R. Todd Constable, Ph.D. - US grants

Epilepsy patients who are candidates for surgical resection of a brain lesion must have some form of functional mapping to determine if the lesion can be removed without creating a functional deficit. The current procedures for mapping language functional areas in these patients are either spatially limited (hemispheric mapping with the Wada test for example) or highly invasive (cortical stimulation using subdural electrodes). Functional MR imaging (fMRI) has the potential to replace the current methods used in Neurosurgical planning. It is completely noninvasive and has been shown to be able to detect functional brain regions. However, the standard echo planar imaging fMRI methods, based on the BOLD activation response, suffer from low spatial resolution, and a sensitivity to static Bomicron magnetic field inhomogeneities which lead to geometric image distortions and low signal intensity. These problems severely limit the ability of fMRI to localize brain activity for Neurosurgical planning. This project is designed to improve fMRI methodology and to perform a thorough comparison between fMRI language mapping and the current gold standard cortical stimulation in patients. This study will determine the ability of fMRI to predict surgical outcome. The patients will have language areas mapped using cortical stimulation and fMRI, and they will undergo behavioral studies pre- and post- surgery in order to measure any deficits that may arise post-surgery. The methodology development will specifically focus on novel techniques we have designed to reduce image distortion in echo planar fMRI, while increasing spatial resolution, and while producing highly robust activation maps even in the presence of field inhomogeneities. Our approach includes modifications to image acquisition strategies in conjunction with new post-processing algorithms. This innovative program will allow for highly robust localization of functional brain regions needed for surgical planning. While the emphasis is on the development and validation of fMRI methodology for Neurosurgical planning in epilepsy, the technical developments will be general and can be applied to any functional MR imaging study. Successful completion of this project may allow fMRI to be used as the primary source of functional localization in the brain for Neurosurgical planning reducing the need for invasive mapping techniques.

DESCRIPTION: (Adapted from applicant's abstract) There is much evidence that the hippocampus and surrounding structures in the medial temporal lobe (MTL) are involved in memory. Exactly what role these structures play and whether or not they can be divided into functionally distinct subunits is unclear and the subject of much controversy in the current literature. The investigators propose to investigate the functional role of the hippocampus in memory processes. The hypothesize that the hippocampus can be subdivided into distinct functional regions that show dependence on both the type of mnemonic task undertaken (encoding versus retrieval), and the characteristics of the memory process being encoded or retrieved (spatial versus temporal, verbal versus visual). The hippocampus is a difficult structure to image with either PET or functional MRI. The investigators have developed a high-resolution fMRI approach, which compensates for signal loss in regions of high magnetic field inhomogeneity such as that found in the MTL. This susceptibility effect has limited the power of previous fMRI experiments and made it particularly difficult to image the anterior MTL region. This technical difficulty is likely the source of conflicting findings between earlier PET and fMRI studies that employed similar tasks. The new imaging approach to generate robust activation maps over the entire length of the hippocampal formation in studies on both normal volunteers will be use, and on MTL patients who present with intractable epilepsy. Such patients are often treated by surgical resection of the epileptogenic foci. The investigators will functionally image these patients both pre- and post- surgery allowing us to validate the pre-surgical fMRI maps through behavioral studies postsurgery, and through cortical stimulation experiments with depth electrodes prior to tissue resection. Functionally mapping the hippocampal formation before and after resection provides a unique opportunity to determine if the remaining MTL structures can compensate for tissue loss and if so identifies the specific structures responsible. This project will increase our understanding of the role of the hippocampus in memory, as well as lead to intelligent paradigms for pre-surgical mapping of patients who are candidates for temporal lobotomy. This work will have significant impact in both the neuroscience and medical communities.

