Andrew R. Mayer, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Cocaine dependence is a debilitating disease affecting millions of Americans and current treatment regimens are ineffective on nearly 90% of patients. Deficits in higher-order attention and memory processes (i.e., executive dysfunction, reduced working memory capacity and difficulties with attentional switching) are common amongst this group and likely contribute to relapse. However, even more basic deficits, including the failure to inhibit repeated sensory stimuli (i.e., sensory gating), are present. These gating deficits may be more severe in abusers with co-morbid psychiatric profiles such as a proneness to experience paranoia or users with more basic attentional disorders. Both of these sub-groups are associated with increased drug dependence and likelihood of relapse. A paradigm that is capable of identifying these sub-groups of users with associated co-morbidity issues would increase our knowledge on the neurobiology of addiction and could be used as a bio-marker for determining the efficacy of alternative treatment regimens, both of which are directly relevant to NIDA's overall mission statement. Therefore, we propose to use multimodal neuroimaging, including functional magnetic resonance imaging (FMRI), electroencephalography (EEG) and magnetoencephalography (MEG), and novel data fusion techniques to investigate basic inhibitory processes (i.e., sensory gating) in 12 healthy normal volunteers and 24 chronic cocaine abusers. Neuropsychological and psychological data will also be collected and correlated with performance on the gating task, with emphasis on clinical measures of attentional dysfunction and cocaine induced paranoia. The proposed task will be a variant of the traditional gating paradigm as participants will be exposed to pairs of identical tones and non-identical tones in addition to clicks. MEG and EEG data will be collected simultaneously, and FMRI data will be collected within 24 hours of the electrophysiological data. The specific aims of this project are 1) a more comprehensive understanding of the neurobiology of addiction by characterizing the neural networks (mesocorticolimbic pathway) underlying inhibitory processes to repeated and novel stimuli in chronic cocaine abusers, 2) to determine if basic failures in inhibition are indicative of faster relapse rates, and 3) to determine if basic inhibitory deficits are related to clinical characteristics (i.e., cocaine induced paranoia and attentional deficits) that are more prominent in certain sub-populations of abusers who might carry dual-diagnoses. This proposal is innovative and unique because it is one of the first attempts to utilize several different imaging modalities (FMRI/MEG/EEG) to investigate the neurobiology of addiction in a group where failures in inhibition have been shown to contribute to likelihood of relapse. Moreover, the use of multimodal neuroimaging and subsequent novel data fusion techniques will resolve a long-standing question in the gating literature, namely "where" and "when" the gating deficit occurs. Our long-term goal (planned R01 submission) is to evaluate the multi-modal imaging data as a predictor of treatment success, and to use task performance to identify a sub-group of patients where alternative treatment interventions should be considered. The minimal cognitive demands of this task also make it ideal for studying cocaine dependence in animals so that novel models of addiction can be developed and pharmacologically tested. Cocaine abuse continues to be a major health problem in the United States with approximately 1.8 million current users. Chronic cocaine abuse and dependence are associated with major medical, neurological, neuropsychiatric, social and interpersonal complications for the individual, their support network and society at whole. This grant will utilize neuroimaging techniques to increase our understanding of the neurobiology of addiction and to determine whether these techniques may be a more sensitive measure and predictor of relapse amongst certain sub-groups of cocaine users. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): It is estimated that about 50 million people in the United States suffer from persistent, serious pain. Response to pain involves both peripheral and central mechanisms with several systems, neurotransmitters and receptors playing a role in pain transmission and response. The neural structures supporting the perception of pain as experience of an unpleasant stimulus strongly overlap with those that support the experience of negative emotion and those areas proposed to be involved in a final common pathway for initiation of drug seeking behaviors in addiction. How acute pain in response to an injury or disease transitions to a chronic pain syndrome, and the underlying neurobiology of pain are still poorly understood. This project proposes to extend previous findings using functional Magnetic Resonance Spectroscopy (fMRS) in pain by linking changes in neural activation to changes in concentration of the neurotransmitter glutamate and one of it's intermediates, glutamine, in response to pain. We hypothesize 1) that painful stimuli administered to healthy humans will increase central neuronal activity and glutamatergic neurotransmission in regions of the brain