CRHD Human Connectome Project for Early Psychosis

Study Overview

The main goal of the Human Connectome Project for Early Psychosis is to acquire high quality imaging, behavioral, clinical, cognitive, and genetic data on an important cohort of early psychosis patients, in a manner consistent with the original Human Connectome Project, where data from this project will be made available to the research community for future studies. 

We focus on early psychosis (both affective and non-affective psychosis), within the first 3 years of the onset of psychotic symptoms. This is a critical time period when there are fewer confounds such as prolonged medication exposure and chronicity, and when early intervention strategies will be most effective, prior to the progression that often leads to debilitating and chronic illnesses, to great suffering, and to an enormous public health problem and economic burden. The data acquired will make it possible to identify disruptions in neural connections in early psychosis that likely underlie both brain function and dysfunction, and these data can be linked to behavioral, cognitive, and other measures, consistent with the goals of this funding initiative. Such an approach will lead not only to a better understanding of neural network disruptions in psychotic illnesses but will also lead to more targeted treatment interventions early in the course of illness to prevent the cascade of progression to chronicity where changes in the brain are likely not reversible.

Project Timespan: August  5, 2016 – July 31, 2020

Investigators

Martha Shenton

Martha Shenton, Ph.D. - BWH Principal Investigator

Contact PI

Contact: Email

Alan Breier

Alan Breier, M.D. - Indiana Principal Investigator

Multiple PI

Contact: Email

Larry Seidman

Larry Seidman, Ph.D. - MGH

Beth Israel Deaconess Medical Center (Site / Co-PI)

Dost Öngür

Dost Öngür, M.D., Ph.D. - Harvard

McLean Hospital (Site PI)

Daphne Holt

Daphne Holt, M.D., Ph.D. - MGH

Massachusets General Hospital (Site PI)

Matcheri Keshavan

Matcheri Keshavan, M.D. - BID - MMHC

Beth Israel Deaconess- Massachusetts Mental Health Center (Site PI)

Study Protocol Overview

Data being collected

Imaging is conducted at multiple sites in two cities. In Boston: Brigham and Women’s Hospital, Beth Israel Deaconess-Massachusetts Mental Health Center, McLean Hospital, and Massachusetts General Hospital. In Annapolis, IN: Indiana University School of Medicine. All sites are using a 3T Siemens Prisma MR scanner.

  • Standard HCP Demographics
  • Imaging: 
    • sMRI: T1w (MPRAGE) and T2w (SPACE) - 0.8mm isotropic resolution.
    • fMRI: 4 resting state fMRI scans - 420 measurements, 2mm isotropic resolution, multiband (MB) factor of 8, TR 800ms, 420 measurements - 2 scans acquired with AP and 2 with PA phase encoding.
    • dMRI: 4 diffusion MRI  scans - 1.5mm isotropic, MB acceleration factor of 4, 92 directions in each shell (b=1500 and 3000) acquired twice: once with AP and once with PA phase encoding.
  • Clinical / Behavioral: NIH Toolbox measures; Delay discounting, Penn Progressive Matrices, and Penn Emotion recognition; Parental Socioeconomic Status using the Hollingshead Two-Factor Scale; Structured Clinical Interview for DSM-V-RV; Positive and Negative Syndrome Scale; Clinical Assessment Interview for Negative Symptoms; Young Mania Rating Scale; Montgomery-Asberg Depression Rating Scale; MIRECC Global Assessment of Functioning; antipsychotic medication dosage as CPZ equivalents; WASI-II; Seidman Auditory Continuous Performance Test.
  • Blood: Blood will be drawn and shipped to the Rutgers University Cell & DNA Repository (RUCDR), where it will be made available to qualified researchers for future genetic analyses adhering to the NIH Genomic Data Sharing (GDS) Policy.


Cohort Description

The study includes 320 male or female outpatients, between the ages of 16 to 30 years of age, within 3 years of onset of initial psychotic symptoms, and 80 controls. 


Data Release Plans

An early release is planned for Year 2 of the project. The other two releases will be in Years 3 and 4.