DESCRIPTION (provided by applicant): Each year a significant number of epilepsy patients present to the Yale Epilepsy Center with highly debilitating intractable epilepsy. When epilepsy is refractory to drug therapy, the best outcome occurs if the epileptogenic tissue is removed surgically. However, this approach to curing epilepsy is only effective if the epileptogenic tissue is limited in extent (focal) and identifiable. Many of these patients have no abnormalities visible on MR, PET, or SPECT scanning, or they have discordant findings across several measures, making localization of the epileptogenic tissue that generates the seizures difficult. This proposal is aimed at further developing and understanding combined electroencephalography and functional magnetic resonance imaging (EEG-fMRI). In this approach, EEG monitoring is performed during a functional MRI scanning session. A number of functional imaging approaches including, blood oxygenation level dependent (BOLD) contrast, cerebral blood flow (CBF), and cerebral metabolic rate of oxygen consumption (CMRO2)) will be investigated to identify local tissue regions that exhibit signal changes in synchrony with interictal epileptiform discharges (lEDs). The experiments are designed to improve our understanding of the relationship between MR measures of neuronal activity in the presence of epileptiform activity, and neuronal signatures of activity based on surface or depth recorded EEG. Characteristics of the measured response (peak integration, time-to-peak, amplitude, and duration) for specific tissues will be compared in an F-test with type of epilepsy and concordance with difference SPECT and intracranial recordings. In addition, the EEG-fMRI localization will be directly compared spatially, with the epileptogenic tissue localization obtained using difference SPECT imaging, and with the clinical gold standard of invasive recordings from intracranial implanted electrodes, and finally with surgical outcome. Little is currently known about the neurophysiological response to lEDs, the relationship between EEG and fMRI measures, nor of the relationship between this inter-ictal and ictal activity. The experiments proposed in this work will provide a better understanding of these issues at a basic neuroscience level, while also allowing validation through invasive monitoring. These developments will improve the efficacy of seizure localization, allow for more precise targeting of surgical interventions through better localization, and improve outcomes from surgery. A large epilepsy population exists that could benefit greatly from better mapping techniques and these techniques may ultimately replace invasive methods decreasing health care costs and morbidity.

DESCRIPTION (provided by applicant): Sharp transients, in electrical recordings, represent a measure of neural activity corresponding to an action potential at a single neuron. Such spike activity reflects the output of a given brain area, yet many regions receive input in the form of excitatory or inhibitory synaptic potentials without generating spikes. This input activity is an important form of computational integration, detected in extracellular recordings as perturbations of the local field potential (LFP). Quantitative analysis of the LFP is performed in the frequency domain, providing a measure of synchronous activity across neurons. Logothetis et al. (2001) showed that BOLD may reflect an area's input in the form of synaptic potentials, rather than its output in the form of spikes. Synaptic inputs can be excitatory or inhibitory, and both forms involve metabolic demands that may alter BOLD and complicate models interpreting BOLD as a proxy for cognitive engagement. The time- courses of oscillations in various frequency bands, and excitatory and inhibitory synaptic potentials, and the relationship between these forms of activity and cognition as reflected by BOLD, is poorly understood. Thus, it is essential to examine the correspondence between certain forms of neural activity, BOLD, and the engagement of cognitive processes. Negative BOLD signals in some cases, for example, demand a nuanced interpretation. The subtractive nature of fMRI initially suggests that negative BOLD simply reflects increased activation during the baseline. However, a number of findings have suggested that negative BOLD represents a distinct phenomenon. This proposal is focused on examining the evidence that negative BOLD reflects decreases in neural activity, associated with cognition. Calibrated MR measures of BOLD and CBF will be performed using tasks previously shown to produce reliable deactivations. These MR measures of flow and oxygenation will be used to determine relative CMRO2 and the oxygen extraction to fully assess the physiologic underpinnings of BOLD. Simultaneous EEC will be recorded and EEC power in multiple frequency bands compared with the MR measures. Much work has been performed characterizing EEC changes in the tasks to be used, but little work has attempted to relate EEC to MR signals. This work will provide insight into the relationship between MR signal changes in cognitive tasks, and EEC changes as measured with surface, and in a limited number of patients, subdural electrodes.