associated with pain perception, 2) Glutamine levels measured with 1H-MRS will reflect relative levels of activity and glutamatergic transmission and 3) Pain thresholds will be negatively correlated with reports of negative emotion and somatic complaints, while glutamate and glutamine responses to a painful stimulus will be positively correlated with these same measures. The ability to measure such activation and neurotransmitter increases will provide a novel surrogate marker for categorizing pain syndromes. Such investigations of the underlying central neurochemical responses to pain and the development of a technique to precisely measure these responses will have implications extending beyond a better understanding of pain and improving pain treatment and may even impact on the important related issue of addiction to analgesics. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): A recent meta-analysis involving 1463 cases (39 different studies) of mild traumatic brain injury (TBI) indicated that cognitive dysfunction was typically present in the semi-acute phase of injury (effect size d = .54) but that no neuropsychological deficits were observable at three months post-injury. Of all cognitive deficits following mild TBI, difficulties with attention and distractibility are one of the most commonly reported, and observed, symptoms. However, the neuropathology underlying attentional dysfunction in the first few weeks of injury and the subsequent recovery process are currently understudied using newer neuroimaging techniques. The current application proposes to use neuropsychological testing and two laboratory measures (orienting and selective attention tasks) to quantify this attentional deficit, and functional magnetic resonance imaging (FMRI), diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) to quantify the underlying neuronal changes that occur as a function of time in mild TBI. Specifically, 27 mild TBI patients and 15 non-cranial trauma controls will undergo neuropsychological testing and an extensive imaging battery 3 weeks and 3-5 months post injury. During the FMRI session, participants will be asked to perform a spatial orienting task and a task that requires them to process conflicting information from two sensory modalities (Numeric Stroop). To date, the vast majority of TBI neuroimaging studies have employed only a single imaging modality (MRS or FMRI or DTI), have selected patients without controlling for time post-injury or severity of injury, and have not studied patients longitudinally. Thus, the impact and innovation of the current proposal therefore lies on several levels. Foremost, it addresses an important gap in our current knowledge regarding the development of standardized protocols that are capable of capturing the dynamic neurological changes that occur after a mild TBI. Routine clinical imaging modalities (MRI and CT scans) are usually insensitive to both the neuronal pathology underlying acute cognitive deficits as well as to the subsequent recovery process that occurs in the majority (80-90%) of patients. Second, each of the selected imaging modalities contains different information about the functioning of different classes of neuronal tissues (i.e., FMRI = indirect measure of gray matter functioning and vasculature;DTI = measure of white matter integrity;MRS = direct measure of neuronal and axonal health). The combination of information from these three different imaging techniques is likely to be synergistic and exceed the sum of each individual modality alone. We will directly test this hypothesis by applying novel multivariate statistical techniques (joint independent component analyses;J-ICA) to the acquired imaging data. Finally, a longitudinal study of mild TBI during both the semi-acute and chronic phase using these neuroimaging modalities will provide the foundation for a human recovery model in TBI. While it is unlikely that neuroimaging techniques alone will ever be able to provide an independent objective diagnosis, it is likely that they will provide incremental information that will be important for both differential diagnosis and predictions about future outcome. Importantly, the realization of the above will be critical for eventually identifying the minority of mild TBI patients at risk for developing future complications so that intervention can occur acutely, when there is a better chance of success. PUBLIC HEALTH RELEVANCE: In the United States alone, there are approximately 1.2 million mild traumatic brain injury (TBI) cases per year that result in an estimated cost of $56 billion dollars. The symptoms of mild TBI can range from severe physical and mental disability to subtle problems with attention, concentration, or emotional control. Cognitive difficulties are often present in the first few weeks of injury, but typically remit 3-5 months post injury in the majority (approximately 80-90%) of patients. The first step for understanding these cognitive difficulties is to develop biomarkers that are sensitive to neuronal injury and the subsequent recovery process. This will be critical not only for mild TBI, but also for more severe forms of TBI as well. However, the identification of the pathology underlying cognitive deficits in the acute or chronic phases of mild TBI is often subtle, and hard to detect with conventional