Altered working memory-related brain activity in children at familial high risk for psychosis: A preliminary study.

BACKGROUND: Schizophrenia spectrum disorders are heritable illnesses that usually manifest in early adulthood but are increasingly viewed as neurodevelopmental disorders. Functional magnetic resonance imaging (fMRI) studies show altered brain activity during performance of working memory (WM) tasks in both individuals with schizophrenia and their first-degree relatives as compared to healthy controls (HC). This study examined whether similar changes are already present in pre-adolescent children at familial high-risk (FHR) for psychosis. METHODS: 37 children (17 FHR, 20 HC) between 7 and 12 years old participated in this study. WM performance was assessed using the Wechsler Intelligence Scale for Children-IV (WISC-IV). To assess brain activation during WM performance, participants completed a visual block-designed n-back task with 2 conditions (2-back and 0-back) during scanning. fMRI data was preprocessed and analyzed using FSL Feat. RESULTS: Compared to HC, FHR children showed significantly lower WISC-IV WM scores. In addition, FHR children exhibited hypoactivation in the 2-back (versus 0-back) condition in a cluster encompassing bilateral precuneus and cuneus and right posterior cingulate cortex. There were no significant group-differences in n-back task performance and brain activation. The precuneus cluster was not correlated with n-back performance or WISC WM scores. CONCLUSIONS: The current results provide preliminary evidence of impaired WM function and altered brain activity during WM performance in children with a familial predisposition for psychosis. Longitudinal studies are needed to determine whether these findings are related to abnormal brain development and predictive of cognitive deficits and psychosis later in life.

Functional connectivity associated with improvement in emotion management after cognitive enhancement therapy in early-course schizophrenia.

BACKGROUND: The ability to manage emotions is an important social-cognitive domain impaired in schizophrenia and linked to functional outcome. The goal of our study was to examine the impact of cognitive enhancement therapy (CET) on the ability to manage emotions and brain functional connectivity in early-course schizophrenia. METHODS: Participants were randomly assigned to CET (n = 55) or an enriched supportive therapy (EST) control group (n = 45). The resting-state functional magnetic resonance imaging scans and measures of emotion management performances were collected at baseline, 9, and 18 months follow-up. The final sample consisted of 37 CET and 25 EST participants, including 19 CET and 12 EST participants with imaging data. Linear mixed-effects models investigated the impact of treatment on emotion management and functional connectivity from the amygdala to ventrolateral and dorsolateral prefrontal cortex (dlPFC). RESULTS: The CET group showed significant improvement over time in emotion management compared to EST. Neither functional connectivity changes nor main group differences were observed following treatment. However, a significant between-group interaction showed that improved emotion management ability was associated with increased functional connectivity between the left amygdala and the left dlPFC in the CET group exclusively. CONCLUSION: Our results replicate the previous work demonstrating that CET is effective at improving some aspects of social cognition in schizophrenia. We found evidence that improvement in emotion management may be associated with a change in amygdala-dlPFC connectivity. This fronto-limbic circuit may provide a mechanistic link between the biology of emotion management processes that can be enhanced in individuals with schizophrenia.

Hyperactivation of Posterior Default Mode Network During Self-Referential Processing in Children at Familial High-Risk for Psychosis.