DESCRIPTION (provided by applicant): Despite the widespread clinical use of anesthetics and the volume of research focused on brain function, few studies have used neuroimaging techniques to better understand the mechanisms of anesthetic agents. Functional MRI relying on the Blood Oxygenation Level Dependent (BOLD) contrast mechanism has rapidly become a valuable tool for neuroscientists and could provide insight into the neurophysiological impact of anesthetic agents. Yet the relationship between BOLD signal changes and neuronal activity is not well understood particularly in the presence of an agent that might alter the normal coupling between BOLD signal changes and the underlying neuronal activity. Changes in baseline brain activity, metabolism or flow may influence the amplitude of the BOLD signal measured in an activation experiment and while many studies have examined such effects in animal studies there are almost no calibrated human studies of these effects. Calibration of the fMRI experiment allows pure physiological changes such as changes in baseline cerebral blood flow (CBF), to be dissociated from changes in neuronal activity normally reflected in the BOLD signal measured. It is particularly challenging when such studies are performed in humans because it is difficult to design informative but passive tasks that are ammenable to the MR setting. This work will focus on a series of hierarchichal but passive tasks involving either sensory/motor stimuli or auditory stimuli, applied to humans in the awake and anesthetized state. Anesthetic agents Sevoflurane and Propofol will be investigated at different dose levels (Sevoflurane 0.25MAC, 0.5MAC, Propofol 1micro-g/kg and 2micro-g/kg) while stimuli are presented and BOLD and CBF measured. Calibration experiments linking flow and metabolism as measured by the cerebral metabolic rate of oxygen consumption (CMRO2) will be performed prior to the activation experiments. Combined measures of BOLD and CBF will allow investigation of the coupling between flow, oxygenation, and CMRO2 across a range of stimuli under different anesthetic conditions. These experiments will provide insight into the brain's response to stimuli under anesthetic conditions and reveal the impact of anesthetics on specific cortical regions as well as larger networks. These experiments will also lay the ground work for future studies investigating higher order cognitive function such as those associated with attention and memory.