imaging techniques such as CT or MRI. This suggests that the diagnostic utility and predictive validity of more research-based neuroimaging techniques, such as functional magnetic resonance imaging (FMRI), diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) needs to be explored. The use of multiple neuroimaging techniques is crucial because different modalities measure different signals (e.g., hemodynamic, metabolic or electrophysiological) that originate from different tissue sources in the brain (e.g., white versus gray matter), which will be important for identifying the diffuse injuries that may occur following head trauma. It is likely that the underlying acute pathology is multifaceted and involves both white and gray matter, suggesting that sampling several different domains of neuronal integrity is a necessary first step to understanding the acute cognitive deficits as well as the subsequent normal recovery process. Moreover, these bio- markers may be useful for distinguishing the small percentage of mild TBI patients who continue to have cognitive problems due to the injury.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The initial aims of the current project were to evaluate the temporal and spatial integrity (i.e., connectivity) of the auditory attention network in patients with schizophrenia (SP) and healthy controls (HC) by studying the electromagnetic (magnetoencephalogram;MEG) and hemodynamic (functional magnetic resonance imaging;FMRI) response to basic auditory stimuli. To different paradigms were utilized. The first paradigm examined passive attentional responses to pairs of identical and non-identical tones, as well single tones (FMRI only). The second paradigm examined how patients and controls actively allocate attentional resources to extrapersonal space based on auditory cues and targets (FMRI and MEG). In addition, we also proposed to examine the relationship between imaging markers of basic auditory attention, clinical performance on cognitive testing and single nucleotide polymorphisms.

DESCRIPTION (provided by applicant): Cocaine abuse and dependence are chronic, relapsing disorders for which there are few effective treatments. Changes in frontal and sub-cortical neural circuitry following prolonged drug exposure can last for years after cessation and may compromise an addict's ability to suppress drug seeking when exposed to drug- related cues. Attentional Bias Modification (ABM) training purportedly reduces the attentional response to salient drug stimuli and has been shown to be efficacious in treating alcohol dependence; however, the efficacy of ABM in treating individuals with cocaine addiction has yet to be empirically determined. Previous research suggests that chronic cocaine users also exhibit a decreased neuronal response during inhibitory control in addition to the enhanced neuronal response to salient drug cues. Preliminary neuroimaging data obtained during our R03-ISTART grant supports both lines of research, as individuals with cocaine abuse and dependence (CCA) exhibited increased activation in response to realistic cocaine cues and a profound lack of activation during inhibitory control. Although extensive evidence of these two neuronal abnormalities exists, to date we are not aware of a study that has directly compared the differential validity of these two metrics (i.e., enhanced cue reactivity and decreased inhibitory control) for predicting relapse. Additionally, our preliminary data provides evidence of increased intrinsic neuronal activity (functional connectivity; fcMRI) within a frontal sub-cortical circuit in CCA relative to controls. Therefore, the current application has two primary objectives that are both clinically significant and highly innovative. First, we will investigate the efficacy and mechanism of action of ABM in treating cocaine addiction (Aim 1). Second, we will determine which of the three neuronal abnormality or abnormalities (i.e., enhanced cue reactivity or decreased inhibitory control or increased fcMRI) are more predictive of relapse and drug utilization (Exploratory Aim 1). To achieve these two objectives, forty treatment-seeking CCA will be randomized to one of two groups in a blinded fashion: five sessions of ABM treatment or five sessions of a similar categorization control task. All participants will complete an extensive clinical and fMRI battery pre- and post-treatment designed to measure activation during cocaine cue processing, inhibitory control, and functional connectivity. We predict that ABM will prove to be efficacious in reducing relapse and that it will exert its greatest effect on reducing fcMRI and cue reactivity within frontal (orbital frontal cortex and anterior cingulate gyrus) and sub-cortical (ventral striatum) regions implicated in addiction. We also predict that individuals with increased fcMRI within frontal, sub-cortical circuits at baseline will be more likely to relapse, suggesting that repeated exposure to cocaine stimuli may result in changes in the underlying circuitry that are independent of exposure to drug stimuli. The goals of this study are clinically significant as they will potentially provide a new treatment for CCA or, at a minimum, examine whether increased fcMRI, enhanced cue reactivity or decreased inhibitory control are more predictive of relapse.