Patients with schizophrenia spectrum disorders show disturbances in self-referential processing and associated neural circuits including the default mode network (DMN). These disturbances may precede the onset of psychosis and may underlie early social and emotional problems. In this study, we examined self-referential processing in a group of children (7-12 years) at familial high risk (FHR) for psychosis (N = 17), compared to an age and sex-matched group of healthy control (HC) children (N = 20). The participants were presented with a list of adjectives and asked to indicate whether or not the adjectives described them (self-reference condition) and whether the adjectives described a good or bad trait (semantic condition). Three participants were excluded due to chance-level performance on the semantic task, leaving N = 15 FHR and N = 19 HC for final analysis. Functional MRI (fMRI) was used to measure brain activation during self-referential vs. semantic processing. Internalizing and externalizing problems were assessed with the Child Behavior Checklist (CBCL). Evaluating main effects of task (self > semantic) showed activation of medial prefrontal cortex in HC and precuneus/posterior cingulate cortex (PCC) in FHR. Group-comparison yielded significant results for the FHR > HC contrast, showing two clusters of hyperactivation in precuneus/ PCC (p = 0.004) and anterior cerebellum / temporo-occipital cortex (p = 0.009). Greater precuneus/PCC activation was found to correlate with greater CBCL internalizing (r = 0.60, p = 0.032) and total (r = 0.69, p = 0.009) problems. In all, this study shows hyperactivity of posterior DMN during self-referential processing in pre-adolescent FHR children. This finding posits DMN-related disturbances in self-processing as a developmental brain abnormality associated with familial risk factors that predates not just psychosis, but also the prodromal stage. Moreover, our results suggest that early disturbances in self-referential processing may be related to internalizing problems in at-risk children.

Cross-paradigm connectivity: reliability, stability, and utility.

While functional neuroimaging studies typically focus on a particular paradigm to investigate network connectivity, the human brain appears to possess an intrinsic "trait" architecture that is independent of any given paradigm. We have previously proposed the use of "cross-paradigm connectivity (CPC)" to quantify shared connectivity patterns across multiple paradigms and have demonstrated the utility of such measures in clinical studies. Here, using generalizability theory and connectome fingerprinting, we examined the reliability, stability, and individual identifiability of CPC in a group of highly-sampled healthy traveling subjects who received fMRI scans with a battery of five paradigms across multiple sites and days. Compared with single-paradigm connectivity matrices, the CPC matrices showed higher reliability in connectivity diversity, lower reliability in connectivity strength, higher stability, and higher individual identification accuracy. All of these assessments increased as a function of number of paradigms included in the CPC analysis. In comparisons involving different paradigm combinations and different brain atlases, we observed significantly higher reliability, stability, and identifiability for CPC matrices constructed from task-only data (versus those from both task and rest data), and higher identifiability but lower stability for CPC matrices constructed from the Power atlas (versus those from the AAL atlas). Moreover, we showed that multi-paradigm CPC matrices likely reflect the brain's "trait" structure that cannot be fully achieved from single-paradigm data, even with multiple runs. The present results provide evidence for the feasibility and utility of CPC in the study of functional "trait" networks and offer some methodological implications for future CPC studies.

Altered resting-state functional connectivity in young children at familial high risk for psychotic illness: A preliminary study.

Multiple lines of evidence suggest that illness development in schizophrenia and other psychotic disorders predates the first psychotic episode by many years. In this study, we examined a sample of 15 pre-adolescent children, ages 7 through 12 years, who are at familial high-risk (FHR) because they have a parent or sibling with a history of schizophrenia or related psychotic disorder. Using multi-voxel pattern analysis (MVPA), a data-driven fMRI analysis, we assessed whole-brain differences in functional connectivity in the FHR sample as compared to an age- and sex-matched control (CON) group of 15 children without a family history of psychosis. MVPA analysis yielded a single cluster in right posterior superior temporal gyrus (pSTG/BA 22) showing significant group-differences in functional connectivity. Post-hoc characterization of this cluster through seed-to-voxel analysis revealed mostly reduced functional connectivity of the pSTG seed to a set of language and default mode network (DMN) associated brain regions including Heschl's gyrus, inferior temporal gyrus extending into fusiform gyrus, (para)hippocampus, thalamus, and a cerebellar cluster encompassing mainly Crus I/II. A height-threshold of whole-brain p < .001 (two-sided), and FDR-corrected cluster-threshold of p < .05 (non-parametric statistics) was used for post-hoc characterization. These findings suggest that abnormalities in functional communication in a network encompassing right STG and associated brain regions are present before adolescence in at-risk children and may be a risk marker for psychosis. Subsequent changes in this functional network across development may contribute to either disease manifestation or resilience in children with a familial vulnerability for psychosis.

