Michele T. Diaz

Working memory and DLPFC inefficiency in schizophrenia: The FBIRN study

BACKGROUND The Functional Imaging Biomedical Informatics Network is a consortium developing methods for multisite functional imaging studies. Both prefrontal hyper- or hypoactivity in chronic schizophrenia have been found in previous studies of working memory. METHODS In this functional magnetic resonance imaging (fMRI) study of working memory, 128 subjects with chronic schizophrenia and 128 age- and gender-matched controls were recruited from 10 universities around the United States. Subjects performed the Sternberg Item Recognition Paradigm1,2 with memory loads of 1, 3, or 5 items. A region of interest analysis examined the mean BOLD signal change in an atlas-based demarcation of the dorsolateral prefrontal cortex (DLPFC), in both groups, during both the encoding and retrieval phases of the experiment over the various memory loads. RESULTS Subjects with schizophrenia performed slightly but significantly worse than the healthy volunteers and showed a greater decrease in accuracy and increase in reaction time with increasing memory load. The mean BOLD signal in the DLPFC was significantly greater in the schizophrenic group than the healthy group, particularly in the intermediate load condition. A secondary analysis matched subjects for mean accuracy and found the same BOLD signal hyperresponse in schizophrenics. CONCLUSIONS The increase in BOLD signal change from minimal to moderate memory loads was greater in the schizophrenic subjects than in controls. This effect remained when age, gender, run, hemisphere, and performance were considered, consistent with inefficient DLPFC function during working memory. These findings from a large multisite sample support the concept not of hyper- or hypofrontality in schizophrenia, but rather DLPFC inefficiency that may be manifested in either direction depending on task demands. This redirects the focus of research from direction of difference to neural mechanisms of inefficiency.

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. J. Magn. Reson. Imaging 2012;36:39–54.

Voxel-based Morphometric Multisite Collaborative Study on Schizophrenia

Regional gray matter (GM) abnormalities are well known to exist in patients with chronic schizophrenia. Voxel-based morphometry (VBM) has been previously used on structural magnetic resonance images (MRI) data to characterize these abnormalities. Two multisite schizophrenia studies, the Functional Biomedical Informatics Research Network and the Mind Clinical Imaging Consortium, which include 9 data collection sites, are evaluating the efficacy of pooling structural imaging data across imaging centers. Such a pooling of data could yield the increased statistical power needed to elucidate effects that may not be seen with smaller samples. VBM analyses were performed to evaluate the consistency of patient versus control gray matter concentration (GMC) differences across the study sites, as well as the effects of combining multisite data. Integration of data from both studies yielded a large sample of 503 subjects, including 266 controls and 237 patients diagnosed with schizophrenia, schizoaffective or schizophreniform disorder. The data were analyzed using the combined sample, as well as analyzing each of the 2 multisite studies separately. A consistent pattern of reduced relative GMC in schizophrenia patients compared with controls was found across all study sites. Imaging center-specific effects were evaluated using a region of interest analysis. Overall, the findings support the use of VBM in combined multisite studies. This analysis of schizophrenics and controls from around the United States provides continued supporting evidence for GM deficits in the temporal lobes, anterior cingulate, and frontal regions in patients with schizophrenia spectrum disorders.

Schizophrenia miR-137 Locus Risk Genotype Is Associated with Dorsolateral Prefrontal Cortex Hyperactivation

BACKGROUND miR-137 dysregulation has been implicated in the etiology of schizophrenia, but its functional role remains to be determined. METHODS Functional magnetic resonance imaging scans were acquired on 48 schizophrenia patients and 63 healthy volunteers (total sample size N = 111 subjects), with similar mean age and sex distribution, while subjects performed a Sternberg Item Response Paradigm with memory loads of one, three, and five numbers. Dorsolateral prefrontal cortex (DLPFC) retrieval activation for the working memory load of three numbers, for which hyperactivation had been shown in schizophrenia patients compared with control subjects, was extracted. The genome-wide association study confirmed schizophrenia risk single nucleotide polymorphism rs1625579 (miR-137 locus) was genotyped (schizophrenia: GG n = 0, GT n = 9, TT n = 39; healthy volunteers: GG = 2, GT n = 15, and TT n = 46). Fishers exact test examined the effect of diagnosis on rs1625579 allele frequency distribution (p = nonsignificant). Mixed model regression analyses examined the effects of diagnosis and genotype on working memory performance measures and DLPFC activation. RESULTS Patients showed significantly higher left DLPFC retrieval activation on working memory load 3, lower working memory performance, and longer response times compared with controls. There was no effect of genotype on working memory performance or response times in either group. However, individuals with the rs1625579 TT genotype had significantly higher left DLPFC activation than those with the GG/GT genotypes. CONCLUSIONS Our study suggests that the rs1625579 TT (miR-137 locus) schizophrenia risk genotype is associated with the schizophrenia risk phenotype DLPFC hyperactivation commonly considered a measure of brain inefficiency.

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.