DESCRIPTION (provided by applicant): Psychotic spectrum disorders (PSD) are difficult to differentially diagnose and treat, typically leaving their victims with lifetime disability. It is increasingly becoming recognized that traditionally distinct disorders such as schizophrenia, schizoaffective disorder and bipolar disorder with psychotic features share overlapping symptoms. For example, in addition to positive symptoms, PSD patients also experience deficits in cognitive control/executive functioning, which likely result from dysregulation of the mesocortical and mesostriatal pathways. Importantly, cognitive deficits contribute to deficits in interpersonal and occupational functioning, more traditional clinical symptoms (e.g., disorganized thinking) and are currently refractory to treatment. The current application will use novel recruiting strategies and novel multivariate analytic techniques to establish empirical, neuronally-based cluster metrics (i.e., circuit-level pathologies) that are associated with impairments in cognitive control (primary outcome) and everyday functioning (secondary outcome) in PSD regardless of traditional diagnoses (DSM-V). Other potential mediating variables evaluated in the current model include negative symptoms and disorganized thinking. We investigate potential causal mechanisms for these circuit- level pathologies by examining the aggregation of specific genetic mutations (single nucleotide polymorphisms; SNPs) within three neurotransmitter (dopamine, glutamate and GABA) signaling pathways, axonal guidance pathway, and synaptic long-term potentiation pathways based on our preliminary data. Finally, an exploratory aim evaluates whether the expression of cognitive control deficits across multiple psychiatric illnesses is mediated by each individual's total number of rare deletions in DNA (copy number variations; CNVs). To evaluate these hypotheses, 175 continuously recruited PSD patients will complete an extensive clinical battery and undergo multimodal neuroimaging. Evoked and intrinsic hemodynamic activity will be used in conjunction with white matter assays (diffusion tensor imaging) to investigate the integrity and connectivity of the cognitive control circuit (dorsal medial prefrontal cortex, lateral prefrontal cortex and caudate nucleus) during a multisensory cognitive control task with real-world validity. PSD patients will be classified into meaningful entities based on univariate and multivariate indices of grey/white matter pathology in the cognitive control network using a K-means algorithm. We will then determine the predictive validity of these clusters for describing deficits in cognitive control and everyday functioning, using the leave-one-out methodology to verify the model. Thus, the current application utilizes multiple units of analyses (genes, circuits, self-report, behavior, and paradigms) from the NIMH Research Domain Criteria to develop a novel classification system based on neurophysiological and genetic biomarkers of impaired cognitive control that spans traditional diagnostic categories. We are confident that moving beyond traditional nosologies will result in more meaningful diagnoses and ultimately more successful treatments for refractory symptoms, leading to substantial improvements in mental health care.

