L. Elliot Hong - US grants

[unreadable] DESCRIPTION (provided by applicant): The heterogeneity theory of schizophrenia is generally accepted but identification of subtypes, which is crucial for genetic research, has been difficult. Deficit syndrome schizophrenia has been proposed as a valid subtype and is characterized by patients who exhibit primary enduring negative symptoms. High concordance of deficit schizophrenia in families suggests a shared genetic and/or environmental etiology. This proposed study represents the first effort (to our knowledge) to systematically determine neurobiological markers for deficit schizophrenia by studying their non-psychotic family members. Non-ill relatives may carry smaller numbers of susceptibility genes that do not result in psychosis, but may result in abnormalities that can be detected by neurobiological tests such as eye movements. Identification of heritable cognitive and electrophysiological abnormalities in deficit syndrome will help demarcate the boundary of the disorder and provide alternative phenotypes in genetic studies. Neurobiological abnormalities identified only in deficit patients and their family members may be marking the liability of deficit schizophrenia. In our preliminary study with small sample sizes that examined components of the smooth pursuit eye movement response, we found that impaired smooth pursuit initiation was specifically associated with deficit probands and their relatives, whereas predictive smooth pursuit was equally impaired in patients with and without deficit schizophrenia and in their relatives. This supports the validity of our research approach. In this proposed study, we aim to determine whether pursuit initiation is impaired only in relatives of deficit probands by using a modified initiation task in which predictive factors are minimized. We will also include memory saccade task, antisaccade tasks, and a version of the CPT with degraded presentations. These tasks are chosen because they have shown evidence of association with schizophrenia or deficit syndrome. These tasks will be administered to 30 relatives of deficit probands, 30 relatives of nondeficit probands, and 30 normal controls. Testing in relatives rather than patients will serve to eliminate differences in secondary effects of psychosis and medications. We plan to use the preliminary data collected from this grant support to guide our full-scale search for phenotypic markers specifically associated with the liability for deficit schizophrenia and subsequent molecular genetic studies. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The etiopathophysiology of schizophrenia is incompletely understood. Evidence supports an association between genetic liability for schizophrenia and smooth pursuit eye movement (SPEM) abnormalities, and it has been suggested that SPEM can serve as a phenotype in molecular genetic studies. However, the neural basis of reported abnormalities in SPEM is not well understood, and even less is known about how genetic effects are translated into aberrant neural circuit controlling SPEM. Knowledge of the biological mechanisms underlying SPEM abnormalities and their relationship to the schizophrenia phenotype may provide critical insights into the etiology of this disease. The goal of the proposed research is to combine functional magnetic resonance imaging (fMRI) and SPEM measures to study 1) the underlying neural mechanism of schizophrenia-related SPEM impairments; and 2) the degree to which pursuit-related imaging changes aggregate in families. We have behaviorally modeled the relative contributions of retinal motion and extraretinal motion signals to smooth pursuit maintenance in healthy subjects and in relatives of schizophrenia patients. The results indicate that performance in healthy subjects depends primarily on the predictive, or extraretinal motion input, while relatives of schizophrenia patients show deficits in this component of the pursuit response. This deficit may lead to an increased reliance on the immediate, retinal motion sensory input to maintain smooth pursuit. We hypothesize that this pattern of behavioral abnormality has a neurophysiological basis that will be detectable in fMRI imaging signal as reduced activation in the extraretinal motion processing pathway accompanied by a compensatory increase in activation in regions responsible for retinal motion processing. We further hypothesize that this pattern of neural activity will be present in the clinically unaffected siblings of affected probands, supporting a genetic influence on the neural circuit controlling predictive smooth pursuit deficit in schizophrenia.