Progressive reconfiguration of resting-state brain networks as psychosis develops: Preliminary results from the North American Prodrome Longitudinal Study (NAPLS) consortium.

Mounting evidence has shown disrupted brain network architecture across the psychosis spectrum. However, whether these changes relate to the development of psychosis is unclear. Here, we used graph theoretical analysis to investigate longitudinal changes in resting-state brain networks in samples of 72 subjects at clinical high risk (including 8 cases who converted to full psychosis) and 48 healthy controls drawn from the North American Prodrome Longitudinal Study (NAPLS) consortium. We observed progressive reduction in global efficiency (P = 0.006) and increase in network diversity (P = 0.001) in converters compared with non-converters and controls. More refined analysis separating nodes into nine key brain networks demonstrated that these alterations were primarily driven by progressively diminished local efficiency in the default-mode network (P = 0.004) and progressively enhanced node diversity across all networks (P < 0.05). The change rates of network efficiency and network diversity were significantly correlated (P = 0.003), suggesting these changes may reflect shared neural mechanisms. In addition, change rates of global efficiency and node diversity were significantly correlated with change rate of cortical thinning in the prefrontal cortex in converters (P < 0.03) and could be predicted by visuospatial memory scores at baseline (P < 0.04). These results provide preliminary evidence for longitudinal reconfiguration of resting-state brain networks during psychosis development and suggest that decreased network efficiency, reflecting an increase in path length between nodes, and increased network diversity, reflecting a decrease in the consistency of functional network organization, may be implicated in the progression to full psychosis.

Social cognition in early course of schizophrenia: Exploratory factor analysis.

Social cognition is a central contributor to social functioning in schizophrenia. A better understanding of the underlying structure of social cognition in the early course schizophrenia could help us identify more precise targets for intervention in this population. In the present study, we performed an Exploratory Factor Analysis (EFA) on 90 patients within the early course of schizophrenia using 11 validated subtests assessing various domains of social cognitive skills. The factors derived from this analysis were then used to investigate relationships between these distinct domains of social cognition skills and neurocognitive performance, clinical symptoms, and social functioning satisfaction. The results revealed the presence of a 3-factor solution, representing the domains of Emotion Management, Emotion Recognition, and Theory of Mind, together accounting for 55.88% of the variance. Moreover, higher scores on the Theory of Mind factor were significantly related to higher social functioning satisfaction measures as well as with lower clinical symptoms severity. Our findings suggest that social cognitive skills are composed of three separate domains in the early course of schizophrenia and that theory of mind could be an important therapeutic target for early intervention.

Altered Brain Activation During Memory Retrieval Precedes and Predicts Conversion to Psychosis in Individuals at Clinical High Risk.

Memory deficits are a hallmark of psychotic disorders such as schizophrenia. However, whether the neural dysfunction underlying these deficits is present before the onset of illness and potentially predicts conversion to psychosis is unclear. In this study, we investigated brain functional alterations during memory processing in a sample of 155 individuals at clinical high risk (including 18 subjects who later converted to full psychosis) and 108 healthy controls drawn from the second phase of the North American Prodrome Longitudinal Study (NAPLS-2). All participants underwent functional magnetic resonance imaging with a paired-associate memory paradigm at the point of recruitment and were clinically followed up for approximately 2 years. We found that at baseline, subjects at high risk showed significantly higher activation during memory retrieval in the prefrontal, parietal, and bilateral temporal cortices (PFWE < .035). This effect was more pronounced in converters than nonconverters and was particularly manifested in unmedicated subjects (P < .001). The hyperactivation was significantly correlated with retrieval reaction time during scan in converters (P = .009) but not in nonconverters and controls, suggesting an exaggerated retrieval effort. These findings suggest that hyperactivation during memory retrieval may mark processes associated with conversion to psychosis, and such measures have potential as biomarkers for psychosis prediction.