Keywords

Early Psychosis; Schizophrenia; Bipolar Disorder; Affective Psychosis; Non-Affective Psychosis; Anxiety; Mental Depression; Mood Disorders; White Matter

Publications

  • Abnormalities in High-Energy Phosphate Metabolism in First-Episode Bipolar Disorder Measured Using (31)P-Magnetic Resonance Spectroscopy.

    Fei Du, Cagri Yuksel, Virginie-Anne Chouinard, Polly Huynh, Kyle Ryan, Bruce M Cohen, Dost Öngür
    Biological psychiatry, May 22, 2017 PMID: 28527566
    Show Summary

    Brain energy metabolism is critical for supporting synaptic function and information processing. A growing body of evidence suggests abnormalities in brain bioenergetics in psychiatric disorders, including both bipolar disorder (BD) and schizophrenia. (31)P magnetic resonance spectroscopy provides a noninvasive window into these processes in vivo. Using this approach, we previously showed that patients with BD show normal adenosine triphosphate (ATP) and phosphocreatine levels at rest but cannot maintain normal ATP levels in the visual cortex during times of high energy demand (photic stimulation). Because ATP is replenished from phosphocreatine via the creatine kinase reaction, we have now measured the creatine kinase forward reaction rate constant in BD.

  • Association of Neurocognition With Transition to Psychosis: Baseline Functioning in the Second Phase of the North American Prodrome Longitudinal Study.

    Larry J Seidman, Daniel I Shapiro, William S Stone, Kristen A Woodberry, Ashley Ronzio, Barbara A Cornblatt, Jean Addington, Carrie E Bearden, Kristin S Cadenhead, Tyrone D Cannon, Daniel H Mathalon, Thomas H McGlashan, Diana O Perkins, Ming T Tsuang, Elaine F Walker, Scott W Woods
    JAMA psychiatry, Nov 03, 2016 PMID: 27806157
    Show Summary

    Neurocognition is a central characteristic of schizophrenia and other psychotic disorders. Identifying the pattern and severity of neurocognitive functioning during the "near-psychotic," clinical high-risk (CHR) state of psychosis is necessary to develop accurate risk factors for psychosis and more effective and potentially preventive treatments.

  • Characterization of white matter abnormalities in early-stage schizophrenia.

    Tom A Hummer, Michael M Francis, Jenifer L Vohs, Emily Liffick, Nicole F Mehdiyoun, Alan Breier
    Show Summary

    White matter abnormalities have been reported in schizophrenia and may indicate altered cortical network integrity and structural connectivity, which have been hypothesized as key pathophysiological components of this illness. In this study, we aimed to further characterize the nature and progression of white matter alterations during the early stages of the disorder.

  • Tractography Analysis of 5 White Matter Bundles and Their Clinical and Cognitive Correlates in Early-Course Schizophrenia.

    Johanna Seitz, Jessica X Zuo, Amanda E Lyall, Nikos Makris, Zora Kikinis, Sylvain Bouix, Ofer Pasternak, Eli Fredman, Jonathan Duskin, Jill M Goldstein, Tracey L Petryshen, Raquelle I Mesholam-Gately, Joanne Wojcik, Robert W McCarley, Larry J Seidman, Martha E Shenton, Inga K Koerte, Marek Kubicki
    Schizophrenia bulletin, Mar 25, 2016 PMID: 27009248
    Show Summary

    Tractography is the most anatomically accurate method for delineating white matter tracts in the brain, yet few studies have examined multiple tracts using tractography in patients with schizophrenia (SCZ). We analyze 5 white matter connections important in the pathophysiology of SCZ: uncinate fasciculus, cingulum bundle (CB), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus, and arcuate fasciculus (AF). Additionally, we investigate the relationship between diffusion tensor imaging (DTI) markers and neuropsychological measures.

  • Progress and Future Directions in Research on the Psychosis Prodrome: A Review for Clinicians.

    Kristen A Woodberry, Daniel I Shapiro, Caitlin Bryant, Larry J Seidman
  • Progression from selective to general involvement of hippocampal subfields in schizophrenia.