The influence of sentence novelty and figurativeness on brain activity

The predominance of the left hemisphere in language comprehension and production is well established. More recently, the right hemispheres contribution to language has been examined. Clinical, behavioral, and neuroimaging research support the right hemispheres involvement in metaphor processing. But, there is disagreement about whether metaphors, in and of themselves, engage the right hemisphere or if other factors that vary between metaphors and literal language elicit right hemisphere engagement. It is important to disambiguate these issues to improve our basic knowledge of figurative language processing, to more precisely define how the right hemisphere supports language, and to facilitate our ability to understand and treat language impairments. Here we investigated the role of the right hemisphere in language comprehension with functional magnetic resonance imaging (fMRI) by manipulating familiarity in both literal and metaphoric sentences. In an event-related design, participants viewed English sentences that appeared every 4.5-9s, and to which they made a pleasantness judgment. All sentences elicited activation in traditional language brain regions including left inferior frontal gyrus, left anterior inferior temporal and left posterior middle temporal gyri. Overall, metaphors and novel stimuli elicited activation in bilateral inferior frontal gyri and left temporal regions. Additionally, metaphors elicited greater activation than literal sentences in right temporal pole. Although our results are partially consistent with the graded salience hypothesis and the coarse coding hypothesis, the right hemispheres sensitivity to familiar metaphors suggests that right hemisphere recruitment is most influenced by semantic integration demands.

fMRI Activity Correlated With Auditory Hallucinations During Performance of a Working Memory Task: Data From the FBIRN Consortium Study

INTRODUCTION Auditory hallucinations are a hallmark symptom of schizophrenia. The neural basis of auditory hallucinations was examined using data from a working memory task. Data were acquired within a multisite consortium and this unique dataset provided the opportunity to analyze data from a large number of subjects who had been tested on the same procedures across sites. We hypothesized that regions involved in verbal working memory and language processing would show activity that was associated with levels of hallucinations during a condition where subjects were rehearsing the stimuli. METHODS Data from the Sternberg Item Recognition Paradigm, a working memory task, were acquired during functional magnetic resonance imaging procedures. The data were collected and preprocessed by the functional imaging biomedical informatics research network consortium. Schizophrenic subjects were split into nonhallucinating and hallucinating subgroups and activity during the probe condition (in which subjects rehearsed stimuli) was examined. Levels of activation from contrast images for the probe phase (collapsed over levels of memory load) of the working memory task were also correlated with levels of auditory hallucinations from the Scale for the Assessment of Positive Symptoms scores. RESULTS Patients with auditory hallucinations (relative to nonhallucinating subjects) showed decreased activity during the probe condition in verbal working memory/language processing regions, including the superior temporal and inferior parietal regions. These regions also showed associations between activity and levels of hallucinations in a correlation analysis. DISCUSSION The association between activation and hallucinations scores in the left hemisphere language/working memory regions replicates the findings of previous studies and provides converging evidence for the association between superior temporal abnormalities and auditory hallucinations.

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. Magn Reson Med, 2010.

The influence of context on hemispheric recruitment during metaphor processing

Although the left hemispheres prominence in language is well established, less emphasis has been placed on possible roles for the right hemisphere. Behavioral, patient, and neuroimaging research suggests that the right hemisphere may be involved in processing figurative language. Additionally, research has demonstrated that context can modify language processes and facilitate comprehension. Here we investigated how figurativeness and context influenced brain activation, with a specific interest in right hemisphere function. Previous work in our laboratory indicated that novel stimuli engaged right inferior frontal gyrus (IFG) and that both novel and familiar metaphors engaged right IFG and right temporal pole. The graded salience hypothesis proposes that context may lessen integration demands, increase the salience of metaphors, and thereby reduce right hemisphere recruitment for metaphors. In the present study, fMRI was used to investigate brain function, whereas participants read literal and metaphoric sentences that were preceded by either a congruent or an incongruent literal sentence. Consistent with prior research, all sentences engaged traditional left hemisphere regions. Differences between metaphors and literal sentences were observed, but only in the left hemisphere. In contrast, a main effect of congruence was found in the right IFG, the right temporal pole, and the dorsal medial pFC. Partially consistent with the graded salience hypothesis, our results highlight the strong influence of context on language, demonstrate the importance of the right hemisphere in discourse, and suggest that, in a wider discourse context, congruence has a greater influence on right hemisphere recruitment than figurativeness.

The influence of emotional distraction on verbal working memory: An fMRI investigation comparing individuals with schizophrenia and healthy adults

The ability to maintain information over short periods of time (i.e., working memory) is critically important in a variety of cognitive functions including language, planning, and decision-making. Recent functional Magnetic Resonance Imaging (fMRI) research with healthy adults has shown that brain activations evoked during the delay interval of working memory tasks can be reduced by the presentation of distracting emotional events, suggesting that emotional events may take working-memory processes momentarily offline. Both executive function and emotional processing are disrupted in schizophrenia, and here we sought to elucidate the effect of emotional distraction upon brain activity in schizophrenic and healthy adults performing a verbal working memory task. During the delay period between the memoranda and memory probe items, emotional and neutral distractors differentially influenced brain activity in these groups. In healthy adults, the hemodynamic response from posterior cingulate, orbital frontal cortex, and the parietal lobe strongly differentiated emotional from neutral distractors. In striking contrast, schizophrenic adults showed no significant differences in brain activation when processing emotional and neutral distractors. Moreover, the influence of emotional distractors extended into the memory probe period in healthy, but not schizophrenic, adults. The results suggest that although emotional items are highly salient for healthy adults, emotional items are no more distracting than neutral ones to individuals with schizophrenia.