Jeanne Townsend, Ph.D. - US grants

DESCRIPTION: (Applicant's Abstract) This proposal is in direct response to a call for investigations of "selective cognitive deficits" rising from "neurodevelopmental disorders," and the application of such finding to the understanding of fundamental brain-behavior relationships. Our studies of infantile autism suggest a new and unexpected role for the cerebellum in cognition: rapid orientation and re-orientation of attention. We propose to investigate whether this reflects a general relationship rather than one that is unique to this developmental disorder, and to determine whether systems with which the cerebellum is interconnected (such as frontal and parietal cortex) perform comparable or complementary attentional operations. Hypothesis to be tested in this proposal are: a) the cerebellum is of critical importance for the rapid orientation or re-orientation of an attentional focus; b) parietal cortex is primarily involved in attentional operations outside the central attentional focus (e.g., monitoring information at locations of potential future importance); and c) frontal cortex is primarily involved in attentional operations within an attentional focus (including selection and maintenance of that focus). To test these hypotheses we will study adult patients (age 18-70) with cerebellar, parietal or frontal damage due to stroke, as well as age and gender matched normal controls. Behavior and event-related potentials will be recorded during two different but complementary sets of visual- spatial attention experiments that index the attentional operations of interest. Since we will be testing patients with damage to the cerebellum and frontal lobes, our measures are designed to be independent of motor response. MR imaging will be used to verify and quantify site and size of lesion as well as residual cortical and subcortical parenchyma. ERP and behavioral measures will be correlated with site and size of lesion, a procedure that has been successfully employ in comparable experiments. The experiments proposed here are designed to elicit double dissociations of anatomic damage and impaired concept that the cerebellum plays a specific role in the dynamic control of attentional resources, and will expand our knowledge of the complementary roles of subcortical and cortical systems in human attention.

The overall goal of this research is to examine the association of brain structural changes with attentional deficits in healthy aging. The speed with which attentional resources can be allocated and re-allocated affects the speed of sensory processing and behavioral responding, both of which are slowed with aging. A number of the brain regions that have been identified as important to spatial attentional function, including prefrontal and parietal cortex, the thalamus, and most recently the cerebellum, have, in fact, been reported to show age-related change. We propose to use structural and functional imaging methods to examine whether structural changes and subsequent functional inefficiency in these cortical and subcortical regions, particularly the cerebellum, may underlie attention deficits in aging. Specifically, we propose 1) to identify brain structural changes occurring with healthy aging in cross-sectional samples, 2) to identify behavioral and EEG changes in aging associated with shifting or orienting of attention, and 3) to test the hypothesis that age-related loss in the posterior cerebellum may affect both an anterior attention orienting system, and a posterior spatial attention mapping system. Reduced efficiency in these brain networks would result in slowed attentional shifting and orienting, and associated changes in brain electrophysiological dynamics. We will study 120 males and females aged 21-85. All subjects will receive: (1) neuropsychological evaluation; (2) MR imaging with quantification of gray and white matter and CSF in cortical and subcortical regions of interest, and hyperintensities in intracranial space; (3) attention shift tasks designed to allow separation of electrophysiological and hemodynamic activities linked to sensory, motor, and attentional processes. Behavioral, event-related potential (ERP), and functional magnetic imaging (fMRI) data recorded during these tasks will be compared with neuroanatomic results to address our research hypotheses. New analytic techniques based on Independent Component Analysis will allow us to identify both correlated fMRI signal changes throughout the brain, and overlapping patterns of coherent EEG from ERP data. The proposed experiments will yield convergent evidence concerning the neurologic bases of dynamic attention deficits in aging. These data will also provide methods as well as a baseline dataset of neuroanatomic measures that could be used in future clinical studies.

DESCRIPTION (provided by applicant): Cerebellar abnormality may underlie many of the cognitive and clinical symptoms in autism. While brain abnormalities in autism are diverse and involve cortical and subcortical regions, the cerebellum is the most consistently reported site of damage. Developmental abnormality of the cerebellum has been found in 95% of postmortem autism cases and in several hundred individuals with autism on quantitative MRI studies performed by six independent research groups. More than 60 studies have found molecular, metabolic, functional or structural abnormalities of the cerebellum in autism. A rapidly growing body of literature suggests that the cerebellum controls or modifies diverse cognitive processes, thus altering the traditional neurologic view of the cerebellum as a brain structure that supports only motor function. Work in our laboratory has linked the cerebellum to both cognitive function and neural response not only in autism, but also in normal function. We have proposed that some deficits in autism may reflect fundamental cerebellar dysfunction--failure to track sensory information, predict future events and prepare a response. We now propose to test this emerging model of cerebellar dysfunction in autism using functional and structural imaging. We will assess the specificity of cerebellar involvement in these cognitive operations (track, predict, prepare) by comparison of subjects with autism: 1) to patients with cerebellar damage acquired in early childhood; and 2) to those with Asperger syndrome in which the cerebellum may be less affected. We will ground our results from these comparisons by performing fMRI (functional magnetic resonance imaging) studies in normal control subjects to establish that the cerebellum is normally active during these same operations. The fMRI studies of clinical groups will allow us to investigate whether patterns of activation suggest abnormal interaction of the cerebellum and cerebral cortical systems during these important processing operations. Our studies will link both behavioral and neural response (ERP, fMRI) to the underlying neuroanatomy (MRI). These results will help us understand the specific functional deficits associated with developmental or acquired damage to the cerebellum and thereby will contribute to understanding the brain substrates of behavioral dysfunction in autism. Such knowledge may enable more effective treatment and aid the search for the origins of this debilitating disorder.

