The Function Biomedical Informatics Research Network Data Repository.

The Function Biomedical Informatics Research Network (FBIRN) developed methods and tools for conducting multi-scanner functional magnetic resonance imaging (fMRI) studies. Method and tool development were based on two major goals: 1) to assess the major sources of variation in fMRI studies conducted across scanners, including instrumentation, acquisition protocols, challenge tasks, and analysis methods, and 2) to provide a distributed network infrastructure and an associated federated database to host and query large, multi-site, fMRI and clinical data sets. In the process of achieving these goals the FBIRN test bed generated several multi-scanner brain imaging data sets to be shared with the wider scientific community via the BIRN Data Repository (BDR). The FBIRN Phase 1 data set consists of a traveling subject study of 5 healthy subjects, each scanned on 10 different 1.5 to 4 T scanners. The FBIRN Phase 2 and Phase 3 data sets consist of subjects with schizophrenia or schizoaffective disorder along with healthy comparison subjects scanned at multiple sites. In this paper, we provide concise descriptions of FBIRN's multi-scanner brain imaging data sets and details about the BIRN Data Repository instance of the Human Imaging Database (HID) used to publicly share the data.

Relating Intrinsic Low-Frequency BOLD Cortical Oscillations to Cognition in Schizophrenia.

The amplitude of low-frequency fluctuations (ALFF) in the blood oxygenation level-dependent (BOLD) signal during resting-state fMRI reflects the magnitude of local low-frequency BOLD oscillations, rather than interregional connectivity. ALFF is of interest to studies of cognition because fluctuations in spontaneous intrinsic brain activity relate to, and possibly even constrain, task-evoked brain responses in healthy people. Lower ALFF has been reported in schizophrenia, but the cognitive correlates of these reductions remain unknown. Here, we assess relationships between ALFF and attention and working memory in order to establish the functional relevance of intrinsic BOLD oscillatory power alterations with respect to specific cognitive impairments in schizophrenia. As part of the multisite FBIRN study, resting-state fMRI data were collected from schizophrenia subjects (SZ; n=168) and healthy controls (HC; n=166). Voxelwise fractional ALFF (fALFF), a normalized ALFF measure, was regressed on neuropsychological measures of sustained attention and working memory in SZ and HC to identify regions showing either common slopes across groups or slope differences between groups (all findings p<0.01 height, p<0.05 family-wise error cluster corrected). Poorer sustained attention was associated with smaller fALFF in the left superior frontal cortex and bilateral temporoparietal junction in both groups, with additional relationships in bilateral posterior parietal, posterior cingulate, dorsal anterior cingulate (ACC), and right dorsolateral prefrontal cortex (DLPFC) evident only in SZ. Poorer working memory was associated with smaller fALFF in bilateral ACC/mPFC, DLPFC, and posterior parietal cortex in both groups. Our findings indicate that smaller amplitudes of low-frequency BOLD oscillations during rest, measured by fALFF, were significantly associated with poorer cognitive performance, sometimes similarly in both groups and sometimes only in SZ, in regions known to subserve sustained attention and working memory. Taken together, these data suggest that the magnitude of resting-state BOLD oscillations shows promise as a biomarker of cognitive function in health and disease.

Neural Correlates of Schizophrenia Negative Symptoms: Distinct Subtypes Impact Dissociable Brain Circuits.

BACKGROUND: The negative symptoms of schizophrenia include deficits in emotional expression and motivation. These deficits are stable over the course of illness and respond poorly to current medications. Previous studies have focused on negative symptoms as a single category; however, individual symptoms might be related to separate neurological disturbances. We analyzed data from the Functional Biomedical Informatics Research Network dataset to explore the relationship between individual negative symptoms and functional brain activity during an auditory oddball task. METHODS: Functional magnetic resonance imaging was conducted on 89 schizophrenia patients and 106 healthy controls during a two-tone auditory oddball task. Blood oxygenation level-dependent (BOLD) signal during the target tone was correlated with severity of five negative symptom domains from the Scale for the Assessment of Negative Symptoms. RESULTS: The severity of alogia, avolition/apathy and anhedonia/asociality was negatively correlated with BOLD activity in distinct sets of brain regions associated with processing of the target tone, including basal ganglia, thalamus, insular cortex, prefrontal cortex, posterior cingulate and parietal cortex. CONCLUSIONS: Individual symptoms were related to different patterns of functional activation during the oddball task, suggesting that individual symptoms might arise from distinct neural mechanisms. This work has potential to inform interventions that target these symptom-related neural disruptions.