[unreadable] DESCRIPTION (provided by applicant): This shared instrumentation grant requests funds to partially offset the cost of an upgrade of our 3T Trio to the 3T TIM (Total Image Matrix) platform. Recent improvements to the 3T Trio platform (TIM) and the upgrade that we are requesting will provide 3 primary benefits: a) The improved parallel imaging capabilities will allow for acquisitions with reduced image distortion and facilitate better data collection primarily in the orbital frontal lobes and medial temporal regions in functional imaging studies. Multi-channel capabilities will also provide opportunities for improved whole brain coverage with shorter TR's and thinner slices. The reduced scan times achieved with parallel imaging will improve the success rate of morphologic investigations particularly in studies involving children; b) The addition of multinuclear capabilities will facilitate numerous studies involving calibrated fMRI investigating neuronal energetics through 13C infusions, and anesthesia and drug development/discovery studies through the ability to measure 19F concentrations in localized brain regions (such capabilities will avoid the need to perform calibration studies on one magnet (currently the Bruker 4T) and functional studies on another magnet (the 3T Trio) allowing everything to be done in a single session on a single magnet (the upgraded 3T TIM Trio). c) The greatly reduced gradient acoustic noise reduction (20dB) will improve subject comfort and make language studies involving subtle speech variations much more robust as well as improve success with fMRI studies involving children due to the improved comfort level. Each of these 3 primary improvements will be of tremendous benefit to a number of NIH supported research projects, allow substantial improvements in our current capabilities and expand the capabilities of the center further broadening our user base. [unreadable] [unreadable] Significant advances in neuroscience, drug development, cardiac imaging, and the investigation of numerous neural disorders, have already been generated through work performed at the Yale MRRC. Upgrading the current 3T scanner, which is the workhorse for the majority of the functional MRI performed at Yale will allow this facility to remain state-of-the-art and further support and expand the cutting edge research that is being performed at Yale. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Since the first lesion studies of Broca and Wernicke scientists have been trying to relate function to specific cortical areas and to generate functional maps of the human cortex. Mapping approaches based on histology, morphology, or function (through task-based fMRI and PET), have been used to delineate sub-regions in the brain. This proposal presents a new approach for mapping cortical subunits through analysis of resting-state connectivity data. The over-arching goal is to develop and validate a method that uses resting-state fMRI connectivity data to delineate functional subunits within each cortical and subcortical region throughout the brain and to produce a whole-brain probabilistic atlas based on these functional subunits. These subunits then provide a starting point for network analysis leading ultimately to a human connectome. The aims are to extend our working algorithm to include additional spatial constraints, and to validate the algorithm on data from healthy control subjects using 3 validation approaches. The final aim is to pilot this approach in intractable epilepsy patients to test the hypothesis that this approach allows for the identification of specific abnormal nodes or networks that may be associated with seizure generation. The immediate practical use of a map of the functional subunits throughout the brain will be to provide a framework for simplifying the analysis, interpretation, and reporting, of conventional task-based neuroimaging results aimed at determining the specific functions of these areas. The atlas generated will also provide a basis set from which a range of neurological disorders may be contrasted to reveal abnormal functional units and/or networks that may be affected by disease. This work could have substantial impact in translation clinical application of these methods and in understanding the impact on the functional organization of the brain of a range of neurological disorders such as Alzheimer's, Parkinson's, MS, and epilepsy, and on psychiatric disorders such as schizophrenia. Finally, this work will provide a methodology for assessing individual variance in organization of these functional subunits potentially leading to methods that will allow the impact of disease, genetics, and environment, to be studied without the constraints of task-based fMRI. PUBLIC HEALTH RELEVANCE: This project is aimed at developing a method to produce an atlas of the functional subunits in the human brain. This work could have substantial impact in understanding the impact on the functional organization of the brain of a range of neurological disorders such as Alzheimer's, Parkinson's, MS, and epilepsy and on psychiatric disorders such as schizophrenia. It also represents the first step in the path towards a human connectome.

DESCRIPTION (provided by applicant): Recent improvements in parallel imaging performance have been driven by the use of ever-greater numbers of independent surface coils placed so as to maximize the ability to unwrap the aliasing that occurs along a linear phase encode direction, and this work is proceeding with ever diminishing returns due to both the greatly increasing expense associated with all of the receiver channels, and due to coil coupling problems which dominate as the size of the coil elements decreases. This work introduces a new approach to more efficient parallel imaging (with fewer coils) using novel gradient encoding schemes that provide optimally complementary spatial information relative to that provided by the receiver coils. This approach introduces nonlinear gradient encoding using 1st and 2nd order spherical harmonics. A formalism is introduced for calculating the optimal set of encoding gradient for a given receiver coil array. For each acquired echo, a different gradient from this complementary set is applied during the readout and conventional phase encoding is discarded. The advantage of this approach lies in the complementary spatial encoding contributed by both the receiver coils and the gradient encoding scheme. A further advantage arises with the use of frequency encoding gradients that span the xy-plane and thus provides 2D information in a single echo. With this type of read gradient oversampling in the readout significantly improves the accelerated acquisition with no time penalty. With conventional Cartesian sampling there is no benefit, with respect to aliasing, to over-sampling the read-out. This project is aimed at building a high-speed shield gradient insert capable of generating a series of 2nd order spherical harmonic gradient shapes. This gradient set will be used for proof of principle, and we will simultaneously further develop the theory of Null Space Imaging (how to calculate the optimal gradient set) as well as the reconstruction methodology. The end product from this work would be both a validation of a new methodology for performing highly accelerated parallel imaging, allowing acceleration factors of 8 or more with as few as 8 receiver coils and a design for a larger gradient insert coil capable of imaging the human head. The project carries a natural benefit to public health through acceleration of the data acquisition process, thus allowing for higher resolution, or more thorough examinations on existing platforms, through the application of this Null Space Imaging approach. The proposal also fits with the goals of NIBIB for developments in accelerated parallel MR imaging. PUBLIC HEALTH RELEVANCE: Current methods in accelerating MRI image acquisitions have focused on receiver coil arrays with more and more elements to improve acceleration. This work represents a paradigm shift in parallel imaging by designing the gradient encoding to be complementary to the coil encoding increasing maximum achievable accelerations by more than a factor of 2. The project carries a natural benefit to the public health through acceleration of the data acquisition process, allowing for higher resolution, more thorough examinations on existing platforms through the application of this Null Space Imaging approach.

