Mark D'Esposito - US grants

Memory impairment is a common problem in Parkinson' disease (PD). This proposal investigates working memory (i.e. short-term memory) deficits in PD patients as compared to normal elderly. My first aim is to determine the nature of the working memory deficits in PD. 1 hypothesize an impairment in a specific component of working memory called the "central executive system" (CBS), that is critical for allocating limited attentional resources. This hypothesis will be tested by performing dual- task paradigms designed to directly examine CBS functioning. An alternative hypothesis, that PD patients have weakened working memory representations rather than a defective CBS, will also be tested. The second aim is to define the neuroanatomical basis of working memory. Primate studies have shown that the caudal principal sulcus is critical for working memory. Physiological studies have not examined the CBS of working memory in either primates or humans. Cognitive activation studies during dual-task paradigms using PET and functional MRI will be performed in normal human subjects to define the neural network subserving the CBS of working memory. I hypothesize that the dorsolateral prefrontal cortex (Brodmann areas 9 and 46) will activate during dual-task paradigms. I will also examine PD patients with CBS deficits. I hypothesize that CBS impairments found "off-line" in PD patients will correlate with resting hypoperfusion in the dorsolateral prefrontal cortex. Also, these patients will fail to activate the dorsolateral prefrontal cortex when performing these CBS tasks, suggesting that this region is functionally defective in this disease. The third aim is to determine the neurochemical basis of working memory. The role of dopamine in human working memory will be tested by studying PD patients "on" and "off' medications and investigating the effect of administering a dopaminergic agonist to normal elderly subjects. I hypothesize that the CBS of working memory will improve during the "on" state in PD patients and after dopamine stimulation in normal elderly subjects. In this fashion, a multi-factorial model characterizing the cognitive, neuroanatomical and neurochemical basis for working memory will be defined. These studies will improve our knowledge of working memory and provide a rational basis for diagnostic and therapeutic intervention in patients with working memory impairments.

Memory impairment is a common problem in Parkinson's disease (PD). The overall aim of this proposal is to apply cognitive neuropsychological theories and functional neuroimaging techniques to the study of a specific component of working memory function in Parkinson's disease (PD) patients. We anticipate that these complementary methods will nurture cross- fertilization of cognitive and neural models of working memory, yielding important insights for this elusive cognitive domain. Moreover, these insights will lead to new ways of diagnosing and treating the memory dysfunction in PD patients. The FIRST AIM is to determine the nature of the working memory deficits in PD. We hypothesize an impairment in a specific component of working memory called the "central executive system" (CES), a system that is critical for allocating limited attentional resources and regulating verbal and spatial passive slave memory buffers. We will test the functioning of the CES in PD patients and age-matched controls using dual- task paradigms which have been designed to directly test this system. An alternative hypothesis, that PD patients have weakened working memory representations rather than a defective CES, will also be tested using the fan-effect paradigm. Individual patient analyses will be used to contrast performance on dual-task paradigms, the fan-effect paradigm and clinical measures of executive functioning. We expect that these more narrowly- defined paradigms will identify the specific nature of the working memory deficits found in PD. The SECOND AIM is to define the neural basis of working memory. Nonhuman primate studies suggest that the dorsolateral prefrontal cortex is critical for working memory. Physiological studies have not examined the CES of working memory in either nonhuman primates or humans. Cognitive activation studies during dual-task paradigms using functional MRI will be performed in normal human subjects to define the neural network subserving the CES of working memory. We hypothesize that the dorsolateral prefrontal cortex will activate during dual-task paradigms. Using fMRI, we will also examine the ability of PD patients with CES deficits to recruit dorsolateral prefrontal cortex during dual-task performance. We hypothesize that these patients will fail to activate the dorsolateral prefrontal cortex when performing these CES tasks, suggesting that this region is functionally defective in this Parkinson's disease.