From tones in tinnitus to sensed social interaction in schizophrenia: how understanding cortical organization can inform the study of hallucinations and psychosis.

The content, modality, and perceptual attributes of hallucinations and other psychotic symptoms may be related to neural representation at a single cell and population level in the cerebral cortex. A brief survey of some principles and examples of cortical representation and organization will be presented together with evidence for a correspondence between the neurobiology of brain areas activated at the time of a hallucination and the content of the corresponding hallucinatory and psychotic experiences. Contrasting the hallucinations of schizophrenia with other conditions, we highlight phenomenological aspects of hallucinations that are ignored in clinical practice but carry potentially important information about the brain regions and dysfunctions underlying them. Knowledge of cortical representation and organization are being used to develop animal models of hallucination and to test treatments that are now beginning to translate to the clinical domain.

An application of item response theory to fMRI data: prospects and pitfalls.

When using functional brain imaging to study neuropsychiatric patients an important challenge is determining whether the imaging task assesses individual differences with equal precision in healthy control and impaired patient groups. Classical test theory (CTT) requires separate reliability studies of patients and controls to determine equivalent measurement precision with additional studies to determine measurement precision for different levels of disease severity. Unlike CTT, item response theory (IRT) provides estimates of measurement error for different levels of ability, without the need for separate studies, and can determine if different tests are equivalently difficult when investigating differential deficits between groups. To determine the potential value of IRT in functional brain imaging, IRT was applied to behavioral data obtained during a multi-center functional MRI (fMRI) study of working memory (WM). Average item difficulty was approximately one standard deviation below the ability scale mean, supporting the task's sensitivity to individual differences within the ability range of patients with WM impairment, but not within the range of most controls. The correlation of IRT estimated ability with fMRI activation during the task recognition period supported the linkage of the latent IRT scale to brain activation data. IRT can meaningfully contribute to the design of fMRI tasks.

Hippocampal physiology, structure and function and the neuroscience of schizophrenia: a unified account of declarative memory deficits, working memory deficits and schizophrenic symptoms.

Memory impairment is a consistent feature of the schizophrenic syndrome. Hippocampal dysfunction has also been consistently demonstrated. This review will discuss neurophysiological and neuroanatomical aspects of memory formation and how they relate to memory impairment in schizophrenia. An understanding of the cellular physiology and connectivity of the hippocampus with other regions can also aid in understanding the relationship between schizophrenic declarative or relational memory deficits, working memory deficits and the clinical symptoms of the syndrome.

Schizophrenia as a disorder of social communication.

Evidence is reviewed for the existence of a core system for moment-to-moment social communication that is based on the perception of dynamic gestures and other social perceptual processes in the temporal-parietal occipital junction (TPJ), including the posterior superior temporal sulcus (PSTS) and surrounding regions. Overactivation of these regions may produce the schizophrenic syndrome. The TPJ plays a key role in the perception and production of dynamic social, emotional, and attentional gestures for the self and others. These include dynamic gestures of the body, face, and eyes as well as audiovisual speech and prosody. Many negative symptoms are characterized by deficits in responding within these domains. Several properties of this system have been discovered through single neuron recording, brain stimulation, neuroimaging, and the study of neurological impairment. These properties map onto the schizophrenic syndrome. The representation of dynamic gestures is multimodal (auditory, visual, and tactile), matching the predominant hallucinatory categories in schizophrenia. Inherent in the perceptual signal of gesture representation is a computation of intention, agency, and anticipation or expectancy (for the self and others). The neurons are also tuned or biased to rapidly detect threat-related emotions. I review preliminary evidence that overactivation of this system can result in schizophrenia.

Hippocampal temporal-parietal junction interaction in the production of psychotic symptoms: a framework for understanding the schizophrenic syndrome.