[unreadable] DESCRIPTION (provided by applicant): Several behavioral/neurophysiological abnormalities are proposed as alternatives to the clinical phenotype in marking the liability for schizophrenia. These intermediate phenotypes may mark sub-components of disease risk and more specific biochemical paths contributing to the etiology of schizophrenia. One highly reproducible phenotype is the smooth pursuit eye movement (SPEM, also called eyetracking) abnormality, replicated by over 50 studies with few negative results. Evolutionally this phenotype is unique in that SPEM is a behavior only present in primates. Unfortunately until now there is a void of knowledge in our understanding of the molecular basis of abnormal eyetracking, largely due to the evolutionary characteristics of this phenotype, which limits the development of small animal models. The challenge is how this unique phenotype can be translated into tangible biochemical studies, which is a necessary step to describe the path from genes to behavioral deficits and thereby to establish new molecular treatment targets. We have developed a strategy that allows us to probe the molecular mechanisms of SPEM deficits in schizophrenia. Recent studies suggest that predictive pursuit deficit (PPD) may underlie the eyetracking abnormality in schizophrenia. Predictive pursuit is the primary mechanism for maintaining smooth pursuit in primates. Imaging studies have identified several candidate anatomic loci of the SPEM deficit in schizophrenia. Among these loci, the consistently replicated finding is reduced activation in the frontal eye fields (FEF) during SPEM. This region will be the focus of the proposed study. Predictive pursuit deficit is present in schizophrenia patients and some 1st degree relatives. Critically, family studies examining this refined phenotype revealed a high familiality. The high familiality permits a reasonable chance to identify postmortem tissues more homogenously associated with PPD using proxy measurement in living family members. Combining knowledge learned from functional imaging and family studies, we plan to select subphenotype-specific postmortem brain tissue for the purpose of screening transcripts associated with PPD in schizophrenia. Schizophrenia is a devastating brain illness affecting 1% of our population. There is lack of effective treatment for core physiological and cognitive deficits associated with this illness. This project aims to identify genes and gene products associated with one of these core deficits called eyetracking abnormality in schizophrenia so that drugs can be developed to treat these core physiological and cognitive deficits. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The health risk associated with tobacco use in people with severe mental illness is much higher than the general population. Among them, patients with schizophrenia are the population with perhaps the highest risk for nicotine addition. Current conceptualizations of the possible etiologies of the severe schizophrenia-smoking comorbidity include self-medication for neurocognition deficits, overcoming antipsychotic medication side effects, and shared nicotinic molecular pathways. However, the underlying brain circuitry for the comorbidity is unknown. Identifying brain comorbidity circuitry is critical for developing valid biomarkers for clinical therapeutic development, individualizing treatment selection and outcome prediction. Recent data suggest that the cingulate-ventral striatum circuit appears to be one of the key pathways associated with nicotine addiction. These same areas are also among the regions most commonly implicated in schizophrenia, and additional preliminary studies suggest that the same circuit is impaired in schizophrenia. Therefore, we hypothesize that abnormal cingulate-ventral striatum circuit is a key path for schizophrenia/nicotine addiction comorbidity. We propose to test the hypotheses that the cingulate-ventral striatum circuit is abnormal in nicotine addiction and in schizophrenia, and that schizophrenia pathology disrupts this circuit and predisposes patients to more severe nicotine addiction, leading to the severe nicotine addiction/schizophrenia comorbidity. We will also examine the clinical validities of the circuit in prediction of long-term smoking behavioral change, in genetics, and in its relationships to putative addiction mechanisms. Identifying the key brain circuits associated with smoking in this high risk population will provide concrete biomarkers for new therapeutic development, and ultimately reducing the smoking related health burden in schizophrenia patients. In addition, as public health efforts have reduced smoking, those who still smoke in the population may be more dependent and more treatment-resistant. An effort targeting the population most addicted to smoking may also yield novel perspectives to treat nicotine addiction in the general population.

DESCRIPTION (provided by applicant): Neural Oscillatory Biomarkers for Genetics and Animal Models of Schizophrenia Project Summary: Neural oscillations are electrical activities of the brain measurable at different frequencies. They can be obtained at many levels, ranging from single cell to local field potentials in animals, to large-scale synchronized activities in human scalp. Patients with schizophrenia exhibit impaired neural oscillatory activities during sensory and cognitive tasks such as sensory gating, working memory, executive functions, and even at rest and during processing of monotonous visual and auditory stimuli. New evidence suggests that there may be common underlying abnormalities in oscillatory activities that are associated with schizophrenia-related cognitive and functional impairments. We have modified and developed experimental paradigms that will elicit oscillatory responses from basic sensory to more complex cognitive performance. We plan to isolate the common oscillatory abnormality in schizophrenia across tasks. In addition, since neural oscillations can be measured in animals and in humans in a similar fashion, it is possible to carry out parallel animal and human research using similar neural oscillatory measures as disease biomarkers. Towards this aim, these electrophysiological paradigms are constructed in a way that they are potentially feasible both in clinical population phenotyping and in small animal implementation, so that neural oscillatory biomarkers validated by this study in schizophrenia patients, and subsequent genetic findings from these neural oscillation phenotypes, can be applied to translational research in animals. Using the Building Translational Research in Integrative Behavioral Science mechanism, we propose to initiate similar paradigms in rodents. The basic neuroscience component of this application is to establish analogous rodent models using experimental paradigm closely matched with that of the human experiments, and then to conduct initial mechanistic studies on the pathophysiological origins of the abnormal neural oscillations found in patients with schizophrenia. This effort should lay the necessary groundwork for interpreting clinical findings and ultimately using neural oscillations as a translational tool in studying the molecular path from genes to pathophysiology and their treatment in schizophrenia. The neurogenesis of neural oscillations is under intense study. However, systematic investigations of their roles as disease phenotypes in schizophrenia populations are needed. The potentially novel biomarkers thus described and validated should significantly shorten the research cycle from biomarker discovery to gene identification and novel drug development in animal models.