DESCRIPTION (adapted from investigator's abstract): All higher order cognition (e.g., remembering autobiographical events, reasoning, and problem solving) depends critically on two broad classes of memory function, working memory(WM) and long term memory (LTM). Aging is associated with deficits in both WM and LTM and such deficits have an impact on the cognitive functioning of older adults in all areas of their lives. Working memory refers to the information from perception and long-term memory that is currently active, and the set of processes that maintain and manipulate this active information. It allows us to keep something in mind after the initiating stimulus disappears, make connections and comparisons between events, and sustain goal directed behavior. Furthermore, WM processes are "encoding" processes for information that will be available later in LTM as part of the cumulative record of our past experiences. Neuronal studies with monkeys, human brain damage studies, and recent human neuroimaging studies point to the prefrontal cortex (PFC) as critical for WM and important in understanding memory and aging (e.g., age-related decreases in neuronal loss may be greatest within PFC). By capitalizing on converging developments in current memory theories and breakthroughs in neuroimaging technology, the proposed research combines a component process approach to memory with fMRI imaging techniques in order to characterize more precisely, cognitively and neurally, memory deficits associated with aging. For example, we test the hypotheses that (a) maintenance involves ventral PFC whereas manipulating information (combining features, shifting between tasks, cumulative rehearsal, temporal judgements) involves dorsal PFC and (b) there are greater age-related changes in component process subserved by dorsal than ventral PFC. The proposed project has four major goals: (1) further clarify the component processes that underlie the maintenance and manipulation of information in working memory and to identify their neural bases, (2) Identify the WM component processes most affected by aging (3) explore the relations between WM component processes and LTM, and the implications for LTM of age-related changes in these component processes, (4) further develop and improve fMRI techniques for studying age-related changes in the neural basis of memory.

DESCRIPTION: (Applicant's Abstract) The neurotransmitter dopamine (DA) is crucial to prefrontal function, has been implicated in a variety of neurological disorders (e.g., Parkinson's Disease, schizophrenia), and may play a preferential role in working memory and higher cognitive processes. The long-term objective of this project is to understand the role of dopamine in brain function and dysfunction. This objective is embodied in a series of studies of the effects of dopamine agonists on cognition, which satisfy the two specific aims of this project. First, we propose to study the effects of dopamine agonists on cognitive performance. Cognitive neuropsychological models of prefrontal function suggest that working memory (WM) is a critical component of higher cognitive processes, and that it depends strongly on dopaminergic pathways. A series of challenge protocols will address the basic questions about the interaction of drug effects with individual differences in working memory ability; about the range of cognitive abilities that depend on neural systems affected by these drugs; and about the nature of the tasks that depend on dopamine in the prefrontal cortex. We hypothesize that the effects of dopamine agonists will be predicted by a single model; that there is an optimal level of dopaminergic neurotransmission, and that small differences in individual tuning predict the effects of drugs on behavior. Second, we propose to use a combination of drug challenge and functional neuroimaging methods to identify cortical areas mediating the cognitive effects of these drugs. While previous studies have examined either the behavioral effects of particular drugs, or the neural processes underlying particular cognitive processes, combining these methods lets us examine more directly the neural bases of drug effects on cognition. Existing studies combining these two methods validate the combination of these techniques, but do not address themselves to this basic question. We hypothesize that differences in prefrontal activation -- i.e., both direct and indirect prefrontal cortical effects of dopamine agonists -- underlie drug-related changes in performance, while other potential cortical effects of the drug will be unrelated to performance.

