Objective

We introduce a method for analyzing dynamically changing functional magnetic resonance imaging (fMRI) network connectivity estimates as they vary within and between broad functional domains. The method captures evidence of intertemporal directionality in cross joint functional-domain influence and extends standard whole-brain dynamic network connectivity approaches into additional functionally meaningful dimensions by evaluating transition probabilities between clustered intradomain and interdomain connectivity patterns.  Results: In applying this method to a large (N = 314) multisite resting-state fMRI dataset balanced between schizophrenia patients and healthy controls, we find evidence of joint functional domains that are global catalyzers, broadly shaping downstream functional relationships throughout the brain. Multiple interesting differences between patients and controls in both time-varying joint functional-domain connectivity patterns and in cross joint functional-domain intertemporal information flow were identified. Conclusion and Significance: Our proposed approach, thus, unifies the concepts of brain connectivity and interdomain connectivity and provides a powerful new way to evaluate functional connectivity data in the context of both the healthy and diseased brain.

Abstract

INTRODUCTION

MRZ is a second-generation, irreversible proteasome inhibitor currently in clinical trials for GBM. MRZ has ability to cross the BBB in animal models. CNS side-effects (including hallucinations and cerebellar ataxia) are both common adverse events. Here we report on the regional fMRI-derived functional connectivity changes associated with hallucination severity (graded using CTCAE 4.03) after MRZ treatment, administered at day 1, 8, and 15 every 28 days.

METHODS

Longitudinal resting-state fMRI whole-brain volumes (TR 2500ms, TE 20ms, flip angle = 71°, slice thickness = 3mm, gap = 0 mm, FOV 19.2 cm, matrix = 64 x 64, 51 slices, 120 volumes) were acquired on six participants at baseline (day 0) and days 1 and 15 of the treatment cycle. Preprocessing included: linear detrending, band-pass filtering, EPI signal from the white matter and CSF masks1; hand-drawn tumor masks; rigid-body realignment parameters; and motion and artifact scrubbing2 as implemented in the CONN toolbox3. Linear models were used to assess the correlations of hallucination severity and longitudinal functional connectivity changes in regions from the Harvard-Oxford atlas.

RESULTS

After one day of treatment, we found hallucination severity was associated with decreased functional connectivity between the left lingual gyrus and both the left cerebellum (T(4)=-12.78, p<0.03 FDR) and left temporal cortex (T(4)=-9.56, p<0.04 FDR). After fifteen days, the association persisted but became more prominent between the bi-lateral temporal-occipital fusiform cortex and the bi-lateral cerebellum (left: T(4)=-20.20, p<0.005 FDR; right: T(4)=-17.75, p<0.008 FDR) along with decreased local efficiency in the left lateral occipital cortex (T(4)=-11.25, p<0.05 FDR). CONCLUSIONS: Our data suggest that MRZ induce changes in functional connectivity in selected brain areas, including the optic pathways and the cerebellum, confirming MRZ ability to cross the BBB in humans. Research to determine the relation between functional connectivity and response to MRZ are ongoing.

Repetitive head impacts represent a risk factor for neurological impairment in team-sport athletes. In the absence of symptoms, a physiological basis for acute injury has not been elucidated. A basic brain function that is disrupted after mild traumatic brain injury is the regulation of homeostasis, instantiated by activity across a specific set of brain regions that comprise a central autonomic network. We sought to relate head-to-ball impact exposure to changes in functional connectivity in a core set of central autonomic regions and then to determine the relation between changes in brain and changes in behavior, specifically cognitive control. Thirteen collegiate men's soccer players and eleven control athletes (golf, cross-country) underwent resting-state fMRI and behavioral testing before and after the season, and a core group of cortical, subcortical, and brainstem regions was selected to represent the central autonomic network. Head-to-ball impacts were recorded for each soccer player. Cognitive control was assessed using a Dot Probe Expectancy task. We observed that head-to-ball impact exposure was associated with diffuse increases in functional connectivity across a core CAN subnetwork. Increased functional connectivity between the left insula and left medial orbitofrontal cortex was associated with diminished proactive cognitive control after the season in those sustaining the greatest number of head-to-ball impacts. These findings encourage measures of autonomic physiology to monitor brain health in contact and collision sport athletes.

