches, many of which are targeted at older adult populations who are at risk of AD/ADRD. The proposed research can shed light on the factors that mediate and moderate these types of cognitive interventions and address the extent to which some procedures may, and others may not, lead to improvements in real world cognition. WM deficits exist in a wide range of mental health conditions, cases of disease and brain damage, and in cognitive aging, and training approaches that promote better functioning WM systems can promote health and well-being in these groups. Further this research can elucidate approaches that may not work and help people avoid use of ineffective procedures. The proposed training software will be created on cross-platform game engines to enable us to bring the lab to the participants. In this sense, the research output has innovative and broad impacts that can be directly realized from the proposed research. Programs created in the proposed work will be made publicly available for research dissemination of personalized interventions that can support diverse populations.