[unreadable] DESCRIPTION (provided by applicant): Higher order cognition (e.g., remembering past events, carrying on a conversation, reasoning and problem solving) depends critically on two broad classes of memory function, working memory (WM) and long-term memory (LTM). LTM refers to the cumulative record of our past experiences and WM refers to the information from perception and LTM that is currently active, along with the set of reflective processes that maintain and manipulate this information. WM allows us to keep something in mind after the initiating stimulus disappears, make connections and comparisons between events, have control over what we think about, formulate intentions, and make plans. Thus, WM is cognitive system that comprises both mnemonic processes (i.e. storage and rehearsal) as well as non-mnemonic processes (i.e. executive control processes). Furthermore, WM processes have a large impact on LTM, being essential for the "encoding" and storage of LTM memories, as well as other cognitive systems such as language and perception. Thus, a modern conceptualization of WM emphasizes a system that allows for the active maintenance of relevant information necessary for goal-directed behavior. Neuronal recordings in monkeys, and physiological and lesion studies in humans have shown that prefrontal cortex (PFC) is critical for WM, and current theories have postulated that it is type of representations maintained in PFC that provides the basis for cognitive control. In this proposal, we seek to further characterize PFC representations, as well as investigate the interaction between the PFC and posterior regions during the active maintenance of relevant information. Cognitive theories have long been influenced by neuropsychological patient studies, while recent developments have been greatly influenced by breakthroughs in other technology such as functional MRI (fMRI), event-related potential (ERP) recording and transcranial stimulation (TMS). The current proposal will utilize fMRI, ERP and TMS to precisely characterize, both cognitively and neurally, the role of PFC in cognitive control. Basic knowledge about the functional organization of PFC gained from this work is of central clinical significance, and can provide substantial insights into the nature of a large number of disorders associated with the frontal lobes such as traumatic brain injury, schizophrenia, and attention-deficit hyperactivity disorder (ADHD), as well as a structural and degenerative brain diseases including Parkinson's and Alzheimer's disease. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This proposal seeks to develop a functional architecture of prefrontal cortex. Everyday actions take place in a fluid context in which we must process complex stimuli to achieve multiple goals. The term executive control has been used to account for the various processes required for such flexible behavior and includes the ability to maintain and manipulate information in working memory, establish and monitor internal goals, select task-relevant information, and organize a plan of action to accomplish these goals. The aim of this proposal is to characterize these operations at a psychological level and identify their neural correlates, focusing on the contributions of prefrontal cortex. Neuroimaging and behavioral studies will be conducted with neurologically impaired and healthy populations to address these questions. The first series of studies will use a variety of stimulus materials to systematically explore the role of prefrontal cortex in maintaining and manipulating the contents of working memory. These experiments will contrast different hypotheses concerning the functional organization of prefrontal cortex, determining if the appropriate characterization is best described in terms of processing requirements, processing content, or a hybrid of these two components. In the second and third sections, these ideas will be applied in the study of the neural mechanisms involved in response selection and goal selection. The final section focuses on how information is maintained in working memory, testing specific hypotheses related to inhibitory control. Although inhibitory control plays a predominant role in many conceptualizations of prefrontal function, especially in how it interacts with and facilitates working memory, our knowledge of the neural correlates of this cognitive operation remains limited. Within each of the four sections, various stimulus materials will be used to test the generality of the functions under investigation as well as identify material specific components of the prefrontal network. Taken together, the studies will provide a rich database for assessing, the role of sub regions of prefrontal cortex in various aspects of complex, goal oriented behavior.

DESCRIPTION (provided by applicant): As the percentage of our population over 65 increases, concern about cognitive changes in the healthy elderly grows. All higher order cognition (e.g., remembering autobiographical events, reasoning and problem solving) depends critically on two broad classes of memory function, working memory (WM) and long-term memory (LTM). Aging is associated with deficits in both WM and LTM and such deficits have an impact on the cognitive functioning of older adults in all areas of their lives. WM refers to the information from perception and long-term memory that is currently active, and the set of processes that maintain and manipulate this active information. It allows us to keep something in mind after the initiating stimulus disappears, to make connections and comparisons between events, and to sustain goal-directed behavior. Furthermore, WM processes are "encoding" processes for information that will be available later in LTM as part of the cumulative record of our past experiences. Neuronal studies with monkeys, studies of patients with brain damage, and recent human neuroimaging studies point to the prefrontal cortex (PFC) as critical for WM and LTM. In addition, there is evidence of age-related neuropathology that may disproportionately affect PFC, suggesting that changes in PFC function may, in part, underlie memory dysfunction in older adults. The proposed research combines a component process approach to memory with functional magnetic resonance imaging (fMRI) techniques in order to characterize more precisely, cognitively and neurally, memory deficits associated with aging. The proposed project has four specific aims: (1) To further clarify the component processes of memory and to identify their neural bases. (2) To identify and specify the neural bases of those component processes that are (and are not) affected by aging. (3) To clarify the conditions under which age-related compensatory brain activity is found and the nature of such activity. (4) To explore the relations between component processes engaged during WM (or encoding) and long-term memory and the implications for long-term memory of age-related changes in these component processes.