Introduction

Adverse childhood experiences (ACEs) are linked to higher rates of psychiatric disorders in adults. Previous neuroimaging studies with small samples have shown associations between ACEs and alterations in brain volume, connectivity, and blood flow. However, no study has explored these associations in a large clinical population to identify brain regions that may mediate the relationship between ACEs and psychiatric diagnoses. This study aims to evaluate how patient-reported ACEs are associated with brain function in adults, across diagnoses.

Methods

We analyzed 7,275 adults using HMPAO SPECT scans at rest and during a continuous performance task (CPT). We assessed the impact of ACEs on brain function across psychiatric diagnoses and performed mediation analyses where brain functional regions of interest acted as mediators between patient-reported ACEs and specific psychiatric diagnoses. We further evaluated the risk of being diagnosed with specific classes of mental illnesses as a function of increasing ACEs and identified which specific ACE questions were statistically related to each diagnosis in this cohort.

Results

Increased ACEs were associated with higher activity in cognitive control and default mode networks and decreased activity in the dorsal striatum and cerebellum. Higher ACEs increased the risk of anxiety-related disorders, substance abuse, and depression. Several brain regions were identified as potential mediators between ACEs and adult psychiatric diagnoses.

Discussion

This study, utilizing a large clinical cohort, provides new insights into the neurobiological mechanisms linking ACEs to adult psychiatric conditions. The findings suggest that specific brain regions mediate the effects of ACEs on the risk of developing mental health disorders, highlighting potential targets for therapeutic interventions.

Managing vast datasets collected throughout multiple clinical imaging communities has become critical with the ever increasing and diverse nature of datasets. Development of data management infrastructure is further complicated by technical and experimental advances that drive modifications to existing protocols and acquisition of new types of research data to be incorporated into existing data management systems. In this paper, an extensible data management system for clinical neuroimaging studies is introduced: The Human Clinical Imaging Database (HID) and Toolkit. The database schema is constructed to support the storage of new data types without changes to the underlying schema. The complex infrastructure allows management of experiment data, such as image protocol and behavioral task parameters, as well as subject-specific data, including demographics, clinical assessments, and behavioral task performance metrics. Of significant interest, embedded clinical data entry and management tools enhance both consistency of data reporting and automatic entry of data into the database. The Clinical Assessment Layout Manager (CALM) allows users to create on-line data entry forms for use within and across sites, through which data is pulled into the underlying database via the generic clinical assessment management engine (GAME). Importantly, the system is designed to operate in a distributed environment, serving both human users and client applications in a service-oriented manner. Querying capabilities use a built-in multi-database parallel query builder/result combiner, allowing web-accessible queries within and across multiple federated databases. The system along with its documentation is open-source and available from the Neuroimaging Informatics Tools and Resource Clearinghouse (NITRC) site.

Reproducible research is a key element of the scientific process. Re-executability of neuroimaging workflows that lead to the conclusions arrived at in the literature has not yet been sufficiently addressed and adopted by the neuroimaging community. In this paper, we document a set of procedures, which include supplemental additions to a manuscript, that unambiguously define the data, workflow, execution environment and results of a neuroimaging analysis, in order to generate a verifiable re-executable publication. Re-executability provides a starting point for examination of the generalizability and reproducibility of a given finding.

Managing dynamic information in large multi-site, multi-species, and multi-discipline consortia is a challenging task for data management applications. Often in academic research studies the goals for informatics teams are to build applications that provide extract-transform-load (ETL) functionality to archive and catalog source data that has been collected by the research teams. In consortia that cross species and methodological or scientific domains, building interfaces which supply data in a usable fashion and make intuitive sense to scientists from dramatically different backgrounds increases the complexity for developers. Further, reusing source data from outside one’s scientific domain is fraught with ambiguities in understanding the data types, analysis methodologies, and how to combine the data with those from other research teams. We report on the design, implementation, and performance of a semantic data management application to support the NIMH funded Conte Center at the University of California, Irvine. The Center is testing a theory of the consequences of “fragmented” (unpredictable, high entropy) early-life experiences on adolescent cognitive and emotional outcomes in both humans and rodents. It employs cross-species neuroimaging, epigenomic, molecular, and neuroanatomical approaches in humans and rodents to assess the potential consequences of fragmented unpredictable experience on brain structure and circuitry. To address this multi-technology, multi-species approach, the system uses semantic web techniques based on the Neuroimaging Data Model (NIDM) to facilitate data ETL functionality. We find this approach enables a low-cost, easy to maintain, and semantically meaningful information management system, enabling the diverse research teams to access and use the data.