Toward Leveraging Human Connectomic Data in Large Consortia: Generalizability of fMRI-Based Brain Graphs Across Sites, Sessions, and Paradigms.

While graph theoretical modeling has dramatically advanced our understanding of complex brain systems, the feasibility of aggregating connectomic data in large imaging consortia remains unclear. Here, using a battery of cognitive, emotional and resting fMRI paradigms, we investigated the generalizability of functional connectomic measures across sites and sessions. Our results revealed overall fair to excellent reliability for a majority of measures during both rest and tasks, in particular for those quantifying connectivity strength, network segregation and network integration. Processing schemes such as node definition and global signal regression (GSR) significantly affected resulting reliability, with higher reliability detected for the Power atlas (vs. AAL atlas) and data without GSR. While network diagnostics for default-mode and sensori-motor systems were consistently reliable independently of paradigm, those for higher-order cognitive systems were reliable predominantly when challenged by task. In addition, based on our present sample and after accounting for observed reliability, satisfactory statistical power can be achieved in multisite research with sample size of approximately 250 when the effect size is moderate or larger. Our findings provide empirical evidence for the generalizability of brain functional graphs in large consortia, and encourage the aggregation of connectomic measures using multisite and multisession data.

Cerebello-thalamo-cortical hyperconnectivity as a state-independent functional neural signature for psychosis prediction and characterization.

Understanding the fundamental alterations in brain functioning that lead to psychotic disorders remains a major challenge in clinical neuroscience. In particular, it is unknown whether any state-independent biomarkers can potentially predict the onset of psychosis and distinguish patients from healthy controls, regardless of paradigm. Here, using multi-paradigm fMRI data from the North American Prodrome Longitudinal Study consortium, we show that individuals at clinical high risk for psychosis display an intrinsic "trait-like" abnormality in brain architecture characterized as increased connectivity in the cerebello-thalamo-cortical circuitry, a pattern that is significantly more pronounced among converters compared with non-converters. This alteration is significantly correlated with disorganization symptoms and predictive of time to conversion to psychosis. Moreover, using an independent clinical sample, we demonstrate that this hyperconnectivity pattern is reliably detected and specifically present in patients with schizophrenia. These findings implicate cerebello-thalamo-cortical hyperconnectivity as a robust state-independent neural signature for psychosis prediction and characterization.

Impaired regulation of emotional distractors during working memory load in schizophrenia.

Schizophrenia (SZ) patients exhibit deficits in emotion regulation that affect their daily functioning. There is evidence that the prefrontal cortex plays an important role in emotion regulation. However, it remains unclear how this brain region is involved in emotion regulation deficits in SZ, and how such deficits impact performance on cognitively demanding tasks. We examined how happy and fearful emotional distractors impact performance on working memory (WM) tasks of varying difficulty (0-back, 2-back), and brain activity using fMRI. Participants were 20 patients with SZ and 20 healthy controls (HC) matched on age, sex, race, and IQ. A significant 3-way interaction showed that SZ patients had lower performance compared to HC when exposed to fearful and happy distractors, but only during the 2-back task. Second-level fMRI between-group analysis revealed that compared to SZ patients, HC showed significantly greater increase in brain activity with WM load in the left IFG (BA 45) when exposed to fearful distractors. Less brain activity in this region was also associated with reduction in SZ patients' performance during higher WM load and the presence of fearful distractors. SZ patients had difficulty in performing a WM task when regulating emotions, and they failed to show the emotion-specific modulation of the left IFG observed in HC. These results suggest that SZ patients have difficulty with emotion regulation demands during effortful cognitive tasks. This also provides us with potential insight on how emotion regulation could be rehabilitated in SZ using cognitive training.

Multisite reliability of MR-based functional connectivity.