The nigrostriatal and mesocortical dopamine systems are well known to play an important role in the cognitive processes of working memory and cognitive control. However, accumulating evidence indicates that the effects of dopaminergic drugs are complex: They can improve or impair cognitive function. Such contrasting effects have been observed both in young healthy volunteers, as well as in patients with Parkinson's disease (PD), a movement disorder characterized by severe dopamine depletion. Recent progress reveals that the relationship between dopamine and cognitive performance is qualified by at least three factors. First, drug effects appear dependent on the type of task: while administration of dopaminergic drugs can improve performance on some tasks, it can simultaneously impair performance on other tasks in the same subjects. Second, the effects vary depending on dopamine receptor selectivity of the drug under study. Thus, stimulation of dopamine D1 and D2 receptors has dissociable effects on distinct cognitive functions Third, dopaminergic drugs can improve function in some individuals while impairing the same function in other individuals. The proposed experiments aim to characterize these complex, sometimes paradoxical effects of dopaminergic drugs in both healthy subjects and PD patients as a function of task demands, receptor specificity and individual differences in baseline capacity. Both performance and brain activity (using fMRI and PET)will be assessed. More specifically, drug effects are predicted to differ depending on whether the task requires motor versus cognitive processes, and whether the task requires cognitive flexibility versus cognitive stability. We predict that these dissociable effects reflect differential modulation by dopamine of striatal versus prefrontal brain regions. In addition, they may reflect differential modulation by dopamine at D1 and D2 receptors. Finally, drug effects are hypothesize to differ depending on individual variation in baseline working memory capacity, associated with baseline dopamine function. Dopamine is of fundamental importance to the etiology of a wide variety of neurobehavioral disorders such as PD, attention deficit hyperactivity disorder, schizophrenia and drug addiction. A further understanding of the relationship between dopamine and cognition should further our understanding of the mechanisms underlying cognitive and behavioral deficits in these disorders and provide insight into novel approaches to treating such deficits with medications targeted at specific neurotransmitter systems.

[unreadable] DESCRIPTION (provided by applicant): This proposal focuses on the way reward and motivation are linked to executive function. Reward representation and working memory are key functions of the prefrontal cortex (RFC), but their interactions are not well understood at the neural systems level. This line of functional MRI experiments will test fundamental assumptions about the way motivation and performance are represented in the brain. All experiments use variations of a working memory task requiring the maintenance of faces or scenes that has been shown to recruit PFC and posterior visual areas (Parahippocampal Place Area and Fusiform Face Area). Further, the task allows for the separation of working memory component processes involved in encoding, maintenance, and response. Experiment 1 will test whether manipulations of reward value recruit separable, or additional PFC regions and whether modulations in posterior visual areas can be altered by higher motivation trials. A second experiment will investigate financial penalty trials to assess the differences that may exist in a non- rewarded motivation manipulation. There are several theoretical reasons that reward and penalty activation may differ in important ways and these have not been previously tested using cognitive working memory paradigms. Analyses will include whole-brain, ROI, and correlational approaches to assess the activation differences based on varying reward motivation in the task. We hypothesize that activation within encoding, maintenance, and response related regions will be modulated by varying degrees of task motivation based on reward and punishment respectively. We will also include a modified task that will allow for superior modeling of the task periods by using partial trial methodology. This will allow us to test for timing differences in activation between PFC and posterior visual regions at different task phases. Overall, this research will clarify the functional organization of working memory and motivation. The generation of knowledge about reward and cognition has great clinical relevance for understanding the motivational properties of addictive stimuli such as substances of abuse and may also provide insight into a wide range of neurological disorders such as closed head injury, stroke and dementia that cause PFC dysfunction. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This grant proposes the continued maintenance, testing, and evaluation of the Neuroimaging in Python (NiPy) project. In particular, we propose to apply best practices and proven methods for software design, construction, and implementation to extend the applicability of NiPy to the larger neuroimaging research community. By addressing the parallel achievements and increased interdependence of neuroimaging research and computing sciences, we will benefit the existing NiPy user community as well as increasing the potential for NiPy to attract significantly more developers and users. We will modernize, refactor, and further develop NiPy into an easy to modify and extend software environment with the ability to be repaired and evolved as the needs of the community of users change. Working closely with the existing NiPy developer community, we aim to improve and enhance NiPy in terms of infrastructure, architecture, interoperability, usability, and reproducibility. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Goal-directed behavior requires the ability to monitor and execute internal goals and intentions, maintain and manipulate information in working memory, select task-relevant information, and organize action plans to accomplish these goals. The proposed research program will employ a multidisciplinary approach directed toward investigations of the neural mechanisms underlying such "executive control" processes. Neurocognitive methods-particularly neuroimaging and neuropsychological techniques- have sharpened our understanding of such processes. Indeed, it is well established that the prefrontal cortex (PFC) is critically involved in the executive control of a variety of goal-directed behaviors. Yet, our understanding of how the PFC is itself organized and how it dynamically controls other cortical and subcortical regions is less well understood. We will develop and utilize a wide range of complementary methodologies to explore executive control processes. These methods include physiological techniques (e.g. single unit recording in monkeys, functional MRI in healthy subjects, electocorticography in epilepsy patients), neuropsychological methods (e.g. behavioral studies of patients with focal lesions due to stroke, transcranial magnetic stimulation of healthy subjects), pharmacological techniques (e.g. effects of dopaminergic agents in healthy subjects, behavioral studies of Parkinson's disease patients on and off their medication) and developmental methods (e.g., studies of healthy children). The Core of the Program Project will provide detailed neuropsychological and neuroanatomical assessment of neurological patients, state-of-the-art neuroimaging and electrophysiological facilities, and an integrative intellectual environment that will facilitate cross-fertilization of ideas and methods among investigators. Three proposed projects will address issues of executive control processes associated with goal-directed behavior. Project 1 will address the functional organization of regions within PFC and how they contribute to executive control. Project 2 will focus on mechanisms by which the PFC initiates top-down signals to posterior cortical regions in order execute control over bottom-up activations. Project 3 will focus 'on fronto-striatal circuits and how they contribute to decision-making and response plans. The knowledge gained from this work has the potential to be of central clinical significance, as many neurological disorders include impairment in executive control processes. Moreover, such knowledge may provide a foundation for developing cognitive and pharmacological therapies for treating the wide range of disorders characterized as deficits in executive control.