DESCRIPTION (provided by applicant): Smoking remains the leading cause of preventable diseases and death in the US, and is known to be heritable. This application aims to develop a set of nicotine addiction cell lines based on clinically defined imaging phenotype and genotype. Our goal is to test that neuronal electrophysiological response to nicotinic agonists will be associated with the strength of the clinical imaging based circuit phenotype in patients with severe nicotine addiction and carry smoking related risk alleles. Our innovation here is to closely link these cell lines with state-of-the art clinical measures of nicotine addiction, so that we coud iteratively test electrophysiological phenotypes of the cells that are likely underlying key clinicl nicotine addiction measures.

Schizophrenia pathology has long been associated with stress and/or immunity, although their etiological paths to the disease are far from clear. The kynurenine pathway of tryptophan degradation is a strong candidate for the missing link because enzymes that gate the first step of the conversion of tryptophan to kynurenine are influenced by stress, glucocorticoids and the immune system. However, the downstream mechanisms connecfing increased kynurenine synthesis and pathological events in schizophrenia involve multiple chemical changes, which are not necessarily identical in the periphery and in the brain. In other words, in spite of the attractiveness and plausibility of the hypothetical link between kynurenine pathway metabolism and schizophrenia, and especially the presumed prominent etiological role of the pathway metabolite kynurenic acid, the field lacks a coherent explanatory model, hindering meaningful pre-clinical- clinical translations. The difficulty may be due to the inherent complexity of the system and its interactions with other systems, but also to the lack of a comprehensive clinical effort to understand the connection between the kynurenine pathway and the core features of schizophrenia patients. The present effort is designed to change that by examining the impact of stress and cytokine mechanisms on kynurenine pathway metabolites in schizophrenia patients, and by evaluafing the relevance of these new findings to pathophysiology. Based on the strong pre-clinical evidence for causality and embracing the complexity of the system, the project is designed to test the trajectory from stress/cytokines to kynurenine pathway metabolites to clinical and brain abnormalities in schizophrenia using an array of state-of-the-art imaging, electrophysiology, and modeling approaches. This study will therefore comprehensively investigate the extent of the involvement of the kynurenine pathway in mediating the effects of stress and immune function on core clinical and biological abnormalities in schizophrenia, and define the key biomarkers associated with the kynurenine pathway in schizophrenia. This new knowledge regarding the involvement of kynurenine pathway metabolism in schizophrenia patients will lead to more specific and better treatment targets for drug development.

? DESCRIPTION (provided by applicant): The Amish Connectome Project (ACP) will extend the Human Connectome Project (HCP) to mental illnesses by characterizing brain circuitry and its relation to psychiatric behavior and symptom dimensions. We propose to collect HCP connectomics and whole genome sequencing data in Old Order Amish (OOA) adults recruited from multigenerational families with multiplex mental disorders spanning diagnostic boundaries. Large nuclear families with two or more members with major DSM-5 disorder will be recruited for phenotyping using the full HCP lifespan imaging and behavioral protocol expanded to Research Domain Criteria (RDoC) standard. The advent of non-invasive connectivity-oriented neuroimaging methods has shed new light onto the inner workings of the brain. The brain's functional and structural connectome plays key roles in regulating the pathway from genes to neural systems to mental illnesses. Extending the gene -->connectome HCP approach to gene -->connectome -->mental disorder in HCP-Human Disease adds tremendous opportunity to identify genetic underpinning of heritable mental disorders. ACP offers a uniquely efficient and powerful study design that is critical for a successful breakthrough. The ACP will study large, multigenerational families from a population isolate, which is a powerful statistical design for discovery of genetic linkage between connectomic traits and mental disorders. The OOA sample is unique in its relative genetic uniformity, with ancestry recorded in the NIH database and traceable back fourteen generations to limited founders. This sample is also unique because of its relative uniformity in educational background, life and work conditions, socioeconomic status and much reduced influence by illicit drugs. These unique characteristics of OOA community members, combined with their large family size, makes the OOA a powerful population sample to study the genetic factors that alter cerebral connectivity in mental disorders with familial pattern of inheritance. We will expand upon HCP protocol with the psychiatric diagnosis, broad symptom and RDoC dimensional assessments of behavior and cognition. Whole genome data will be obtained for all participants through next generation sequencing and family-based imputation of GWAS data. These data will be shared with the large research community while protecting the privacy, confidentiality and welfare of participants, with special attention given to protect the welfare of the OOA community. Medical genetic discoveries in OOA have routinely been replicated in general population samples and translated to clinical practice. We are inspired to create opportunities to allow repetitions of suh success in brain connectome and in mental illness through shared data effort, and have assembled an efficient team to lead this endeavor.