A framework is described for understanding the schizophrenic syndrome at the brain systems level. It is hypothesized that over-activation of dynamic gesture and social perceptual processes in the temporal-parietal occipital junction (TPJ), posterior superior temporal sulcus (PSTS) and surrounding regions produce the syndrome (including positive and negative symptoms, their prevalence, prodromal signs, and cognitive deficits). Hippocampal system hyper-activity and atrophy have been consistently found in schizophrenia. Hippocampal activity is highly correlated with activity in the TPJ and may be a source of over-excitation of the TPJ and surrounding regions. Strong evidence for this comes from in-vivo recordings in humans during psychotic episodes. Many positive symptoms of schizophrenia can be reframed as the erroneous sense of a presence or other who is observing, acting, speaking, or controlling; these qualia are similar to those evoked during abnormal activation of the TPJ. The TPJ and PSTS play a key role in the perception (and production) of dynamic social, emotional, and attentional gestures for the self and others (e.g., body/face/eye gestures, audiovisual speech and prosody, and social attentional gestures such as eye gaze). The single cell representation of dynamic gestures is multimodal (auditory, visual, tactile), matching the predominant hallucinatory categories in schizophrenia. Inherent in the single cell perceptual signal of dynamic gesture representations is a computation of intention, agency, and anticipation or expectancy (for the self and others). Stimulation of the TPJ resulting in activation of the self representation has been shown to result a feeling of a presence or multiple presences (due to heautoscopy) and also bizarre tactile experiences. Neurons in the TPJ are also tuned, or biased to detect threat related emotions. Abnormal over-activation in this system could produce the conscious hallucination of a voice (audiovisual speech), a person or a touch. Over-activation could interfere with attentional/emotional gesture perception and production (negative symptoms). It could produce the unconscious feeling of being watched, followed, or of a social situation unfolding along with accompanying abnormal perception of intent and agency (delusions). Abnormal activity in the TPJ would also be predicted to create several cognitive disturbances that are characteristic of schizophrenia, including abnormalities in attention, predictive social processing, working memory, and a bias to erroneously perceive threat.

Function biomedical informatics research network recommendations for prospective multicenter functional MRI studies.

This report provides practical recommendations for the design and execution of multicenter functional MRI (MC-fMRI) studies based on the collective experience of the Function Biomedical Informatics Research Network (FBIRN). The study was inspired by many requests from the fMRI community to FBIRN group members for advice on how to conduct MC-fMRI studies. The introduction briefly discusses the advantages and complexities of MC-fMRI studies. Prerequisites for MC-fMRI studies are addressed before delving into the practical aspects of carefully and efficiently setting up a MC-fMRI study. Practical multisite aspects include: (i) establishing and verifying scan parameters including scanner types and magnetic fields, (ii) establishing and monitoring of a scanner quality program, (iii) developing task paradigms and scan session documentation, (iv) establishing clinical and scanner training to ensure consistency over time, (v) developing means for uploading, storing, and monitoring of imaging and other data, (vi) the use of a traveling fMRI expert, and (vii) collectively analyzing imaging data and disseminating results. We conclude that when MC-fMRI studies are organized well with careful attention to unification of hardware, software and procedural aspects, the process can be a highly effective means for accessing a desired participant demographics while accelerating scientific discovery.

A novel method for quantifying scanner instability in fMRI.

A method was developed to quantify the effect of scanner instability on functional MRI data by comparing the instability noise to endogenous noise present when scanning a human. The instability noise was computed from agar phantom data collected with two flip angles, allowing for a separation of the instability from the background noise. This method was used on human data collected at four 3 T scanners, allowing the physiological noise level to be extracted from the data. In a "well-operating" scanner, the instability noise is generally less than 10% of physiological noise in white matter and only about 2% of physiological noise in cortex. This indicates that instability in a well-operating scanner adds very little noise to functional MRI results. This new method allows researchers to make informed decisions about the maximum instability level a scanner can have before it is taken off line for maintenance or rejected from a multisite consortium. This method also provides information about the background noise, which is generally larger in magnitude than the instability noise.

Multisite reliability of cognitive BOLD data.