The Harry H. Wheeler Brain Imaging Center (BIC) at the University of California, Berkeley consists of a large multidisciplinary group of scientists dedicated to basic and clinical neuroscience using MRI methods. The group has made numerous contributions to the field of systems and cognitive neuroscience through the study of normal and disordered neural processes. Since its inception in 2000, when there was no MRI facility at UC Berkeley, the human functional neuroimaging group has grown to comprise twenty-eight different labs across campus. In addition to the wide range of basic and clinical neuroscience questions being investigated at the Berkeley BIC, physicists, bioengineers and neuroscientists at UC Berkeley have made significant contributions to the development of new MRI hardware and analytical tools to analyze fMRI data. This award provides funds to purchase a Siemens 3T MRI system at the BIC to replace the current Varian 4T MRI scanner which is insufficient for current research purposes. Twenty seven senior researchers will utilize the instrumentation to address a wide range of scientific questions. For example, substantive projects include investigating the neural bases of high-level cognitive processes such as working memory and executive control; understanding the processes that enable goal-directed behavior; examining the neural mechanisms of motivation, both positive reward directed) and negative (punishment avoidance; study of the neural mechanisms underlying vision and visual perception, object recognition and selective attention.

While the primary purpose of this instrumentation is to understand basic brain functioning the work will have strong carryover into clinical research areas. The knowledge gained will be relevant for gaining additional insight, for example, into areas of clinical child and development psychology. The Brain Imaging Center provides important training experience for undergraduates, graduate students and post-doctoral fellows to learn MRI methods and the new imager will further this goal. It will also strengthen the development of a strong coherent university research group.

The broad goal of Project 1 is to advance understanding of the organization of lateral frontal cortex, both in terms of the regional distinctions that define its functional topography and the principles by which these regions interact to produce controlled behavior. The first set of experiments was designed to test the hypothesis that frontal cortex is hierarchically organized, with progressively more anterior regions processing higher-order representations. According to this hierarchical hypothesis, successive stages of processing lead to increased abstraction and complexity of representation along a posterior-anterior gradient across frontal cortex. This hypothesis will be tested with two paradigms and a variety of approaches: behavioral data from patients with focal PFC lesions, temporary lesions with transcranial magnetic stimulation, intracortical recordings in humans prior to epilepsy surgery, and fMRI studies in adults and children. The second set of experiments focuses on the most anterior part of lateral frontal cortex, a region implicated in higher cognition about which relatively little is known. Based on preliminary data, we have argued that this region is involved in the joint consideration of multiple relationships between mental representations - a general function that can be used to compare, evaluate, or integrate across concepts, or to coordinate several ongoing mental processes. A variety of complementary techniques will be used to test whether anterior lateral frontal cortex is sensitive to the need to consider multiple relations between items. Basic knowledge about the functional organization of frontal cortex gained from these proposed studies is of central clinical significance, and can provide substantial insights into the nature of a large number of neurological disorders associated with the frontal lobe dysfunction, such as stroke, traumatic brain injury, and degenerative brain diseases including Parkinson's, Alzheimer's Disease, and frontotemporal dementia.