DESCRIPTION (provided by applicant): Recent improvements in parallel-imaging performance in MRI have been driven by the use of greater numbers of radiofrequency (RF) surface coils placed in an array so as to maximize the ability to unwrap the aliasing that occurs along a linear phase encode direction when the data is undersampled (accelerated). This approach to acceleration is maturing and providing diminishing returns as more and more receiver coils are used, due to coil-coupling problems, which dominate as the size of the coil elements decreases and the number of elements increases. This proposal is aimed at providing further acceleration in parallel imaging through a reassessment of the magnetic field gradients used for spatial encoding. By considering the joint contributions of spatial encoding of the receiver coils and the magnetic fields, we can develop a more efficient approach to spatial encoding. A simple solution to this problem is to use a nonlinear magnetic field gradient, the Z2 gradient. Such a gradient shape (relative to linear X and Y gradients) provides spatial encoding more complementary to that provided by the receiver coils. The approach we have developed, O-space imaging - so named because the isofrequency contours during the readout are in the shape of concentric rings rather than columns as with a linear X-readout - was initially introduced by us in 2010. The theory and preliminary data generated using a small Z2-gradient insert on a clinical MRI scanner have provided evidence that substantial increases in acceleration can be achieved with modest numbers of receiver coils. This proposal is aimed at scaling these tests up to human imaging levels using a head-insert Z2-gradient coil fully integrated with the Siemens 3T Trio scanner. The O-space imaging approach is a general acceleration method that can be adapted to almost any pulse sequence. We will test, in phantom and human imaging experiments, the capabilities of O-space imaging to outperform conventional SENSE imaging using modified spin echo, fast spin echo and 3D imaging sequences at a range of resolutions and acceleration factors and using both an 8-channel and a 32-channel Tx/Rx coil. The end result of this work will be a demonstration of the viability of this new methodology for providing highly accelerated parallel imaging. The project is highly innovative and by reconsidering the spatial encoding gradients it opens up a new area of research in MR accelerated imaging. The project is significant in that providing an acceleration factor of 2 or more to a number of standard clinical MR pulse sequences could provide a huge benefit to public health, allowing for higher resolution, or more detailed examinations, and significantly increased throughput improving access to MRI and/or lowering per-scan costs.

Project Summary This proposal is aimed at converting a head-only 7T Agilent/Varian MRS scanner to a 7T Siemens scanner by replacing the console and all the RF, and gradient hardware. This will yield a state-of-the-art MRS and MRI system to serve the research needs of up to 60 principal investigators that currently scan in the Yale Magnetic Resonance Research Center (MRRC). The upgrade solves several problems. First Agilent has announced it is no longer going to make 7T magnets so if Yale is to have a 7T MRI, upgrading this existing system is the only path forward. Second because of this announcement from Agilent, support for the current system will shortly no longer be available and this expensive/important resource may be lost without such an upgrade. Third we have a strong demand at Yale for both structural and functional imaging capabilities at very high spatial and temporal resolution and by upgrading this magnet we can provide such capabilities to a large research community both within and outside of Yale. Furthermore we have several training programs in both engineering and neuroscience that would benefit from access to this upgraded high field imager. We have the technical expertise, the research relationship with Siemens, several exceptionally strong research programs, and the user needs, to justify this investment. Yale has invested a considerable amount of resources in the MRRC and in this case would provide 50% of the cost of this upgrade demonstrating the importance the university puts on this resource. This would be the only head-MRI 68cm bore 7T Siemens system in the USA. Two others exist in the world - one in Luasanne, Switzerland and the other in Waterloo, Canada and thus this would be a unique resource.