Investigators perform multi-site functional magnetic resonance imaging studies to increase statistical power, to enhance generalizability, and to improve the likelihood of sampling relevant subgroups. Yet undesired site variation in imaging methods could off-set these potential advantages. We used variance components analysis to investigate sources of variation in the blood oxygen level-dependent (BOLD) signal across four 3-T magnets in voxelwise and region-of-interest (ROI) analyses. Eighteen participants traveled to four magnet sites to complete eight runs of a working memory task involving emotional or neutral distraction. Person variance was more than 10 times larger than site variance for five of six ROIs studied. Person-by-site interactions, however, contributed sizable unwanted variance to the total. Averaging over runs increased between-site reliability, with many voxels showing good to excellent between-site reliability when eight runs were averaged and regions of interest showing fair to good reliability. Between-site reliability depended on the specific functional contrast analyzed in addition to the number of runs averaged. Although median effect size was correlated with between-site reliability, dissociations were observed for many voxels. Brain regions where the pooled effect size was large but between-site reliability was poor were associated with reduced individual differences. Brain regions where the pooled effect size was small but between-site reliability was excellent were associated with a balance of participants who displayed consistently positive or consistently negative BOLD responses. Although between-site reliability of BOLD data can be good to excellent, acquiring highly reliable data requires robust activation paradigms, ongoing quality assurance, and careful experimental control.

Color Stroop and negative priming in schizophrenia: an fMRI study.

Disturbances in selective attention represent a core characteristic of schizophrenia, whose neural underpinnings have yet to be fully elucidated. Consequently, we recorded brain activation using functional magnetic resonance imaging (fMRI) while 15 patients with schizophrenia and 15 age-matched controls performed a well-established measure of selective attention-the color Stroop negative priming task. We focused on two aspects of performance: overriding pre-potent responses (Stroop effect) and inhibition of prior negatively primed trials (negative priming effect). Behaviorally, controls demonstrated both significant Stroop and negative priming effects, while schizophrenic subjects only showed the Stroop effect. For the Stroop effect, fMRI indicated significantly greater activation in frontal regions-medial frontal gyrus/anterior cingulate gyrus and middle frontal gyrus for controls-but greater activation in medial parietal regions (posterior cingulate gyrus/precuneus) for patients. Negative priming elicited significant activation in right dorsolateral prefrontal cortex for both groups, but also in left dorsolateral prefrontal cortex for patients. These different patterns of fMRI activation may reflect faulty interaction in schizophrenia within networks of brain regions that are vital to selective attention.

Neuroimaging of semantic processing in schizophrenia: a parametric priming approach.

The use of fMRI and other neuroimaging techniques in the study of cognitive language processes in psychiatric and non-psychiatric conditions has led at times to discrepant findings. Many issues complicate the study of language, especially in psychiatric populations. For example, the use of subtractive designs can produce misleading results. We propose and advocate for a semantic priming parametric approach to the study of semantic processing using fMRI methodology. Implications of this parametric approach are discussed in view of current functional neuroimaging research investigating the semantic processing disturbance of schizophrenia.

An fMRI study of functional abnormalities in the verbal working memory system and the relationship to clinical symptoms in chronic schizophrenia.

There has been evidence for functional abnormalities of the verbal working memory system in schizophrenia. Verbal working memory crucially involves the interplay between the anterior and posterior language systems, and previous studies have shown converging evidence for abnormalities in the posterior language system in schizophrenia. In this functional magnetic resonance imaging study, we measured cortical activity in chronic schizophrenic patients and matched healthy controls during auditory and visual verbal working memory tasks. We employed 1) regional analyses specifically targeting the posterior language system and 2) analyses of functional connectivity between anterior and posterior language regions. We performed these analyses separately for each memory stage and modality. In the regional analyses, the left sylvian-parietal-temporal (Spt) area consistently showed reduced activation during encoding and retrieval stages in schizophrenia. Magnitudes of activation in the left posterior superior temporal sulcus were correlated with the severity of delusions at every memory stage. Functional connectivity analyses revealed reduced connectivity between the left Spt and the anterior insula during the encoding of auditory words. In addition, the connectivity strength was correlated with the severity of auditory hallucinations. These findings identify abnormal components in the verbal working memory system and illustrate their possible overlap with the mechanisms of core schizophrenic symptoms.

