Julius Fridriksson, Ph.D. - US grants

DESCRIPTION (provided by applicant): The long-term objective of this research is to increase understanding of the relationship between brain changes and behavioral recovery from stroke. Recent studies of the relationship between brain perfusion, lesion size, and early severity of aphasia (language disorder) in stroke suggest that these variables are strongly correlated. It is not clear, however, how changes in cerebral perfusion and lesion size may be related to behavioral recovery following stroke. MRI provides means for quick assessment of cerebral perfusion and lesion size in the acute stages of stroke. Along with behavioral testing, MRI makes it possible to investigate how changes in neurological factors are related to stroke recovery. The specific aims of this project are to answer the following questions: 1. Do changes in cerebral hypoperfusion and/or lesion size predict recovery from aphasia and hemispatial neglect during the first month following stroke. 2. Does the extent of cerebral hypoperfusion and/or lesion size in acute ischemic stroke predict recovery from aphasia and hemispatial neglect and clinical outcome at one-month post-onset? Answers to these questions will provide insight into how brain changes and behavioral recovery may be related in early stroke. Consequently, they provide means to improve management of early stroke and, subsequently, aphasia and hemispatial neglect. That is, if the extent of behavioral recovery can be predicted based on brain physiology in the acute care [stage?], it is possible that stroke treatment can be better calibrated.

[unreadable] DESCRIPTION (provided by applicant): This project will investigate the relation between neurophysiology and anomia recovery in aphasia following stroke. Stroke is the leading cause of disability in the United States, with an increasing number of patients surviving stroke, typically to a life of greatly reduced quality. Aphasia is one of the most frequent and tragic impairments that result from stroke. It is crucial to be able to understand how to determine an accurate prognosis, and also to maximize the effects of therapy on recovery. This project is focused on anomia recovery in aphasia, but also has more general applicability to recovery of motor and cognitive function following stroke. Previous research suggests the size and location of brain damage may be important factors in determining the extent of treatment-assisted aphasia recovery. While basic lesion parameters of size and location can be derived from the MRI scans of routine clinical investigation, many more sophisticated modalities of MRI are now available. This proposal will determine the degree to which standard structural scans can be used to predict treatment outcome, and what extra value can be derived from other MRI techniques such as perfusion and diffusion weighted MRI. The present project uses a prospective design to investigate the relation among 'brain fitness' (the structural lesion, cerebral perfusion, fiber density, and peri-lesional gliosis) and treatment assisted anomia recovery in aphasia. A group of persons with aphasia will undergo detailed assessment of neurophysiology using standard and advanced MRI techniques before and after two types of anomia treatment either focusing on phonological or semantic processing. The value of different indices will be assessed using logistic regression techniques that we have recently developed and validated. In addition, this research will investigate the neural basis of treated language recovery using fMRI. The long term goals of this research are to design more accurate and appropriate approaches to determine prognosis of patients with aphasia, maximizing the effects of treatment by ensuring optimal selection of treatment according to lesion parameters, and identifying targets for novel therapeutic interventions by assessing the neural substrates of successful recovery. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Apraxia of speech (AOS) and conduction aphasia are commonly caused by left hemisphere stroke and often severely affect speech production. Although the clinical profile involved in these disorders is different, the most effective methods for managing them are unclear and many patients with AOS or conduction aphasia show limited recovery despite intensive treatment. We suggest that the underlying impairment in both AOS and conduction aphasia is poorly understood and propose a new framework for characterizing both disorders. Building on our previous research as well as the latest models of speech perception and production, this project will examine the neural bases of AOS and conduction aphasia. The result should be increased understanding of normal and disordered speech/language processing as well as offer new insights into rehabilitation of these two poorly understood disorders. Although the critical lesion locations associated with AOS and conduction aphasia have been controversial, recent studies suggest that damage to Broca's area and the left posterior inferior parietal lobe cause AOS and conduction aphasia, respectively. Along with others, our research has identified Broca's area as playing a role in not only the production of speech but also in the visual perception of others' speech motor movements. Similarly, recent studies (including our own) suggest that the left posterior inferior parietal lobe plays a critical role in speech processing as an interface between auditory speech and motor speech output. These findings suggest that individuals with AOS and conduction aphasia have an impaired speech perception component that may negatively affect recovery efforts aimed at improving speech production. Although this previous research has important theoretical and practical implications for understanding the neural basis of human communication as well as the nature of AOS and conduction aphasia, further study of this issue is imperative. This project will involve testing of a large group of stroke patients with left hemisphere damage as well as transcranial magnetic stimulation (TMS) to examine the effect of permanent (brain damage in stroke patients) and transient (TMS in normal participants) cortical interruption on speech processing. The long-term goals of this research are to better understand the neural bases of AOS and conduction aphasia. Treatments aimed at improving speech production in patients with AOS or conduction aphasia have traditionally proceeded with the assumption that speech perception is intact in both disorders. Therefore, it is crucial to understand the relationship between impaired speech production and perception in AOS and conduction aphasia. As a result, future treatments of thes frustrating and recovery resistant disorders can be greatly improved.