? DESCRIPTION (provided by applicant): The purpose of this RFA is to promote the integration of experimental, analytic and theoretical capabilities for the examination of neural circuits and systems. This proposal is highly responsive to the RFA in that it links several different neuroscience labs to develop new technologies that provide for simultaneous multistate imaging and applies these technologies to the examination of how neuronal dynamics in mammalian cortex varies as a function of brain state and development. Paired imaging modalities will bridge the gap from imaging activity in individual neurons to whole brain circuit level analyses. The different scales will be linked with a comprehensive model such that each level of experimentation can inform the other. We will develop the technology to allow simultaneous single cell (two-photon) Ca2+ imaging of a local circuit and cortex-wide mesoscopic (single-photon) Ca2+ imaging across the entire neocortex. In separate paired studies in the same animals we will develop simultaneous mesoscopic Ca2+ imaging across the cortex with whole-brain functional MRI. Whole cortex mesoscopic Ca2+ imaging represents an innovative technology developed by one of the PIs (Crair) that uses mice expressing a genetically encoded Ca2+ indicator (GCaMP6) in all neurons or in select populations of neurons to allow both local neuronal and transcranial population level mesoscopic scale imaging across the cortex in the intact, unanesthetized developing mouse brain. This Ca2+ imaging technique will allow us to directly link single cell imaging to gross circuit level activity across the cortex and whole brain An integrative model is proposed to link these different modalities in order to understand the neural source of macroscopic circuit changes and the factors that influence this organization through development and as a function of behavioral brain state. This work is innovative in the novel Ca2+ imaging strategies to be further developed, and in the design of paired scale imaging to establish links between single neuron activity and circuit level organization. The work is significant in that it will provide a set of tools for detailed investigations of the impact of specific neuronal cell populations on brain circuit functional organization in healthy development and disease models. It is also significant in that new insights into the source and flow of neuronal activity will be obtained that will improve our understanding of the principles guiding self-organization in the developing brain and its dynamic modulation by brain state.

Project Summary This RFA is aimed at bringing together interdisciplinary teams to focus on novel, transformative and integrative efforts that will revolutionize our understanding of the biological and bioinformatics content of the data collected from non-invasive human functional brain imaging techniques. Our proposal does exactly this. We are a multidisciplinary team of scientists with combined expertise in optogenetics, two photon Ca2+ imaging, biomedical engineering, molecular biology, animal and human fMRI, network theory, data analysis and modeling. In this work, we will use a novel imaging device that combines mesoscopic imaging of genetically encoded Ca2+ indicators with very high (50?m) spatial and high temporal (25ms) resolution across the entire cortex and simultaneous fMRI in transgenic mouse models. These animal experiments are designed to complement similar experiments in healthy human subjects. The results from the animal experiments will answer several long-standing questions about the source of the fMRI signal. Specifically, using imaging, we will quantify the contributions of different cell populations (excitatory neurons, inhibitory neurons, and glial cells) to the fMRI signal observed. We will be able to test and validate, for the first time, the application of graph theory approaches to the analysis of human fMRI data, and we will develop and test a new approach based on control theory for extracting more information from the fMRI signal. A powerful set of carefully controlled imaging experiments in mice will inform several aspects of analysis of human data. The human data will contain a test/retest component to ensure replication of the results and to allow predictive models to be built in one data set and tested in another. This work truly bridges scale and modalities and the simultaneous nature of the animal experiments will allow unprecedented clarity on the underlying source of the signal changes observed in fMRI. These animal studies are essential for providing new insights into the basis of human fMRI signals and data of this nature has not previously been available. The work in this proposal is novel in that it will directly inform measures of both evoked and spontaneous activity in terms of the underlying cell signal sources revealing the relative contributions of excitatory, inhibitory and glial cells to the fMRI signal. The implications of the work are multifaceted. This work will provide a platform for evaluating neurological models of disease. For example, mouse models of disease can be used to link to human data in diseases such as PTSD, depression, and autism, to name a few. It will also provide a firmer biological basis for understanding the node and network measures used in assessing the functional organization of the brain and will have important implications for the design of therapeutic interventions across a range of diseases.