The Core of this Program Project consists of four components that represent services that are provided to each of the three research projects. In addition, each of these components will continue to be engaged in development of the infrastructure required for the implementation of the methods in the research plan. The four components of the core described below are: 1. Administrative services 2. Neurological patient and subject recruitment support and development 3. Neuroscientific method support and development 4. Informatics and datacenter support and development.

DESCRIPTION (provided by applicant): Poor goal direction, or loss of ability to concentrate and 'stay on task'in a distracting environment, is a common complaint in advanced age. Such subjective reports are consistent with an emerging consensus in the cognitive aging research literature suggesting that the executive control processes necessary for maintaining goal direction are particularly susceptible to decline with advancing age. Unfortunately, there have been few efficacious treatments for executive control deficits reported in the literature despite their significant impact on daily life functions and the maintenance of functional independence into later life. Here we argue that the efficacy of such treatments is hindered by our poor understanding of the neural mechanisms subserving executive control processing in the brain. The first aim of the proposal is to develop robust biomarkers of executive control processes to complement neurocognitive and functional outcome measures of treatment efficacy. These biomarkers will serve to identify neural processes that are most responsive to treatment and predictive of neurocognitive and functional gain, thus informing the design of more targeted and efficacious brain-based treatments. A second aim of the proposal is to test this brain-based approach explicitly using an integrated strategy-based and targeted process training protocol to enhance executive control processing in healthy aging. Through this combined treatment approach we intend to leverage gains realized from targeted training by reinforcing and contextualizing them in a therapist-guided, strategy-based goal management program. This program is standardized for the process of interest (executive control), but guides strategy application to individually-salient, self-generated goals and personally-relevant real-life situations. Outcomes will be assessed at the neural, neurocognitive and functional outcome levels. Such a scaffolded approach, building from the level of brain to behavior to lasting functional change, ensures that cognitive remediation efforts benefit older adults directly, and society more generally, by delaying the need for home care, nursing home or hospital services while preserving the functional independence and dignity of an aging population. PUBLIC HEALTH RELEVANCE: Cognitive decline associated with normal aging can have a broad impact on an individual's productivity, physical health and general sense of well-being. Especially with the expected increase in the aging population in the next few decades, age-related cognitive decline is a major public health issue. The aim of this project is to investigate the neural mechanisms underlying age-related cognitive decline and to develop interventions and biomarkers to evaluate the efficacy of these interventions.

DESCRIPTION (provided by applicant): Cognitive control and executive function are similar terms used to describe our ability to direct thought and action based on our goals and intentions, rather than being driven automatically by the world around us. Current theories of cognitive control propose that the prefrontal cortex (PFC) is a brain region that is critical for tis ability. The PFC has extensive, reciprocal projections to both cortical and subcortical regions and therefore is in a privileged position to be a source of top-down signals that could sculpt behavior. Building on the progress we have made in the previous funding period, the overall aim of the current proposal is to further advance and refine our understanding of the functional organization of PFC and the neural mechanisms by which the PFC can provide top-down signals that modulate incoming sensory information. We propose that the PFC stores the highest level of representations such as rules and goals, and it is the active maintenance of these representations that bias information processing elsewhere in the brain influencing how we ultimately make decisions and act. In humans, frontal lobe function has been extensively researched both through the careful study of neurological patients with focal lesions (usually due to stroke and traumatic brain injury) and using functional MRI (fMRI) with healthy young subjects. However, there has been surprisingly little work combining these two approaches. Lesion and fMRI methodologies can complement each other in significant ways, and so when combined can be a powerful approach for studying brain-behavior relationships. In this proposal, such a convergent approach will be implemented. Basic knowledge about PFC function and cognitive control can provide substantial insights into the nature of a large number of psychiatric and neurological disorders affecting PFC function such as schizophrenia, dementia, stroke and traumatic brain injury; as well as many other conditions such as attention-deficit disorder, substance addiction and normal aging, that are proposed to involve selective dysfunction of frontal brain systems. Moreover, cognitive and behavioral deficits from PFC damage are particularly challenging to treat. A greater understanding of frontal lobe function is necessary for developing effective therapeutic interventions. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because it will advance our understanding of the role of the frontal lobes in goal-directed behavior. Many psychiatric and neurological disorders such as schizophrenia dementia, stroke and traumatic brain injury affect frontal lobe function; and many other conditions such as attention-deficit disorder, substance addiction and normal aging, are proposed to involve selective dysfunction of frontal brain systems. The proposed research is also relevant to NIH's mission because it will lead to basic knowledge about frontal lobe function that can provide valuable insights into the understanding, diagnosis and treatment of a wide range of clinical conditions.