The goal of this research is to understand how different referential forms are processed in the brain. Most instances of real-life language use involve discourses in which several sentences or utterances are coherently linked through the use of repeated references. Repeated references can be made with different forms. For example, a person mentioned early in discourse (the referent) can be later referred to by a proper name (e.g., Bill), a specific definite description (e.g., the waiter), a less specific definite description (e.g., the man), or a pronoun (e.g., he). The form of referential expressions has played a key role in theories of reference, but not much is known about the underlying brain mechanisms.

This research project will test the theoretical claim that the choice and processing of referential form reflect general memory processes that are involved in the representation of multiple referents and that these processes are prone to interference, especially when the referents are salient. According to this "interference view", high semantic overlap between the referential expression and the representation of the referent in memory results in more interference. General referential forms such as pronouns and general definite descriptions, which represent conditions of low semantic overlap, reduce this interference and these expressions are preferred when referents could be easily identified. At the neural level, the interference view predicts that semantic overlap between the representations of the referential expression and the referent can increase brain activation both in areas that are involved in the semantic representation of referents (e.g., regions in the temporal lobe for many types of object referents) and in areas that are known to support the manipulation and integration of multiple representations (e.g., areas around the intra parietal sulcus (IPS)). Self paced reading and matching functional MRI (fMRI) experiments will test the predictions of this view by examining the relation between brain activation and behavioral aspects of processing definite description references.

The application of converging behavioral and fMRI methodologies is unique in discourse research and holds promise for bridging functional accounts of discourse processes with their possible brain basis. Tying referential processing to underlying brain mechanisms would represent a major leap forward in terms of the scientific understanding of these issues. Moreover, explaining linguistic phenomena on the basis of non language brain mechanisms is a potentially transformative research in that it could disrupt the well accepted theoretical perspective that reference processing is driven by language "rules" or arbitrary conventions.

DESCRIPTION (provided by applicant): Stroke is the leading cause of adult disability in the United States. One of the most devastating impairments resulting from stroke is aphasia, a language impairment caused by left hemisphere damage involving cortical language areas. Although considerable research effort has focused on increasing aphasia treatment efficacy, most chronic stroke patients with aphasia experience limited recovery. Therefore, enhanced aphasia treatment outcome is of paramount interest as it may improve patients' communication ability and quality of life. Recent studies utilizing animal models suggest that low current transcranial direct current stimulation (tDCS) can locally increase the secretion of brain derived neurotrophic factor (BDNF), a protein that is crucial for induction of brain plasticity. Research i humans has further demonstrated the positive effect of anodal tDCS (A-tDCS) on learning in normal subjects. For the first time, we have shown in a pair of studies how A-tDCS can significantly enhance the effect of the behavioral treatment of anomia (impaired ability to name common objects) in patients with chronic stroke-induced aphasia. Capitalizing on these findings as well as our other research aimed at understanding brain plasticity associated with aphasia treatment, we propose to conduct a Phase II clinical trial to examine the effect of A-tDCS on anomia treatment outcome in patients with chronic stroke. This project will include a randomized, prospective, double-blind trial with two arms (active vs. control) wherein chronically stable stroke patients will receive behavioral aphasia treatment coupled with either A-tDCS or sham tDCS (S-tDCS). Because anomia is the hallmark impairment in aphasia and is present in all aphasic patients, regardless of severity or aphasia type, the primary outcome factor will be anomia severity, defined as the ability to correctly name common objects. The long-term goal of this research is to conduct a Phase III trial to determine if A-tDCS significantly enhances the effect of behavioral aphasia treatment. If the A-tDCS is proven to have a positive effect on aphasia treatment outcome, it is possible that patients who currently receive limited or no treatment benefit may respond to treatment when it is coupled with A-tDCS. Similarly, it is possible that A-tDCS may further boost the treatment effect for patients who respond positively to treatment in the absence of direct brain stimulation.