Recent years have witnessed an increasing number of multisite MRI functional connectivity (fcMRI) studies. While multisite studies provide an efficient way to accelerate data collection and increase sample sizes, especially for rare clinical populations, any effects of site or MRI scanner could ultimately limit power and weaken results. Little data exists on the stability of functional connectivity measurements across sites and sessions. In this study, we assess the influence of site and session on resting state functional connectivity measurements in a healthy cohort of traveling subjects (8 subjects scanned twice at each of 8 sites) scanned as part of the North American Prodrome Longitudinal Study (NAPLS). Reliability was investigated in three types of connectivity analyses: (1) seed-based connectivity with posterior cingulate cortex (PCC), right motor cortex (RMC), and left thalamus (LT) as seeds; (2) the intrinsic connectivity distribution (ICD), a voxel-wise connectivity measure; and (3) matrix connectivity, a whole-brain, atlas-based approach to assessing connectivity between nodes. Contributions to variability in connectivity due to subject, site, and day-of-scan were quantified and used to assess between-session (test-retest) reliability in accordance with Generalizability Theory. Overall, no major site, scanner manufacturer, or day-of-scan effects were found for the univariate connectivity analyses; instead, subject effects dominated relative to the other measured factors. However, summaries of voxel-wise connectivity were found to be sensitive to site and scanner manufacturer effects. For all connectivity measures, although subject variance was three times the site variance, the residual represented 60-80% of the variance, indicating that connectivity differed greatly from scan to scan independent of any of the measured factors (i.e., subject, site, and day-of-scan). Thus, for a single 5min scan, reliability across connectivity measures was poor (ICC=0.07-0.17), but increased with increasing scan duration (ICC=0.21-0.36 at 25min). The limited effects of site and scanner manufacturer support the use of multisite studies, such as NAPLS, as a viable means of collecting data on rare populations and increasing power in univariate functional connectivity studies. However, the results indicate that aggregation of fcMRI data across longer scan durations is necessary to increase the reliability of connectivity estimates at the single-subject level.

Auditory Vigilance and Working Memory in Youth at Familial Risk for Schizophrenia or Affective Psychosis in the Harvard Adolescent Family High Risk Study.

BACKGROUND: The degree of overlap between schizophrenia (SCZ) and affective psychosis (AFF) has been a recurring question since Kraepelin's subdivision of the major psychoses. Studying nonpsychotic relatives allows a comparison of disorder-associated phenotypes, without potential confounds that can obscure distinctive features of the disorder. Because attention and working memory have been proposed as potential endophenotypes for SCZ and AFF, we compared these cognitive features in individuals at familial high-risk (FHR) for the disorders. METHODS: Young, unmedicated, first-degree relatives (ages, 13-25 years) at FHR-SCZ (n=41) and FHR-AFF (n=24) and community controls (CCs, n=54) were tested using attention and working memory versions of the Auditory Continuous Performance Test. To determine if schizotypal traits or current psychopathology accounted for cognitive deficits, we evaluated psychosis proneness using three Chapman Scales, Revised Physical Anhedonia, Perceptual Aberration, and Magical Ideation, and assessed psychopathology using the Hopkins Symptom Checklist -90 Revised. RESULTS: Compared to controls, the FHR-AFF sample was significantly impaired in auditory vigilance, while the FHR-SCZ sample was significantly worse in working memory. Both FHR groups showed significantly higher levels of physical anhedonia and some psychopathological dimensions than controls. Adjusting for physical anhedonia, phobic anxiety, depression, psychoticism, and obsessive-compulsive symptoms eliminated the FHR-AFF vigilance effects but not the working memory deficits in FHR-SCZ. CONCLUSIONS: The working memory deficit in FHR-SZ was the more robust of the cognitive impairments after accounting for psychopathological confounds and is supported as an endophenotype. Examination of larger samples of people at familial risk for different psychoses remains necessary to confirm these findings and to clarify the role of vigilance in FHR-AFF. (JINS, 2016, 22, 1026-1037).

Abnormal interactions of verbal- and spatial-memory networks in young people at familial high-risk for schizophrenia.