Abstract This project will image 150 children (~ aged 12) with and without autism spectrum disorder to reveal the changes in functional brain organization that relate to autism severity and associated behavioral measures. The children will represent 3 distinct groups of 50 kids each (high risk children with autism, high risk siblings without autism and low risk healthy controls) and we will contrast these groups to understand the major functional network changes associated with autism. We will also develop connectome based predictive models to relate individual functional connectivity profiles to autism scores (using ADOS-2 social affect as the primary measure and RRB as a secondary measure) and examine the extent to which the models localize to specific networks including the executive control, the salience, and the default mode networks. The connectivity input data will be of unprecedented quality and extent (at least 20minutes of resting-state data providing highly reliable single subject data). In addition to the resting-state, we will include data collected during continuous performance tasks (an attention task: gradCPT and a selective social attention task previously characterized with eye-tracking data). Sex differences will be of specific interest in understanding network changes with autism severity. We will also identify the altered networks associated with ASD and provide these networks for exploratory analysis in project 1 (infants) and project 4 (fetal brains) to examine the extent to which these networks are altered early in development. The neural characterization performed in project 3 will be on a subset of the subjects studied in this project and thus we will have direct neural characteristics to relate to the connectivity changes we will quantify. This will be one of the first times neuronal structural features have been related to macroscopic connectivity data.

A primary challenge facing functional neuroimaging is the translation of research findings to the clinical setting. In part, fMRI has struggled as a clinical tool due to the lack of functional phenotypes that characterize patients. To address this, we have developed connectome-based predictive modeling (CPM) to identify and validate predictive models of behavior/symptoms based on functional connectivity data. The promise of this approach is that by developing predictive models based on the functional organization of an individual?s brain, we may be able to extract a rich connectivity phenotypes to aid in the clinical characterization of patients. This approach has the potential to improve our ability to categorize patients in otherwise heterogeneous groups and monitor the effectiveness of treatment interventions. To do this, modeling methods are needed that are designed to generalize across multiple behaviors, symptoms and diagnostic groups. In this proposal, we will push forward several major developments in CPM focused on generating transdiagnostic models for three specific behaviors (attention, working memory, and fluid intelligence) and factors from clinical tests, that will lead to functional phenotypes. We will collect a battery of continuous performance tasks in a spectrum of (N=300) individuals. We propose three specific aims: (1) To characterize node-boundary x dimensional construct effects; (2) To preform unidimensional and multi-dimensional CPM to predict RDoC constructs; (3) To evaluate the extent to which subjects with similar functional phenotypes cluster into symptom based or DSM-5 categorical clusters. This aim will also allow us to investigate the functional networks that vary with symptom and to investigate categorical subtleties in these symptom based phenotypes. The significance of transdiagnostic predictive models of behavior from functional connectivity data lay in their ability to delineate clinically relevant information from any individual (i.e. patient or control). The current lack of transdiagnostic predictive models limits the clinical utility of fMRI, providing a framework for, and generating, these models could have important implications in translating fMRI into a viable clinical tool. The innovation of this proposal is fourfold: 1) the collection of a novel trans-diagnostic data set to be made publicly available; 2) the development of an approach to generate personalized functional atlases to account for individual differences in anatomy; 3) the development of methods to delineate meaningful functional phenotypes to assess symptoms, and 4) to provide a means for comparing alignment of subjects on symptom dimensions versus DSM-5 categories using these functional phenotypes. These developments will be validated using a combination of novel data to be collected here as well as 3 publicly available data sets. The final deliverables will yield tools for measuring functional phenotypes reflecting symptom scores suitable for an individualized approach to medicine.