? DESCRIPTION (provided by applicant): Stroke is the leading cause of serious disability among adults in the United States.1 Aphasia, a language disorder caused by damage to the speech and language regions in the left hemisphere, is one of the most devastating results of stroke and affects individuals' ability to communicate effectively. Broca's aphasia is one of the most common types of aphasia and is characterized by restricted speech output, often not exceeding 1- 3 words per utterance, and relatively preserved auditory comprehension. Once in the chronic phase, most patients with Broca's aphasia experience very limited improvement in speech production. In a recent study2, we showed that patients with Broca's aphasia could produce fluent speech while mimicking an audio/visual speech model. In short, patients were able to mimic a one-minute script that was prerecorded and presented so that the speaker's mouth was seen on a computer screen and the speech was heard via headphones. We refer to this effect as speech entrainment, where the audio/visual speech model yokes the speech of the non-fluent patient, allowing him/her to produce fluent speech. Whereas speech entrainment might be important for understanding normal speech production, we propose that it could have important implications for rehabilitating patients with Broca's aphasia by allowing them to practice fluent speech production, something that is inherently very difficult for this population. The purpose of this pilot project is to estimate effect sizes associated with improvements in speech production as a result of speech entrainment treatment (SET). If SET results in medium or large effect sizes for improvements in speech production, we will move on to a larger trial where the effects of SET can be established and compared to other kinds of treatments for speech production in aphasia. The second goal is to understand cognitive-linguistic factors in relation to patients' ability to speak with the aid of speech entrainment. This will allow us to identify factors that are contraindicative for SET (to define inclusion/exclusion criteria in a larer trial) as well as relate our findings to contemporary models of speech processing. The long-term goal is to develop a treatment approach that can be used to improve speech production in Broca's aphasia, something that has been shown to be particularly resistant to treatment. We emphasize that the treatment approach presented here represents a starting point in our development; more data will allow us to modify SET and better tailor it towards specific patients.

The purpose of the Administrative Core (Leader: Fridriksson) is to maintain oversight of each of the four projects and two scientific cores. As during the current phase of C-STAR, core and project leaders will be in charge of everyday operations with the Administrative Core ensuring that planned activities are initiated in an expeditious manner and carried out as described in the research plan. In addition, the Administrative Core will continue to manage the overall budget of the project, including financial oversight of each research site, and conducting thorough audits of all past and planned expenditures. With the aid of the Data Coordination Unit (DCU) at the Medical University of South Carolina (MUSC), the Administrative Core coordinates data collection across each clinical site ? University of South Carolina (UofSC), MUSC, Johns Hopkins University (JHU), and University of California Irvine (UCI). During the current phase of C-STAR, the DCU has provided data management for all data collection on the project and will continue to do so if the current proposal is funded. The DCU has been instrumental for the success of the current trial and will aid in collection, coordination, storage, analyses, and dissemination of all behavioral data. The Administrative Core will continue to be responsible for coordinating communication across research cores and projects. This includes scheduling meetings at appropriate intervals to discuss progress, coordinate similar activities across different sites, and if needed, solve problems. These meetings focus on resolving discrepancies in data entry and to modify data collection efforts to best fit the long-term goals of the project. The Administrative Core supervises coordination of all meetings, including setting meeting agendas and recording meeting minutes. To coordinate meetings across sites, we will continue to rely on conference services provided by GoToMeeting? (www.gotomeeting.com).