BACKGROUND: Working memory impairment (especially in verbal and spatial domains) is the core neurocognitive impairment in schizophrenia and the familial high-risk (FHR) population. Inconsistent results have been reported in clinical and neuroimaging studies examining the verbal- and spatial-memory deficits in the FHR subjects, due to sample differences and lack of understanding on interactions of the brain regions for processing verbal- and spatial-working memory. METHODS: Functional MRI data acquired during a verbal- vs. spatial-memory task were included from 51 young adults [26 FHR and 25 controls]. Group comparisons were conducted in brain activation patterns responding to 1) verbal-memory condition (A), 2) spatial-memory condition (B), 3) verbal higher than spatial (A-B), 4) spatial higher than verbal (B-A), 5) conjunction of brain regions that were activated during both A and B (A∧B). Group difference of the laterality index (LI) in inferior frontal lobe for condition A was also assessed. RESULTS: Compared to controls, the FHR group exhibited significantly decreased brain activity in left inferior frontal during A, and significantly stronger involvement of ACC, PCC, paracentral gyrus for the contrast of A-B. The LI showed a trend of reduced left-higher-than-right pattern for verbal-memory processing in the HR group. CONCLUSIONS: Our findings suggest that in the entire functional brain network for working-memory processing, verbal information processing associated brain pathways are significantly altered in people at familial high risk for developing schizophrenia. Future studies will need to examine whether these alterations may indicate vulnerability for predicting the onset of Schizophrenia.

Hyperactivity of caudate, parahippocampal, and prefrontal regions during working memory in never-medicated persons at clinical high-risk for psychosis.

BACKGROUND: Deficits in working memory (WM) are a core feature of schizophrenia (SZ) and other psychotic disorders. We examined brain activity during WM in persons at clinical high risk (CHR) for psychosis. METHODS: Thirty-seven CHR and 34 healthy control participants underwent functional MRI (fMRI) on a 3.0T scanner while performing an N-back WM task. The sample included a sub-sample of CHR participants who had no lifetime history of treatment with psychotropic medications (n=11). Data were analyzed using SPM8 (2-back>0-back contrast). Pearson correlations between brain activity, symptoms, and WM performance were examined. RESULTS: The total CHR group and medication-naive CHR sub-sample were comparable to controls in most demographic features and in N-back WM performance, but had significantly lower IQ. Relative to controls, medication-naïve CHR showed hyperactivity in the left parahippocampus (PHP) and the left caudate during performance of the N-back WM task. Relative to medication-exposed CHR, medication naïve CHR exhibited hyperactivity in the left caudate and the right dorsolateral prefrontal cortex (DLPFC). DLPFC activity was significantly negatively correlated with WM performance. PHP, caudate and DLPFC activity correlated strongly with symptoms, but results did not withstand FDR-correction for multiple comparisons. When all CHR participants were combined (regardless of medication status), only trend-level PHP hyperactivity was observed in CHR relative to controls. CONCLUSIONS: Medication-naïve CHR exhibit hyperactivity in regions that subserve WM. These regions are implicated in studies of schizophrenia and risk for psychosis. Results emphasize the importance of medication status in the interpretation of task - induced brain activity.

Sexual dimorphic abnormalities in white matter geometry common to schizophrenia and non-psychotic high-risk subjects: Evidence for a neurodevelopmental risk marker?

The characterization of neurodevelopmental aspects of brain alterations require neuroimaging methods that reflect correlates of neurodevelopment, while being robust to other progressive pathological processes. Newly developed neuroimaging methods for measuring geometrical features of the white matter fall exactly into this category. Our recent work shows that such features, measured in the anterior corpus callosum in diffusion MRI data, correlate with psychosis symptoms in patients with adolescent onset schizophrenia and subside a reversal of normal sexual dimorphism. Here, we test the hypothesis that similar developmental deviations will also be present in nonpsychotic subjects at familial high risk (FHR) for schizophrenia, due to genetic predispositions. Demonstrating such changes would provide a strong indication of neurodevelopmental deviation extant before, and independent of pathological changes occurring after disease onset. We examined the macrostructural geometry of corpus callosum white matter in diffusion MRI data of 35 non-psychotic subjects with genetic (familial) risk for schizophrenia, and 26 control subjects, both male and female. We report a reversal of normal sexual dimorphism in callosal white matter geometry consistent with recent results in adolescent onset schizophrenia. This pattern may be indicative of an error in neurogenesis and a possible trait marker of schizophrenia.