    N F Ho, J E Iglesias, M Y Sum, C N Kuswanto, Y Y Sitoh, J De Souza, Z Hong, B Fischl, J L Roffman, J Zhou, K Sim, D J Holt
    Molecular psychiatry, Feb 24, 2016 PMID: 26903271
    Show Summary

    Volume deficits of the hippocampus in schizophrenia have been consistently reported. However, the hippocampus is anatomically heterogeneous; it remains unclear whether certain portions of the hippocampus are affected more than others in schizophrenia. In this study, we aimed to determine whether volume deficits in schizophrenia are confined to specific subfields of the hippocampus and to measure the subfield volume trajectories over the course of the illness. Magnetic resonance imaging scans were obtained from Data set 1: 155 patients with schizophrenia (mean duration of illness of 7 years) and 79 healthy controls, and Data set 2: an independent cohort of 46 schizophrenia patients (mean duration of illness of 18 years) and 46 healthy controls. In addition, follow-up scans were collected for a subset of Data set 1. A novel, automated method based on an atlas constructed from ultra-high resolution, post-mortem hippocampal tissue was used to label seven hippocampal subfields. Significant cross-sectional volume deficits in the CA1, but not of the other subfields, were found in the schizophrenia patients of Data set 1. However, diffuse cross-sectional volume deficits across all subfields were found in the more chronic and ill schizophrenia patients of Data set 2. Consistent with this pattern, the longitudinal analysis of Data set 1 revealed progressive illness-related volume loss (~2-6% per year) that extended beyond CA1 to all of the other subfields. This decline in volume correlated with symptomatic worsening. Overall, these findings provide converging evidence for early atrophy of CA1 in schizophrenia, with extension to other hippocampal subfields and accompanying clinical sequelae over time.

  • McLean OnTrack: a transdiagnostic program for early intervention in first-episode psychosis.

    Ann K Shinn, Kirsten W Bolton, Rakesh Karmacharya, Kathryn E Lewandowski, Cagri Yuksel, Justin T Baker, Virginie-Anne Chouinard, Samira M Pingali, Hilary Bye, Katherine Cederbaum, Dost Öngür
    Show Summary

    Most programs specializing in the treatment of first-episode psychosis in the United States focus on schizophrenia. However, many early psychosis patients do not fit into this diagnostic category. Here we describe McLean OnTrack, an intensive outpatient treatment program that accepts all comers with first-episode psychosis.

  • Functional neuroanatomical correlates of episodic memory impairment in early phase psychosis.

    Michael Matthew Francis, Tom A Hummer, Jenifer L Vohs, Matthew G Yung, Emily Liffick, Nicole F Mehdiyoun, Alexander J Radnovich, Brenna C McDonald, Andrew J Saykin, Alan Breier
    Brain imaging and behavior, Mar 10, 2015 PMID: 25749917
    Show Summary

    Studies have demonstrated that episodic memory (EM) is often preferentially disrupted in schizophrenia. The neural substrates that mediate EM impairment in this illness are not fully understood. Several functional magnetic resonance imaging (fMRI) studies have employed EM probe tasks to elucidate the neural underpinnings of impairment, though results have been inconsistent. The majority of EM imaging studies have been conducted in chronic forms of schizophrenia with relatively few studies in early phase patients. Early phase schizophrenia studies are important because they may provide information regarding when EM deficits occur and address potential confounds more frequently observed in chronic populations. In this study, we assessed brain activation during the performance of visual scene encoding and recognition fMRI tasks in patients with earlyphase psychosis (n = 35) and age, sex, and race matched healthy control subjects (n = 20). Patients demonstrated significantly lower activation than controls in the right hippocampus and left fusiform gyrus during scene encoding and lower activation in the posterior cingulate, precuneus, and left middle temporal cortex during recognition of target scenes. Symptom levels were not related to the imaging findings, though better cognitive performance in patients was associated with greater right hippocampal activation during encoding. These results provide evidence of altered function in neuroanatomical circuitry subserving EM early in the course of psychotic illness, which may have implications for pathophysiological models of this illness.