There is no question that the vulnerabilities of the developing brain and the potential for recovery are unique, or that pediatric mild traumatic brain injury (pmTBI) represents a major public health concern with ?400,000 new cases annually. Although the neurobehavioral symptoms of pmTBI are well-documented in the first days to weeks post-injury, few well-designed studies have examined the long-term consequences of injury. Even less is known about the neuropathology underlying the expression of post-concussive symptoms (PCS) and the impact on clinical outcomes. Thus, clinicians currently do not understand how children typically recover in the first year of injury from either a clinical or neurophysiologic perspective. The current application addresses this critical knowledge gap by collecting longitudinal (1 week, 4 months and 1 year post-injury) neuroimaging and clinical data on a large cohort of pmTBI patients (N = 150) and healthy controls (N = 125). Our preliminary data suggests diffuse white matter injuries, hemodynamic abnormalities in deep gray matter, and signs of cortical atrophy at 4 months post-injury in a relatively small sample. Consistent with animal models, these data indicate that multiple imaging measures at multiple time-points are needed to understand the dynamic effects of pmTBI on neurophysiology and underlying contributory factors (e.g., cerebral blood flow, cerebral vascular reactivity). The current study will extend these findings to the early chronic and chronic injury stages, determine how these diffuse injuries relate to clinical outcomes, and determine the individual ?recovery time-courses? of selected biomarkers. Ratings of PCS are collected from both child and parent in conjunction with computerized cognitive testing, quality of life measures, and assessments of pre-morbid functioning. A multi-shell high angular resolution diffusion imaging sequence provides unique information on potential underlying mechanisms of action (water fractions). Functional activity is measured during a spatial attention task and through connectivity analyses. Additional quantitative measurements of resting cerebral blood flow and cerebral vascular reactivity will disambiguate hemodynamic from neuronal dysfunction. These independent measures will also provide critical information on how the vasculature in deep gray matter structures is affected by trauma, providing mechanisms of target engagement for future therapeutic trials. Growth curve modeling provides preliminary analyses of different recovery trajectories (fully versus partially recovered) for both clinical and imaging data. The public health significance of the current application is multifold. First, late childhood and adolescence constitutes a critical time for brain development, and persistent neurobehavioral symptoms following pmTBI can interfere with subsequent academic achievements and interpersonal relationships for years post-injury. Second, developing objective biomarkers that track injury progression will aid in diagnosis of injury severity and provide an empirical foundation for determining when it is truly safe for children to return to learn/physical activity. Finally, understanding the mechanisms of injury represents a critical first step for developing novel therapies that target neuropathology (i.e. target engagement) rather than symptom mitigation, the current approach for all pmTBI therapies.

ABSTRACT Our Phase 1 (P-I)/Phase 2 (P-II) effort has enabled us to define the study of neuropsychiatric illness through the lens of systematic multimodal imaging as the thematic area of focus. We feel that we can be competitive at the national level for a center grant beyond the P-III given our current trajectory. During P-I/P-II we developed a strong state-of-the-art infrastructure and a strong research base composed of established faculty and successfully graduated junior PIs, some of whom now serve as core directors and mentors as part of our P-II and Phase 3 (P-III) COBRE programs (detailed in the various cores). Although the number of R01 grants won by local investigators meets the minimum requirement for consideration for a center grant, we still need to increase the number of R01s from MRN/UNM and other research institutions in NM in order to be competitive nationally. The proposed Pilot Project Program (PPP) is designed to maximize our ability to achieve this goal. The PPP will fund three categories of faculty members: (1) current P-II junior PIs and pilot project PIs who have existing pilot projects and need further support beyond their P-II projects; (2) junior faculty members with strong proposals who will be supported as new investigators during P-III; and (3) senior faculty members who wish to include neuroimaging as a new component of their pre-clinical or clinical research program to expand the scope of research. We will allocate a total of up to $250,000/year for our PPP, consisting of $125,000/year requested from the NIGMS and $125,000/year in institutional match funds. This funding will be used to support up to 5 projects at $50,000/project/year. To encourage productivity, each project will be funded for 1 year at a time, with the possibility for competitive renewal if meeting documented criteria and after evaluation by the steering committee (SC). The PPP will establish a training program for each successful PPP investigator on the use of the cores and will implement a mentoring program reminiscent of our P-II mentoring program, to provide mentorship to all 3 categories of funded faculty members. The selection of PPP-supported investigators and the oversight of our PPP will be carried out by the SC consisting of members of our P-II internal faculty development committee along with an administrative member and three core users. 2