? DESCRIPTION (Description as provided by applicant): Stroke is the leading cause of adult disability in the United States, making it a major public health concern (1). The Centers for Disease Control (CDC) estimates the annual cost of stroke in the United States to be $36.5 billion (1). Accordingly, it is clear that the negative personal and societal impact of stroke is vry high. Stroke is typically thought to affect older persons; however, many younger individuals also suffer strokes. For example, at least half of all stroke patients in the state of South Carolina ar under the age of 60 (2). Approximately a quarter of all chronic stroke survivors present with aphasia, a language disorder caused by damage to the speech and language areas of the brain (3, 4). The prevalence of chronic aphasia in the United States is estimated to be one million. Aphasia can vary in severity from very profound impairment that renders patients mute and without the ability to understand others' speech, to milder forms where patients have great difficulty retrieving specific words. In the chronic stage of stroke, aphasia has been identified a the strongest predictor of poor quality of life. Aphasia not only influences the ability to communicate with family and friends, but also drastically decreases education and employment opportunities. Although some degree of spontaneous recovery from aphasia is typical in the first weeks and months following stroke, many patients are left with devastating communication problems. Once aphasia has become a chronic condition, the only road to recovery is through aphasia therapy. Several meta-analysis studies suggest that aphasia therapy is effective. In spite of decades of research, very little is known about which patients benefit the most from treatment and what kind of treatment should be administered to patients with different impairment profiles. The overarching goal of the research proposed here is to improve aphasia treatment effectiveness as well as identify patient factors that can be used to improve diagnosis of language impairment, guide aphasia treatment, and predict prognosis. Specifically, the focus of our center (Center for the Study of Aphasia Recovery; C-STAR) is to examine the extent to which factors such as behavioral aphasia treatment, electrical brain stimulation, and residual brain function influence aphasia recovery. To accomplish our research goals, this project will rely on collaboration among four main investigators: Drs. Julius Fridriksson, Argye Hillis, Chris Rorden, and Greg Hickok. Projects led by Fridriksson (chronic patients) and Hillis (acute patients) will focus on factors that may promote improved outcome of aphasia therapy. Both projects will yield a vast, unique dataset including measures of brain status and response to aphasia treatment. Relying on this dataset, Rorden's project will predict recovery from aphasia using machine learning approaches whereas Hickok will utilize the same data to better understand aphasic impairment in relation to contemporary models of speech and language processing.

Summary: Project 1 Stroke is the leading cause of serious adult disability in the United States. One of the most devastating impairments resulting from stroke is aphasia, a language impairment caused by left hemisphere damage involving cortical language areas. It is generally accepted that behavioral aphasia treatment is effective. Nevertheless, different patients experience very different degrees of benefit from aphasia treatment. Despite considerable differences in the response to aphasia treatment, the relationship between patient factors and treatment response is poorly understood and very few reliable prognostic indicators have been identified. This is a major problem, as both time and resources are wasted when clinicians do not know what patients are likely to respond to treatment, or which treatment best fits individual patients. The purpose of the current project is to develop a model that includes biographical and cognitive/linguistic factors to predict patients' response to aphasia treatment. Aphasia severity is one of the few factors that has been identified as a reliable predictor of performance in treatment; it is generally accepted that more severe aphasia is associated with poorer treatment outcomes. However, aphasia severity is a multidimensional construct and patients with similar overall severity scores might demonstrate very different language impairment profiles. To better understand how language impairment relates to treatment outcomes, the dual stream model (DS model;1) will be consulted. Specifically, we will test whether measures of proportional damage to the cortical areas that comprise the DS model improve prediction of aphasia treatment response, beyond biographical and cognitive/linguistic factors. Although the DS model is a functional model grounded in neuroanatomy, we expect measures of speech and language that assess processes supported by the two major components of the DS model ? the dorsal and ventral streams ? might be redundant with measures of cortical damage. To understand whether our predictive model can be generalized across different kinds of treatment foci, each patient will undergo treatment devoted to phonological stimulation and a separate treatment phase focusing on semantic stimulation. Ultimately, the goal here is to construct a predictive model that will be made available on- line so that clinicians can enter test scores from individual patients to predict how likely a given patient is to respond to treatment, as well as the focus of that treatment. There is a great need for prognostic indicators of aphasia treatment response. At the completion of our research, we will understand why some patients respond better to aphasia treatment than others. We have selected treatment approaches that are routinely used in clinical practice, allowing for immediate translation of the findings directly into patient management. The current project will yield a vast dataset that will be made publicly available allowing others to study further aphasia treatment response in relation to cognitive/linguistic and lesion factors.  