Alterations of lateral temporal cortical gray matter and facial memory as vulnerability indicators for schizophrenia: An MRI study in youth at familial high-risk for schizophrenia.

BACKGROUND: Structural alterations of the lateral temporal cortex (LTC) in association with memory impairments have been reported in schizophrenia. This study investigated whether alterations of LTC structure were linked with impaired facial and/or verbal memory in young first-degree relatives of people with schizophrenia and, thus, may be indicators of vulnerability to the illness. METHODS: Subjects included 27 non-psychotic, first-degree relatives of schizophrenia patients, and 48 healthy controls, between the ages of 13 and 28. Participants underwent high-resolution magnetic resonance imaging (MRI) at 1.5Tesla. The LTC was parcellated into superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, and temporal pole. Total cerebral and LTC volumes were measured using semi-automated morphometry. The Wechsler Memory Scale - Third Edition and the Children's Memory Scale - Third Edition assessed facial and verbal memory. General linear models tested for associations among LTC subregion volumes, familial risk and memory. RESULTS: Compared with controls, relatives had significantly smaller bilateral middle temporal gyri. Moreover, right middle temporal gyral volume showed a significant positive association with delayed facial memory in relatives. CONCLUSION: These results support the hypothesis that smaller middle temporal gyri are related to the genetic liability to schizophrenia and may be linked with reduced facial memory in persons at genetic risk for the illness. The findings add to the growing evidence that children at risk for schizophrenia on the basis of positive family history have cortical and subcortical structural brain abnormalities well before psychotic illness occurs.

Reliability of an fMRI paradigm for emotional processing in a multisite longitudinal study.

Multisite neuroimaging studies can facilitate the investigation of brain-related changes in many contexts, including patient groups that are relatively rare in the general population. Though multisite studies have characterized the reliability of brain activation during working memory and motor functional magnetic resonance imaging tasks, emotion processing tasks, pertinent to many clinical populations, remain less explored. A traveling participants study was conducted with eight healthy volunteers scanned twice on consecutive days at each of the eight North American Longitudinal Prodrome Study sites. Tests derived from generalizability theory showed excellent reliability in the amygdala ( Eρ2 = 0.82), inferior frontal gyrus (IFG; Eρ2 = 0.83), anterior cingulate cortex (ACC; Eρ2 = 0.76), insula ( Eρ2 = 0.85), and fusiform gyrus ( Eρ2 = 0.91) for maximum activation and fair to excellent reliability in the amygdala ( Eρ2 = 0.44), IFG ( Eρ2 = 0.48), ACC ( Eρ2 = 0.55), insula ( Eρ2 = 0.42), and fusiform gyrus ( Eρ2 = 0.83) for mean activation across sites and test days. For the amygdala, habituation ( Eρ2 = 0.71) was more stable than mean activation. In a second investigation, data from 111 healthy individuals across sites were aggregated in a voxelwise, quantitative meta-analysis. When compared with a mixed effects model controlling for site, both approaches identified robust activation in regions consistent with expected results based on prior single-site research. Overall, regions central to emotion processing showed strong reliability in the traveling participants study and robust activation in the aggregation study. These results support the reliability of blood oxygen level-dependent signal in emotion processing areas across different sites and scanners and may inform future efforts to increase efficiency and enhance knowledge of rare conditions in the population through multisite neuroimaging paradigms.