DESCRIPTION (provided by applicant): The brain's potential to flexibly engage different functional networks in a rapidly changing environment is crucial both for facilitating a wide variety of behaviors and adaptively reorganizing following damage. This network plasticity can emerge through both changes in the local connectivity strengths within functional networks and the more global network structure of the whole brain. A recent surge of studies has assessed the intrinsic functional connectivity of local networks of brain regions during rest using functionl MRI (fMRI). Quantifying the global properties of this complex brain organization is now possible using graph theoretical tools, in which brain regions are defined as nodes and connections between regions are defined as edges. The broad goal of this proposal is to apply local, network-specific connectivity measurements as well as global, graph theoretical methods to examine the capacity for neuroplasticity under two different contexts: disruption of cortical function (acute and chronic) and specific cognitive task demands. Studies of the effect of brain damage on network organization have focused on the local, network specific effects of damage, generally finding that damage to one portion of a network effects connected but undamaged regions. The consequence of focal damage on global brain organization has primarily been examined with simulated lesion data and it is proposed that brain regions particularly important for integrating information across networks, are most critical to maintaining network integrity. Here we will test this prediction by using resting state fMRI data collected from patients with focal brain lesions and healthy participants following transcranial magnetic stimulation (TMS). We will test the hypothesis that perturbation of intrinsic brain organization results in both local decreases in the affected network and global reconfiguration of brain modules. Moreover, we hypothesize that the roles of nodes within networks that have reconfigured following brain damage is compensatory. Another approach for investigating network reconfiguration is to compare brain organization at rest to that during a cognitive task. Thus, we will also test the hypothesis that, similar to the adaptive reorganization after damage, specific task demands will result in rapid alteration of network organization at both the global and local level. This proposa will further knowledge about brain organization and its potential for plasticity in various context, such as brain damage and the dynamics cognitive demands of daily life. Moreover, we propose that network approaches such as those applied in this proposal can provide empirical data to reconcile strictly localizationalist vs. distributionist accounts of brain function. Relevant to th NIH mission, the neural mechanisms underlying brain plasticity identified in the proposed studies can serve as targets for the development of diagnostic biomarkers as well as cognitive therapy interventions for rehabilitation of patients with brain damage from prevalent neurological disorders such as stroke and traumatic brain injury.

DESCRIPTION (provided by applicant): This application is directed towards understanding the role of the dopaminergic system in higher cognitive function such as working memory and cognitive control. These somewhat ill-defined terms generally refer to cognitive systems that require two functionally opposing processes: (1) the stable 'on-line' maintenance of information (necessary for cognitive stability) and (2) the flexible updating of that information in response to novel task-relevant information (necessary for cognitive flexibility). We will test the hypothesis that these cognitive processes are highly dependent on precisely balanced dopaminergic transmission within the striatum and prefrontal cortex (PFC). Specifically, we will test the hypothesis that augmentation of dopamine in the PFC promotes cognitive stability by increasing distractor-resistance whereas dopamine augmentation in the striatum promotes cognitive flexibility by allowing the updating of newly relevant representations. Manipulation of the dopaminergic system has been shown to modulate the function of fronto-striatal circuitry, but the direction and extent of these effects vary widely across individuals and tasks. Through pharmacological manipulation and genetic variation of dopamine in humans, and measurements of their effects with both fMRI and PET, we expect to elucidate the factors that determine this large variability in drug effects and characterize the nature of the complex relationship between dopamine and cognition. Dopamine is of fundamental importance to the etiology and clinical manifestations of a wide variety of neurological and psychiatric disorders such as Parkinson's disease, traumatic brain injury, attention deficit hyperactivity disorder, schizophrenia and drug addiction. A further understanding of the relationship between dopamine and cognition should advance our understanding of the mechanisms underlying cognitive and behavioral deficits in these disorders and provide insight into novel approaches to treating such deficits with medications targeted at specific neurotransmitter systems.