Project Summary / Abstract The advent of non-invasive connectivity-oriented neuroimaging methods has shed new light onto the inner workings of the brain. The brain's functional and structural connectome play key roles in regulating the pathways from genes to neural systems to mental illnesses. Along these pathways, we hypothesize that abnormal activity in the innate stress-immune pathways has a major contribution to the brain connectome disruption in early stage of schizophrenia spectrum disorder and to its clinical consequence. The project proposes to extend the Connectome Project in Mental Illness to characterize brain circuitry and its relation to stress-immune axis dysfunction in early stage of schizophrenia spectrum disorder in China. We propose a longitudinal study in a large sample of patients that aims to overcome the heterogeneity in the relationship between mental illness and stress-immune-connectome axis, a well-recognized barrier to advancing research and treatment. We will recruit 500 patients with schizophrenia spectrum disorders within five years of disease onset. They will be assessed using modern chronic stress and acute psychological stress laboratory paradigms to define the stress biomarkers at baseline. The patients will be compared with 250 age and sex matched healthy controls. The collaboration leverages the clinical stress research expertise by the U.S. partner and the the clinical immunology research expertise in schizophrenia by the Chinese partner. The proposed study also builds on our ongoing work using acute and chronic stress paradigms to understand how stress is linked to brain structural and functional connectome in schizophrenia spectrum disorders. This novel proposition in U.S. and Chinese mental health research field is strongly supported by preliminary data. The ability to apply the cutting edge connectome protocol using the advanced research designated scanner in Beijing will also enhance our ability to use multimodal imaging tools to aid biologically based heterogeneity reduction. Together, this study will generate actionable strategies to treat and prevent brain connectome deterioration and facilitate clinical recovery after psychosis onset.

Project Summary Brain imaging research has revealed accelerated age-related white matter, neurochemical and perhaps cortical changes in patients with schizophrenia spectrum disorders. However, imaging studies are typically brain-focused without system-level investigations on the risk factors. Patients with schizophrenia spectrum disorders also have a much shorter lifespan and high morbidity and mortality. However, medical comorbidity studies typically do not include brain-based investigations. It remains unclear why schizophrenia spectrum disorders have high age-related medical burden. Cumulative stress effects are predictive of successful aging in healthy older adults. In patients with schizophrenia spectrum disorders, cumulative stress may disrupt brain structure and function, and/or impaired brain structure and function may distort normal responses to stress leading to increased cumulative stress effects. The proposal research will study cumulative stress and brain imaging age-progression in an age span of 45 years, using a combined longitudinal and age-cohort cross- sectional design. The study proposes to track the progression of stress-related risk factors in the periphery, and the age-related changes in the brain, and to determine whether they will independently or interactively contribute to age-related medical health and functional outcomes in patients with schizophrenia spectrum disorders. These findings may guide the development of clinically actionable strategies to intercept abnormal aging and promote successful aging in patients with this devastating illness.