Medial temporal lobe default mode functioning and hippocampal structure as vulnerability indicators for schizophrenia: a MRI study of non-psychotic adolescent first-degree relatives.

BACKGROUND: Clues to the etiology and pathophysiology of schizophrenia can be examined in their first-degree relatives because they are genetically related to an ill family member, and have few confounds like medications. Brain abnormalities observed in young relatives are neurobiological indicators of vulnerability to illness. We examined the hypothesis that the hippocampus and parahippocampus are structurally abnormal and are related to default mode network (DMN) function and cognitive abnormalities in relatives of probands. METHODS: Subjects were 27 non-psychotic, first-degree relatives of individuals diagnosed with schizophrenia, and 48 normal controls, ages 13 to 28, undergoing high-resolution magnetic resonance imaging (MRI) at 1.5 T. After structural scan acquisition a subset of subjects performed 2-back working memory (WM) and 0-back tasks during functional MRI (fMRI) alternating with rest. fMRI data were analyzed using SPM-8. Volumes of total cerebrum, hippocampus, and parahippocampal gyrus were measured using semi-automated morphometry. RESULTS: Compared to controls, relatives had significantly smaller left hippocampi, without volumetric reduction in the parahippocampus. Relatives showed significantly less suppression of DMN activity in the left parahippocampal gyrus. Left hippocampal and posterior parahippocampal volumes were inversely and significantly associated with DMN processing (smaller volumes, less suppression) in relatives. Task suppression in parahippocampal gyrus significantly correlated with WM performance within the relatives. CONCLUSION: Results support the hypothesis that the vulnerability to schizophrenia includes smaller hippocampi and DMN suppression deficits, and these are associated with poorer WM. Findings suggest a primary structural, neurodevelopmental, medial temporal lobe abnormality associated with altered DMN function independent of psychosis.

Reliability of functional magnetic resonance imaging activation during working memory in a multi-site study: analysis from the North American Prodrome Longitudinal Study.

Multi-site neuroimaging studies offer an efficient means to study brain functioning in large samples of individuals with rare conditions; however, they present new challenges given that aggregating data across sites introduces additional variability into measures of interest. Assessing the reliability of brain activation across study sites and comparing statistical methods for pooling functional data are critical to ensuring the validity of aggregating data across sites. The current study used two samples of healthy individuals to assess the feasibility and reliability of aggregating multi-site functional magnetic resonance imaging (fMRI) data from a Sternberg-style verbal working memory task. Participants were recruited as part of the North American Prodrome Longitudinal Study (NAPLS), which comprises eight fMRI scanning sites across the United States and Canada. In the first study sample (n=8), one participant from each home site traveled to each of the sites and was scanned while completing the task on two consecutive days. Reliability was examined using generalizability theory. Results indicated that blood oxygen level-dependent (BOLD) signal was reproducible across sites and was highly reliable, or generalizable, across scanning sites and testing days for core working memory ROIs (generalizability ICCs=0.81 for left dorsolateral prefrontal cortex, 0.95 for left superior parietal cortex). In the second study sample (n=154), two statistical methods for aggregating fMRI data across sites for all healthy individuals recruited as control participants in the NAPLS study were compared. Control participants were scanned on one occasion at the site from which they were recruited. Results from the image-based meta-analysis (IBMA) method and mixed effects model with site covariance method both showed robust activation in expected regions (i.e. dorsolateral prefrontal cortex, anterior cingulate cortex, supplementary motor cortex, superior parietal cortex, inferior temporal cortex, cerebellum, thalamus, basal ganglia). Quantification of the similarity of group maps from these methods confirmed a very high (96%) degree of spatial overlap in results. Thus, brain activation during working memory function was reliable across the NAPLS sites and both the IBMA and mixed effects model with site covariance methods appear to be valid approaches for aggregating data across sites. These findings indicate that multi-site functional neuroimaging can offer a reliable means to increase power and generalizability of results when investigating brain function in rare populations and support the multi-site investigation of working memory function in the NAPLS study, in particular.