A Cognitive Neuroscience View of Schizophrenic Symptoms: Abnormal Activation of a System for Social Perception and Communication.

We will review converging evidence that language related symptoms of the schizophrenic syndrome such as auditory verbal hallucinations arise at least in part from processing abnormalities in posterior language regions. These language regions are either adjacent to or overlapping with regions in the (posterior) temporal cortex and temporo-parietal occipital junction that are part of a system for processing social cognition, emotion, and self representation or agency. The inferior parietal and posterior superior temporal regions contain multi-modal representational systems that may also provide rapid feedback and feed-forward activation to unimodal regions such as auditory cortex. We propose that the over-activation of these regions could not only result in erroneous activation of semantic and speech (auditory word) representations, resulting in thought disorder and voice hallucinations, but could also result in many of the other symptoms of schizophrenia. These regions are also part of the so-called "default network", a network of regions that are normally active; and their activity is also correlated with activity within the hippocampal system.

Functional and anatomical connectivity abnormalities in left inferior frontal gyrus in schizophrenia.

Functional studies in schizophrenia demonstrate prominent abnormalities within the left inferior frontal gyrus (IFG) and also suggest the functional connectivity abnormalities in language network including left IFG and superior temporal gyrus during semantic processing. White matter connections between regions involved in the semantic network have also been indicated in schizophrenia. However, an association between functional and anatomical connectivity disruptions within the semantic network in schizophrenia has not been established. Functional (using levels of processing paradigm) as well as diffusion tensor imaging data from 10 controls and 10 chronic schizophrenics were acquired and analyzed. First, semantic encoding specific activation was estimated, showing decreased activation within the left IFG in schizophrenia. Second, functional time series were extracted from this area, and left IFG specific functional connectivity maps were produced for each subject. In an independent analysis, tract-based spatial statistics (TBSS) was used to compare fractional anisotropy (FA) values between groups, and to correlate these values with functional connectivity maps. Schizophrenia patients showed weaker functional connectivity within the language network that includes left IFG and left superior temporal sulcus/middle temporal gyrus. FA was reduced in several white matter regions including left inferior frontal and left internal capsule. Finally, left inferior frontal white matter FA was positively correlated with connectivity measures of the semantic network in schizophrenics, but not in controls. Our results indicate an association between anatomical and functional connectivity abnormalities within the semantic network in schizophrenia, suggesting further that the functional abnormalities observed in this disorder might be directly related to white matter disruptions.

Dysregulation of working memory and default-mode networks in schizophrenia using independent component analysis, an fBIRN and MCIC study.

Deficits in working memory (WM) are a consistent neurocognitive marker for schizophrenia. Previous studies have suggested that WM is the product of coordinated activity in distributed functionally connected brain regions. Independent component analysis (ICA) is a data-driven approach that can identify temporally coherent networks that underlie fMRI activity. We applied ICA to an fMRI dataset for 115 patients with chronic schizophrenia and 130 healthy controls by performing the Sternberg Item Recognition Paradigm. Here, we describe the first results using ICA to identify differences in the function of WM networks in schizophrenia compared to controls. ICA revealed six networks that showed significant differences between patients with schizophrenia and healthy controls. Four of these networks were negatively task-correlated and showed deactivation across the posterior cingulate, precuneus, medial prefrontal cortex, anterior cingulate, inferior parietal lobules, and parahippocampus. These networks comprise brain regions known as the default-mode network (DMN), a well-characterized set of regions shown to be active during internal modes of cognition and implicated in schizophrenia. Two networks were positively task-correlated, with one network engaging WM regions such as bilateral DLPFC and inferior parietal lobules while the other network engaged primarily the cerebellum. Our results suggest that DLPFC dysfunction in schizophrenia might be lateralized to the left and intrinsically tied to other regions such as the inferior parietal lobule and cingulate gyrus. Furthermore, we found that DMN dysfunction in schizophrenia exists across multiple subnetworks of the DMN and that these subnetworks are individually relevant to the pathophysiology of schizophrenia. In summary, this large multisite study identified multiple temporally coherent networks, which are aberrant in schizophrenia versus healthy controls and suggests that both task-correlated and task-anticorrelated networks may serve as potential biomarkers.

Tuning in to the voices: a multisite FMRI study of auditory hallucinations.