Abstract In spite of recent advances in the treatment of acute stroke, 20% of chronic stroke survivors suffer from long-lasting language impairments (aphasia). Non-fluent aphasia is one of the most common forms of aphasia, and it is directly associated with social isolation, decreased participation in rehabilitation therapies, and low quality of life. The reestablishment of fluent speech is one of the most challenging aspects during the treatment of subjects with chronic non-fluent aphasia. As a novel alternative to this problem, our group has optimized a new and promising treatment approach entitled speech entrainment therapy (SET), where the subject's speech is pulled along (guided by) an audio-visual model presented on a laptop computer. In a preliminary and proof of concept study, we observed that subjects with non-fluent aphasia could overcome the barrier towards fluency and produce more fluent speech with SET. They had greater than 20% improvement in verbs per minute (VPM) during spontaneous speech at three months after therapy. These are very encouraging findings because they represent sustained post-treatment gains in producing verbs during discourse, which is a valid ecological measure, and a better predictor of language abilities compared with producing nouns or naming objects. Motivated by these findings, we propose a prospective controlled randomized assessor blinded phase II clinical trial entitled Speech entrainment for Aphasia Recovery (SpARc) to better assess the linguistic improvements associated with SET, and to determine the optimal dose of SET. This trial will be a multisite (5 sites) project that will enroll 150 chronically stable stroke survivors with non-fluent aphasia, and the primary outcome will be VPM at 3 months post-therapy. We will use a Seamless Two-Stage Dose Selection design, which will include a Stage 1 to choose the best SET dose, and a Stage 2 to assess the full effects of SET. In Stage 1, the patients will be randomized to 3 different doses of SET: 3 or 4.5 or 6 weeks of 1 hour daily SET, or a control (no treatment) condition (20 patients in each one of the 4 groups). Based on a pre-defined rule, we will select the dose that demonstrated adequate tolerability and was associated the highest group average VPM at 3 months post treatment. In Stage 2, we will enroll 70 additional patients and randomly assign them 1:1 to either the selected SET duration or the control group. The final analysis will test whether the change from baseline in VPM for the selected SET duration group is better than the control group using patients enrolled in Stages 1 and 2. SET will be considered worthy of further study if it leads to an improvement in 20% or more in VPM at 3 months after therapy compared with the no treatment control condition. This study will provide a better understanding of the therapeutic benefits of SET, determine its best dose, and decide whether its effects would justify future studies of this new and promising form of therapy.

Project Summary/Abstract The Center for the Study of Aphasia Recovery (C-STAR, P50-DC014664) explores recovery from language impairments following stroke, bringing together a diverse team of specialists from communication sciences, neurology, psychology, statistics and neuroimaging. This project acquires a broad range of magnetic resonance imaging (MRI) modalities (structural, diffusion, arterial spin labelling, functional, resting state) from stroke survivors to understand the brain areas critical for language, improve prognosis, and identify the optimal treatment or compensation strategy for each individual. The neuroimaging core for C-STAR has developed unique methods to visualize these different modalities, in support of the research projects. These methods have dramatically extended our popular MRIcroGL and Surfice tools to better leverage modern hardware and provide unique visualizations. However, these tools are currently available only as native standalone desktop applications for Windows, Linux and MacOS. The primary aim of this supplement will be to translate our native applications to cloud-based solutions. Specifically, we will use modular JavaScript and Vue.js components that can be embedded into web pages. This will allow users to visually inspect and disseminate results regardless of operating system or device. Our novel techniques are compatible with any web browser that supports the WebGL 2 standard, thereby supporting computers, tablets and phones. Already, the developers of the popular FSL pipeline plan to use our modules to create interactive images to replace the static web pages generated by their current FEAT tool. While other solutions exist for this niche, none provide the unique visualization properties we have developed in our current applications. Indeed, the open source web-based tool we will develop will showcase these features and allow other developers to use our code to improve their own tools. Because we use GitHub and the NeuroImaging Tools & Resources Collaboratory (NITRC, www.nitrc.org), users will be able to post issues, request new features, and submit improvements. Our automated tests allow Continuous Integration (CI) and validated performance. Translation of our current suite of visualization tools to cloud-based programs will make data more findable, accessible, interoperable, and reusable (FAIR).