DESCRIPTION (provided by applicant): A large body of work has demonstrated that human cognition depends on the activity in large-scale brain networks. This network activity has been linked to the emergence of consciousness, to a variety of individual traits as diverse as motivation, empathy, neuroticism, extraversion, and IQ and to clinical conditions such as Alzheimer's, stroke, traumatic brain injury, schizophrenia and depression. Thus, characterizing the pattern and dynamics of brain connectivity is of utmost importance for understanding the workings of the human brain in both health and disease. However, large-scale brain networks are typically studied with correlational methods such as functional MRI (fMRI), EEG or MEG, which cannot detect causal relationships. Consequently, the focus to date has been on characterizing the spatial composition of the brain's networks with less emphasis on the dynamics of intra- and inter-network communication. We propose that the method of simultaneous transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) can fill this gap and provide an invaluable tool for understanding network communication. This method allows researchers to observe the spread of an artificially induced neural signal to the rest of the brain in the context of different tasks. The central hypothesis of this proposal is that the effect of TMS will only extend within the targeted region's network during rest or tasks that engage preferentially the said network, but that regions of other networks will also be affected in tasks that engage the two networks simultaneously. Specifically, we will first test whether brain networks emerge spontaneously as a result of the spread of artificially induced neural signals during rest. Then, we will further explore the role o engagement in a task that either preferentially activates the network of the targeted brain region, or a competing brain network. Finally, we have developed a novel task that activates two separate brain networks in order to test whether the coordination between them will result in a change in the spread of neural signals originating in a region belonging to one of the networks. In this way, the proposed project will pave the way for a wide range of studies on the dynamics of neural networks that can lead to fundamental insights of cognition, as well as a deeper understanding of brain dysfunction. Relevant to the NIH mission, identification of brain networks as proposed in these studies can serve as targets for the development of diagnostic biomarkers as well as cognitive therapy interventions for rehabilitation of patients with cognitive deficits de to neurological or psychiatric disorders.

PROJECT SUMMARY/ABSTRACT Intentional and flexible behavior, often called ?cognitive control?, requires the maintenance and selection of perceptual, mnemonic, and response representations consistent with the broader context and higher-level goals. One of the most challenging problems in neuroscience is determining how voluntary, goal-directed behavior arises from the distributed activity of billions of neurons in the brain. To tackle this problem, one must understand the cognitive and neural mechanisms of working memory (WM), a fundamental ability underlying goal-directed behavior. The study of WM, however, has only minimally benefited from the revolution in neural dynamics that has been experienced in other fields. Discovery of WM neural dynamics is particularly important given that WM requires the interaction of multiple brain systems, notably the lateral PFC (lPFC) and posterior processing systems. Thus, a determination of the neural mechanisms underlying lPFC function, the most elaborated neocortical region in primates, and WM, remains a fundamental goal of neuroscience research. To achieve this goal, three different methods will be implemented in human subjects in this proposal during the performance of WM task ? ECoG, fMRI and TMS. This will provide a convergent approach that tests hypotheses regarding the spatio-temporal basis of WM and will be able to determine the causality of the electrophysiological and neuroimaging findings. Although not the prime focus of the proposal, the ECoG data will also provide a link to monkey neurophysiology and the neural drivers of the fMRI BOLD signal. Basic knowledge about WM and frontal lobe function can provide substantial insights into the nature of a large number of psychiatric and neurological disorders affecting PFC function such as schizophrenia, dementia, stroke and traumatic brain injury; as well as many other conditions such as attention-deficit disorder, substance addiction and normal aging, that are proposed to involve selective dysfunction of frontal brain systems. Moreover, cognitive and behavioral deficits from PFC damage are particularly challenging to treat. A greater understanding of frontal lobe function is necessary for developing effective therapeutic interventions.