DESCRIPTION (provided by applicant): We propose to conduct a first-ever comprehensive quantitative investigation of motor function in autism using simultaneous brain and movement imaging. A novel system developed by Co- Investigator Makeig and his colleagues (Mobile Brain/Body Imaging, MoBI), will allow us to measure timing, accuracy and efficiency of natural full body motion during self-initiated and directed movement while simultaneously recording high density EEG. We will test 25 ASD adolescents (aged 12-16) and 25 typically developing age- and IQ-matched controls. Participants will complete a series of neuropsychological tests, functional assessments, MR and Diffusion Tensor Imaging and MoBI brain and movement imaging. An additional 10 low-functioning young children with autism (aged 4-8) who evidence frequent episodes of repetitive, stereotyped movements will participate in brain and movement imaging during stereotypies. The objective of this exploratory R21 project is to develop and refine data collection and analytic methods for use with ASD individuals in order to: (1) specify the nature of abnormalities of motor function in adolescents with autism or Asperger's disorder;(2) identify the associated underlying brain networks that support motor anticipation, planning and execution in ASD and in typically developing controls;(3) investigate the association of motor dysfunction with other cognitive (e.g., dyspraxia, visual-motor integration) and social symptoms of ASD;and (4) examine motor function and brain activation during repetitive and stereotyped movements in a small sample of low functioning children with autism. Relevance: The recognition that motor dysfunction is a prominent feature in ASD and that these problems may even be a contributing factor in some cognitive and social deficits has led to a variety of interventions featuring motor or sensory-motor training. However, because little is known about the specific nature of motor dysfunction in ASD, these therapies have little scientific guidance. Specific abnormalities and severity of motor symptoms vary from individual to individual, and there is currently no accepted model for organizing this variability or forming sub-types based on patterns of motor dysfunction. Moreover, because of problems inherent in imaging motion, little is known about brain function underlying motor symptoms. The proposed study will address these issues. The study goal is to provide an initial exploration of patterns of motor and associated brain function that may be used to organize the variability in ASD motor dysfunction, and an exploration of the association of motor dysfunction with other cognitive and social symptoms. Methods and data from this exploratory study will also provide the base for a large sample study from which explanatory models can be tested. Isolating specific underlying mechanisms that lead to a variety of motor impairments (e.g., timing, anticipation) would inform effective intervention that may in turn improve not only motor competence but also behavioral problems that are affected by motor dysfunction. PUBLIC HEALTH RELEVANCE: Problems with motor function are prominent in autism, but may differ greatly from person to person. While motor problems can clearly affect daily function, they may also affect social function and may contribute to difficulty learning social skills during early childhood. Our novel system for imaging natural movement and brain activity at the same time will allow us to identify underlying similarities across different impaired movements which will increase our understanding of the nature of motor behavior in ASD and will guide development of effective intervention.

DESCRIPTION (provided by applicant): Abnormal responses to sensory stimulation are a commonly reported clinical feature of autism spectrum disorder (ASD). Sensory symptoms are included in the ASD profile on a number of standardized assessments, and studies based on these self- or observational reports find increased rates of sensation seeking or sensation avoidance in all sensory modalities, although the nature and affected sensory modality of these abnormalities varies greatly between individuals. Despite the general consensus that sensory abnormalities are an important clinical symptom in autism, there is little or no understanding of the underlying mechanisms. Further, because the vast majority of evidence regarding these symptoms is based solely on behavioral descriptions, it is not clear if these symptoms are truly sensory in nature or if they reflect abnormalities of general arousal levels, attention or perception. Based upon our own work and existing evidence, we suggest a model in which basic sensory function is intact in ASD and abnormalities in sensory behavior result instead from the influence of poorly modulated arousal and attention on sensory responsiveness. We propose to address this important issue using electroencephalography (EEG) and physiological measures of arousal (skin conductance and heart rate) in young adults and children with ASD. We will assess auditory and visual sensory functions including levels of sensory response, habituation and neural response recovery, and will examine the influence of arousal and attention on sensory responsiveness. A wide variety of therapeutic interventions target sensory function, but there is scant evidence for the efficacy of these treatments. Understanding the nature of sensory abnormalities and the processing level at which sensory behavior is perturbed will guide the development of more effective therapeutic interventions and/or specific pharmacological treatments. Because abnormal sensory behavior is among the most troublesome of ASD symptoms, providing a scientific basis for treatment of these symptoms would have a significant impact on the field.