Project Summary/Abstract The Center for the Study of Aphasia Recovery (C-STAR, P50-DC014664) explores recovery from language impairments following stroke. The center acquires a broad range of magnetic resonance imaging (MRI) modalities as well behavioral measures from stroke patients experiencing language impairments. Like all modern large scale NIH grants, C-STAR has a resource sharing plan that guides dissemination of curated data (following an embargo). However, in addition to this data, the C-STAR team has been acquiring images from people with aphasia using our Siemens 3T MRI scanner since 2006. This trove of data, which we refer to as the `Aphasia Recovery Cohort', or ARC, is the product of both internally supported and NIH funded awards that did not require resource sharing plans and includes data from 250 stroke survivors scanned during 5776 unique sessions. In addition to the imaging sessions, ARC patients participated in numerous treatment and assessment sessions providing a rich range of behavioral measures. The current proposal seeks to curate these data to provide an anonymized public database and search tool (ARCquery). This will allow data scientists from around the world to apply their expertise to this archival dataset, providing new insights into brain function as well as identifying predictors of recovery. This repository will provide a Findable, Accessible, Interoperable, and Re-usable (FAIR) dataset.

Summary: Project 1 It is now commonly accepted that aphasia therapy in chronic stroke is effective for improving language processing, and perhaps to a lesser extent, quality of life. Nevertheless, most persons with chronic aphasia in the United States have very limited access to therapy. Although the reasons for this state of affairs are several, two factors are particularly important: insufficient reimbursement for therapy services and lack of access to local transportation to and from therapy. A way to tackle both of these problems is to provide aphasia therapy at a lower cost and eliminate the need for transportation. Providing aphasia therapy via telemedicine (clinician administered therapy across the internet) will provide cheaper therapy by eliminating the need for a physical facility to provide services and by reducing the need for transportation to and from therapy for either the clinician (home health) or the patient (outpatient clinic). The purpose of Project 1 is to conduct a phase II, non- inferiority trial of telerehab for aphasia therapy (aphasia remote therapy; ART), which will be exclusively administered by a speech-language pathologist. All participants (N=100) will be randomized to receive either telerehab (ART) or in-clinic therapy (I-CT) using the same kind of therapy we are currently using in Project 1. The outcome measure will focus on speech production and combines correct naming and correct words produced per minute during discourse. The primary endpoint is change in the outcome measure at 6 months compared to baseline. The non-inferiority margin will be set so that if ART leads to less than 50% improvement than the improvement following I-CT, it will be considered inferior for therapy delivery. In addition to comparing the difference in outcome for ART and I-CT, we will also explore factors that influence the efficacy of telerehab for aphasia therapy. For this purpose, we use a theoretical framework that is typically used to study the acceptance of and personal attitudes towards telemedicine. Moreover, we will test participants? cognitive- linguistic status and collect biographical information to study which participants may have difficulty with telerehab and may be poor candidates in a future, phase III trial. If our trial finds that ART is non-inferior to I- CT, it will provide strong motivation to proceed with a phase III trial on a therapy modality that could significantly alter and improve access to aphasia therapy for a population that now is estimated to exceed 2 million individuals in North America. In addition to conducting a very timely clinical trial on ART, the work proposed here will continue to expand our database on aphasia therapy outcome that is being populated in the current phase of Project 1. Accordingly, the synergy between the current and the proposed work in Project 1 will be maintained. Moreover, Project 1 will continue to provide data for Projects 3 and 4 to study brain health in relation to aphasia therapy outcome and neuropsychological models of language, respectively.