Project summary Perturbations in the kynurenine pathway metabolites have been associated with alterations in glutamate, acetylcholine, serotonin and dopamine signaling, and have been linked to schizophrenia. During the first 5 year of the Conte project, we have developed new evidence that kynurenergic effects in schizophrenia maybe dynamically related to stress response and genetics. Identifying the underlying mechanism would be critical to determine whether this pathway is critical in schizophrenia and how it is related to the known pathophysiological glutamate, acetylcholine, serotonin and dopamine signaling in this illness. The downstream substrates of the tryptophan-kynurenine mechanism involve multiple and frequently opposite actions. Although many of these actions have implications in schizophrenia, the field lacks a coherent schizophrenia-kynurenine model, hindering meaningful preclinical-clinical translations. The difficulty may be due to the inherent complexity of the system and its interactions with genetics and developmental risk factors. We will employ a combination of cellular to patient ex-vivo cellular genetic approaches to analyze the role genetic effects on the kynurenine pathway signaling in schizophrenia. The empahsis is on stress-induced kynurenergic response and its associated brain circuitry and glutamatergic signaling biomarkers. The project is ambitious and translational, involving clinical, brain imaging, and cellular models for specific genetic effects. However, we have formed a strong, highly integrated team and project design, and the preliminary studies support our proposed specific aims, demonstrate feasibility, and suggest a significant potential for novel discoveries if these aims are supported in the proposed studies. Knowledge on how the kynurenine pathway is involved in clinical schizophrenia patients will lead to more specific and better treatment targets for drug development.

Project summary While available tobacco smoking cessation aids, therapies, and public health efforts have reduced the overall smoking rate, patients with schizophrenia spectrum disorders continue to have high rate of smoking. Recent imaging research has identified key brain circuitries likely contributing to the high rate of smoking in these patients, in an overlapping pathophysiological neural circuitry between schizophrenia and nicotine addiction. Targeted correction of this overlapping circuitry may improve the patients' chances of success in quitting smoking. The proposed study is to use a novel approach to design rTMS treatment that is based on a neural circuitry mechanism on nicotine addiction in schizophrenia. The project will recruit patients with schizophrenia spectrum disorders and randomize patients into active rTMS versus sham rTMS groups followed by fMRI based target engagement outcome assessments. The proposal will use new stimulation site conceptualized to be more closely linked to neural circuitry mechanisms of nicotine addiction in schizophrenia. The proposal will include two phases as two separate projects. The first proposed project is a UG3 for two years. If the Go/Nogo milestones are not met, the study will end. If all Go/Nogo milestones are met, it will proceed to a UH3 project for another three years. The trial will test the proposed mechanism of action at brain circuitry level and determine whether the new stimulation site will indeed significantly engage the proposed circuitry through modulating its functional connectivity in the direction for helping patients to reduce and quit smoking.

Project Summary / Abstract Vascular biology and white matter may be some of the key junctures that harbor early risk mechanisms that precipitate vascular contributions to cognitive impairment and Alzheimer's disease. This process may start as early as adolescence and young adulthood, and through our lifespan. While cardiovascular impacts on white matter health are well-established, our understanding of the lifetime course and the associated mechanisms are less clear. Our efforts aim to identify the earliest possible vascular biomarkers and risk factors for abnormal white matter changes for the corresponding cognitive declines. Cardiovascular-brain studies typical focus on structural imaging changes that are difficult to reverse. We hypothesize that white matter lifespan changes can be more sensitively tracked by combining standard structural imaging techniques with state-of-the-art connectome era multimodal imaging. The goal is to uncover novel vascular - white matter mechanisms and biomarkers that provide early warnings before the irreversible structural changes occur. The proposal builds upon the productivity of the Amish Connectome Project as baseline data, and leverages the collaboration between our brain imaging and cardiovascular medicine groups. The Old Order Amish/Mennonite population has a more uniform genetic profile, rural lifestyle and low alcohol and tobacco use that greatly reduce uncontrollable variability, thus providing a particularly advantageous platform to study the vascular mechanisms on white matter. Cerebral white matter will also be studied in the context of predicting white matter vulnerability to Alzheimer's disease. Tracking when the aberrant vascular ? white matter coupling occurs may provide insights into the timing and mode for more effective prevention. This proposal is responsive to the new NIH Inclusion Across the Lifespan policy. If successful, the proposed study should strongly support the prevention goal highlighted in the National Alzheimer's Project Act, which supports increased public research to prevent the onset of and develop effective treatments for AD by 2025. Prevention programs can be benefited by more nuanced understanding of the pathways connecting early vascular changes to irreversible white matter changes. Therefore, we propose to use cutting-edge white matter imaging that is informative of the underlying mechanisms, combined with standard but state-of-the-art vascular assessments, to study the interaction between vascular and white matter changes across lifespan.