Project Summary/Abstract This Phase III (P-III) COBRE project will extend the cores that have been successfully leveraged in our Phase I (P-I) and Phase II (P-II) COBRE projects and sustain these unique resources in New Mexico through the im- plementation of a business plan. Over the past eight years we have built up infrastructure and created a cutting edge brain imaging center, our P-II project is just over half-way through and is even more successful than our P- I was at this point in time. The Mind Research Network (MRN) houses an Elekta Neuromag 306-channel MEG System, a high density EEG lab, a 3T Siemens Trio MRI scanner, and a mobile 1.5T Siemens Avanto MRI scanner. Additional resources include a centralized neuroinformatics system, a strong IT management plan, and state-of-the-art image analysis expertise and tools. This P-III COBRE center will continue our momentum and move the cores we have developed into a position of long term sustainability. We will continue with the technical cores established during the P-II project including multimodal data acquisition (MDA), algorithm and data analy- sis (ADA), and biostatistics and neuro-informatics (BNI). These cores have begun to serve MRN and the greater community, as well as other institutions including extensive collaborations with IDeA funded projects in New Mexico and other states. We believe this P-III COBRE is extremely well-positioned to establish and sustain New Mexico as one of the premier brain imaging sites. We include an extensive pilot project program (PPP) that is built on the successful pilot programs implemented as part of the earlier COBRE phases. This includes an ex- tensive educational, mentoring, and faculty development program to carefully mentor and position faculty who use the cores to maximize their potential to successfully compete for external funding, thus fulfilling the ultimate goals of the COBRE program. 2

Abstract The administrative core (ADM) will function in an overall supervisory capacity for our Phase III COBRE. It is comprised of a steering committee, external and internal advisory committees, and other stakeholders. The ADM core will be directed by Dr. Vince Calhoun, the PI for the current proposal. It will also operate under the supervision of a well-respected psychiatric clinician-researcher, Dr. Juan Bustillo, and Dr. Nora Perrone-Bizzozero, an established neuroscientist and educator. Drs. Jeff Lieberman, MD and Charles Bowden, MD will serve as external consultants. The core director will coordinate the duties and goals of the ADM core, focused on three aims: 1) to coordinate all the specific budgetary, regulatory, and personnel aspects required in the three technical cores and Pilot Project Program; 2) set up a strong community outreach program and support new investigator projects using our pilot project core; and 3) maintain and continue to develop vital core facilities in consultation with internal and external advisors. A long-term aim of this Phase III award is to expand the capability of our facilities and further develop a diversified neuroimaging research environment that will continue to be competitive nationally and internationally. We believe that through the support of a COBRE Phase III, our cohesive and collaborative program of interdisciplinary and translational research can be leveraged into a center-level grant (e.g. P41, P50) which will be submitted approximately 3 years after the start of the Phase III award. Hence, this Phase III award is essential for the overall success of our New Mexico program on multimodal imaging of neuropsychiatric illness.

Project Summary/Abstract The algorithm and data analysis (ADA) core of this phase III COBRE will provide basic and advanced centralized image analysis resources for processing multimodal imaging data. These resources include tools designed for basic and advanced analysis of structural MRI (sMRI), MR spectroscopy (MRS), function MRI (fMRI), diffusion MRI (dMRI), magnetoencephalography (MEG), electroencephalography (EEG), and genetics data. The ADA Core will play a leading role in developing and providing software that is needed to solve basic image analysis problems that arise when working with MR and MEG/EEG data. This will be accomplished by providing a core set of tools and approaches for analysis of imaging and genetic data. The core set of resources includes expertise and tools for analyzing all first level-imaging data (automated pipeline preprocessing) as well as advanced algorithms for network-based functional and structural connectivity measures to address in a comprehensive way the scientific questions being asked. We will work with the tools developed locally as well as widely- used tools developed by other groups to enable network-based analysis, data-fusion of multimodal data, and prediction/classification approaches. Importantly, a key aspect of this COBRE and the ADA core is focused on combining multimodal data enabling investigators to leverage additional information via joint analysis of multiple modalities (data fusion). An additional area of emphasis will be on the development of realistic simulation approaches, to enable comparisons of algorithms, optimization of parameters, and to provide intuition about how new algorithms work. Finally, the ADA core will also provide essential training about data analysis of brain imaging and genetic data, as well as mentoring for specific projects. This will ensure investigators and potential core users are informed about the various algorithms, understand how to make analysis choices given a particular hypothesis, and have a basic idea of how to implement such algorithms themselves. The director of the ADA Core is Dr. Calhoun, who has over 20 years of experience in developing tools and approaches for working with unimodal and multimodal imaging and genetics data. Co-director Dr. Cheryl Aine has extensive experience in unimodal and multimodal imaging with MEG/EEG. 1