  • Excessive extracellular volume reveals a neurodegenerative pattern in schizophrenia onset.

    Ofer Pasternak, Carl-Fredrik Westin, Sylvain Bouix, Larry J Seidman, Jill M Goldstein, Tsung-Ung W Woo, Tracey L Petryshen, Raquelle I Mesholam-Gately, Robert W McCarley, Ron Kikinis, Martha E Shenton, Marek Kubicki
    Show Summary

    Diffusion MRI has been successful in identifying the existence of white matter abnormalities in schizophrenia in vivo. However, the role of these abnormalities in the etiology of schizophrenia is not well understood. Accumulating evidence from imaging, histological, genetic, and immunochemical studies support the involvement of axonal degeneration and neuroinflammation--ubiquitous components of neurodegenerative disorders--as the underlying pathologies of these abnormalities. Nevertheless, the current imaging modalities cannot distinguish neuroinflammation from axonal degeneration, and therefore provide little specificity with respect to the pathophysiology progression and whether it is related to a neurodegenerative process. Free-water imaging is a new methodology that is sensitive to water molecules diffusing in the extracellular space. Excessive extracellular volume is a surrogate biomarker for neuroinflammation and can be separated out to reveal abnormalities such as axonal degeneration that affect diffusion characteristics in the tissue. We applied free-water imaging on diffusion MRI data acquired from schizophrenia-diagnosed human subjects with a first psychotic episode. We found a significant increase in the extracellular volume in both white and gray matter. In contrast, significant signs of axonal degeneration were limited to focal areas in the frontal lobe white matter. Our findings demonstrate that neuroinflammation is more prominent than axonal degeneration in the early stage of schizophrenia, revealing a pattern shared by many neurodegenerative disorders, in which prolonged inflammation leads to axonal degeneration. These findings promote anti-inflammatory treatment for early diagnosed schizophrenia patients.

  • Early and broadly defined psychosis risk mental states.

    Matcheri S Keshavan, Lynn E DeLisi, Larry J Seidman
    Schizophrenia research, Dec 03, 2010 PMID: 21123033
    Show Summary

    Current definitions of the prodromal (or at-risk mental state) phase of schizophrenia include attenuated and/or transient psychotic symptoms as well as a combination of different risk indicators and a recent significant deterioration in global functioning. Data accumulated to date suggest rates of conversion to frank psychosis within two years in 25 to 40% of cases supporting the validity of these criteria. However, at this late phase of illness, functional deterioration is often already pronounced, highlighting the need for earlier identification. Moreover, negative symptoms and social impairments, cognitive deficits, other non-psychotic psychopathology and/or functional decline and non-specific biological indicators, often can be detected well before the at-risk mental state as currently defined; indicating that a broad characterization of an earlier stage may be possible. Identifying specific criteria to define this group of individuals, starting from the framework of familial high-risk, can help define a broader group of people, including earlier at-risk mental states, for future research. The hope is that this research will help facilitate intervention at earlier stages that may in turn minimize functional deterioration, and delay, attenuate or even prevent transition to psychosis. The disadvantages as well as the potential benefits of this approach are discussed.

  • The evaluation and management of patients with first-episode schizophrenia: a selective, clinical review of diagnosis, treatment, and prognosis.

    Oliver Freudenreich, Daphne J Holt, Corinne Cather, Donald C Goff
    Show Summary

    Patients who present with a first episode of psychosis pose many challenges to psychiatry. While some morbidity from schizophrenia is probably not modifiable once acute psychosis has occurred, the best management of this stage of illness nevertheless holds the promise of improving long-term outcomes. We review the clinical literature on first-episode psychosis to derive clinical guidance with regard to timely diagnosis and optimal pharmacological and nonpharmacological treatment. We describe the illness course and the prognosis for this acute phase of illness and the immediate, postpsychotic period.

  • Early intervention in schizophrenia: Current and future perspectives

    Matcheri S. Keshavan, Ali Amirsadri

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