DESCRIPTION (provided by applicant): Autism Spectrum Disorder (ASD) is a lifelong disorder that severely affects the ability to learn and function in a social environment. In typica function, higher level social, language and communication skills develop over the first few years of life and depend upon the critical building blocks of sensory-motor and attention abilities. Similarly in autism, higher level problems with social communication develop over the first two post- natal years and are preceded by subtle but abnormal visual attention and motor skills. Trainings to improve social interaction and communication are the most common of behavioral interventions in ASD. These therapies may improve the specific behaviors that are targets of the training, but rarely do they generalize to broader function or other clinical symptoms. We propose that interventions aimed instead at the early deficits that support social and language skills would be more broadly effective. Because disruption of attention is one of the earliest and most persistent symptoms in autism, and because attention is highly subject to improvement with training, it is an important target for intervention. We propose a novel intervention to trai the speed and accuracy of attention orienting and eye movement. The training is designed to target attentional behaviors that have been shown to be impaired in autism, including attention orienting, disengagement and shifting, and a restricted attentional field. Because eye movement and attention are tightly linked, eye movement deficits in ASD parallel those found in spatial attention. Eye movements provide a marker for attention and the proposed training is designed to improve speed, accuracy and flexibility of eye movement and attention simultaneously. Training will use a series of entertaining video games to gradually shape behavior using visual and auditory feedback provided in real time from wireless EEG mounted in lightweight headgear designed for home use. We plan three levels of outcome measures for pre- and post-training to test the effectiveness of the intervention (direct tests of attention and eye movement; tests of improvement in attentional and visual monitoring and speed and accuracy of response in a simulated environment; tests of behavior in an actual social environment). During the R21 phase of this application we will: complete and test hardware and software; validate EEG and eye-tracking methods; test feasibility of the system for use at home; design, program and pilot test the video games. During the R33 phase of this project we will conduct clinical trials with control conditions (e.g., standard video games without training elements) with a small sample of ASD children aged 9-15. If this initial work is successful, the long term goal would be to develop a readily available inexpensive EEG-based system for home use that is suitable for a broad age range of ASD children and adults. PUBLIC HEALTH RELEVANCE: Current therapies target social and language behaviors, but due to the high-level nature of these skills any improvement rarely extends beyond the targeted behavior. This project uses new technology to implement a novel concept for behavioral intervention to improve basic attention and eye movement skills in ASD. Because these basic skills form the foundation for good social communication, training these abilities has the potential to improve a broad spectrum of clinical symptoms, and in young children may affect the course of development.

ABSTRACT: By 2030, older adults will outnumber children with 25% of the population of the United States age 65 or older. The rate of Alzheimer?s disease (AD) and related dementias will also increase as the size and proportion of the older adult population continues to expand. In the past decade, deaths from AD have increased more than 120% in the US and AD is currently a leading cause of death. The impact on public health systems from increased care for those with declining medical and mental health is a major concern. An additional important concern is for the quality of life in older adults who are aging typically but experiencing decline in memory and cognitive function. Mild cognitive impairment (MCI) can begin in middle age and increase throughout the lifespan affecting many aspects of daily function. To date there is no effective cure or treatment to slow progression of MCI or AD. Prevention, however, is a growing possibility with some recent evidence that enhancement of cognitive function may reduce effects and delay the onset of MCI, AD and related dementias. One of the more promising current approaches to enhancing cognitive performance is use of video-games. Action video games can improve selective attention, processing speed and working memory. Advantages of game-based cognitive training include the ease of use at home which provides for extended distributed practice and high engagement. We propose a project that uses video-games for cognitive enhancement that differ critically from those currently in use. Our training games use gaze to train attention which forces a constant high level of engagement. Additionally, these games target specific attentional skills that are affected in typical aging (distraction and response inhibition) and that affect executive and memory function as well as practical function such as driving safety. These games have been used successfully to train impaired attention including resistance to distraction in teens and young adults with developmental disorders. We expect training to be equally effective in older adults. We propose to use the 2-year planning period to conduct a clinical trial that aims: to identify and address any modifications of the games required for adaptation to diminished sensory abilities in older adults; to optimize training dosage and test timing of retention of effects; and to test and refine the battery of outcome assessments. A subsequent large sample randomized control trial of healthy adults aged 60-80 would employ: 4 participant groups (active trainees, 2 active control groups, a group with MCI); 4 levels of outcome assessment (1. primary measures of attention; 2. EEG, FMRI, structural and DTI biomarkers of change (with a focus on brain regions vulnerable in AD such as hippocampus, medial temporal lobe); 3. assessment of cognitive/memory function; and 4. assessment of practical function and perception of self-efficacy). A long-term follow-up would assess the rate of MCI, AD and related dementias in trained compared to control samples. Our cross-disciplinary leadership team represents expertise in AD/MCI research, neuropsychology, geriatric mental health, clinical trial methods, biostatistics and development and use of games for health-related assessment and intervention.