INTRODUCTION: Auditory hallucinations or voices are experienced by 75% of people diagnosed with schizophrenia. We presumed that auditory cortex of schizophrenia patients who experience hallucinations is tonically "tuned" to internal auditory channels, at the cost of processing external sounds, both speech and nonspeech. Accordingly, we predicted that patients who hallucinate would show less auditory cortical activation to external acoustic stimuli than patients who did not. METHODS: At 9 Functional Imaging Biomedical Informatics Research Network (FBIRN) sites, whole-brain images from 106 patients and 111 healthy comparison subjects were collected while subjects performed an auditory target detection task. Data were processed with the FBIRN processing stream. A region of interest analysis extracted activation values from primary (BA41) and secondary auditory cortex (BA42), auditory association cortex (BA22), and middle temporal gyrus (BA21). Patients were sorted into hallucinators (n = 66) and nonhallucinators (n = 40) based on symptom ratings done during the previous week. RESULTS: Hallucinators had less activation to probe tones in left primary auditory cortex (BA41) than nonhallucinators. This effect was not seen on the right. DISCUSSION: Although "voices" are the anticipated sensory experience, it appears that even primary auditory cortex is "turned on" and "tuned in" to process internal acoustic information at the cost of processing external sounds. Although this study was not designed to probe cortical competition for auditory resources, we were able to take advantage of the data and find significant effects, perhaps because of the power afforded by such a large sample.

Brain-performance correlates of working memory retrieval in schizophrenia: a cognitive modeling approach.

Correlations of cognitive functioning with brain activation during a sternberg item recognition paradigm (SIRP) were investigated in patients with schizophrenia and in healthy controls studied at 8 sites. To measure memory scanning times, 4 response time models were fit to SIRP data. The best fitting model assumed exhaustive serial memory scanning followed by self-terminating memory search and involved one intercept parameter to represent SIRP processes not contributing directly to memory scanning. Patients displayed significantly longer response times with increasing memory load and differed on the memory scanning, memory search, and intercept parameters of the best fitting probability model. Groups differed in the correlation between the memory scanning parameter and linear brain response to increasing memory load within left inferior and left middle frontal gyrus, bilateral caudate, and right precuneus. The pattern of findings in these regions indicated that high scanning capacity was associated with high neural capacity among healthy subjects but that scanning speed was uncoupled from brain response to increasing memory load among schizophrenia patients. Group differences in correlation of the best fitting model's scanning parameter with a quadratic trend in brain response to increasing memory load suggested inefficient or disordered patterns of neural inhibition among individuals with schizophrenia, especially in the left perirhinal and entorhinal cortices. The results show at both cognitive and neural levels that disordered memory scanning contributes to deficient SIRP performance among schizophrenia patients.

Functional neuroimaging of word priming in males with chronic schizophrenia.

Word-priming studies have suggested that the associative disturbance of schizophrenia may reflect aberrant spread of activation through the lexicon of the brain. To explore this, we examined lexical activation using a semantic word-priming paradigm coupled with functional magnetic resonance imaging (fMRI). We also wanted to determine whether brain activation to this paradigm correlated with relevant clinical symptom measures. In addition to completing clinical symptom measures, twelve chronic patients and twelve demographically matched control subjects completed a lexical-decision semantic-priming paradigm developed as an event-related BOLD fMRI task. This paradigm consisted of words that differed in connectivity. Words with many connections between shared semantic associates are considered high in connectivity and produce the largest behavioral semantic priming effects in control subjects, while words with few connections between shared semantic associates are considered low in connectivity and produce a relatively smaller amount of semantic priming. In fMRI, a respective step-wise increase in activation from high connectivity to low connectivity to unrelated word pairs was expected for normal subjects. Controls showed the expected pattern of activation to word connectivity; however, patients showed a less robust pattern of activation to word connectivity. Furthermore, this aberrant response correlated with measures of Auditory Hallucinations, Distractive Speech, Illogicality, and Incoherence. The patients did not display left frontal and temporal activation as a function of the degree of word connectivity as seen in healthy controls. This may reflect a disease-related disturbance in functional connectivity of lexical activation, which in turn may be associated with clinical symptomatology.