Social feedback biases emerge during recall but not prediction and shift across the development of social anxiety.

Memory is a reconstructive process that can result in events being recalled as more positive or negative than they actually were. While positive recall biases may contribute to well-being, negative recall biases may promote internalizing symptoms, such as social anxiety. Adolescence is characterized by increased salience of peers and peak incidence of social anxiety. Symptoms often wax and wane before becoming more intractable during adulthood. Open questions remain regarding how and when biases for social feedback are expressed and how individual differences in biases may contribute to social anxiety across development. Two studies used a social feedback and cued response task to assess biases about being liked or disliked when retrieving memories vs. making predictions. Findings revealed a robust positivity bias about memories for social feedback, regardless of whether memories were true or false. Moreover, memory bias was associated with social anxiety in a developmentally sensitive way. Among adults (study 1), more severe symptoms of social anxiety were associated with a negativity bias. During the transition from adolescence to adulthood (study 2), age strengthened the positivity bias in those with less severe symptoms and strengthened the negativity bias in those with more severe symptoms. These patterns of bias were isolated to perceived memory retrieval and did not generalize to predictions about social feedback. These results provide initial support for a model by which schemas may infiltrate perceptions of memory for past, but not predictions of future, social events, shaping susceptibility for social anxiety, particularly during the transition into adulthood.

Irritability and rejection-elicited aggression in adolescents and young adults.

BACKGROUND: Violence exacts staggering personal and financial costs - a burden disproportionally born by adolescents and young adults. This may be partially due to an increased sensitivity to social rejection during this critical phase of development. Irritability, a transdiagnostic symptom, is often elicited by social interactions. Yet, little is known about age differences in social rejection-elicited aggression and irritability. Progress toward testing such relations has been hindered by a lack of ecologically-valid tasks that enable the measurement of in-the-moment social rejection-elicited aggression. METHODS: In this paper, we describe an initial study of young adults (n = 55) that demonstrates the efficacy of a novel Virtual School and Aggression Paradigm (VS-AP). Next, we replicate these results in a second study of adolescents and young adults (ages 11-25 years; n = 173) and examine relations between social rejection-elicited aggression, irritability, and age. RESULTS: We found that aggressive behavior in the VS-AP differed for accepting, rejecting, and unpredictable peer types (Study 1: F(2, 108) = 20.57, p < .001, ε2 = .28; Study 2: F(2, 344) = 152.13, p < .001, ε2 = .47), demonstrating that the VS-AP successfully models social rejection-elicited aggression. In Study 2, age was negatively correlated with aggressive behavior (r = -.29, p < .001) and irritability (r = -.28, p < .001), while irritability was positively correlated with aggressive behavior (r = .28, p < .001). Age moderated the relation between social rejection-elicited aggression and irritability. Specifically, irritability was more predictive of aggression in young adults than in adolescents (F(3, 167) = 7.07, p < .001). CONCLUSIONS: Data suggest mechanisms promoting rejection-elicited aggression may differ across development and vary for those with and without high levels of irritability. The VS-AP is a promising tool for probing neurocognitive, developmental, and clinically relevant mechanisms underlying social rejection-elicited aggression.

Testing effects of social rejection on aggressive and prosocial behavior: A meta-analysis.

Social rejection elicits profound feelings of distress. From an evolutionary perspective, the best way to alleviate this distress is to behave prosocially, minimizing the likelihood of further exclusion. Yet, examples ranging from the playground to the pub suggest rejection commonly elicits aggression. Opposing theoretical perspectives and discordant empirical results have left a basic question unanswered: does rejection more commonly elicit prosocial or aggressive behavior? We conducted three meta-analyses (one with studies measuring aggressive behavior; one with studies measuring prosocial behavior; and one with studies measuring both aggressive and prosocial behavior; N = 3864) to quantify: (1) the extent to which social rejection elicits prosocial or aggressive behavior and (2) potential moderating effects on these relations. Random-effects models revealed medium effects such that social rejection potentiated aggressive behavior (k = 19; d = 0.41, p < .0001) and attenuated prosocial behavior (k = 7; d = 0.59, p < .0001), an effect that remained consistent even when participants were given the option to behave prosocially or aggressively (k = 15; d = 0.71, p < .0001). These results cast doubt on the theory that rejection triggers prosocial behavior, and instead suggest it is a robust elicitor of aggression. Statement of Relevance: To our knowledge, these meta-analyses are the first to directly test whether social rejection elicits aggressive or prosocial behavior. By including a comprehensive collection of both published and unpublished research studies, and examining a wide variety of previously untested moderators, we show that social rejection robustly elicits aggressive behavior and inhibits prosocial behavior. Additionally, we demonstrate that aggressive behavior following social rejection is not simply a function of limited choices in response options. In fact, aggressive behavior was evoked even when the option to engage in prosocial behavior was provided. Furthermore, we conducted a comprehensive narrative review of the neural mechanisms underlying social rejection-elicited aggressive and prosocial behavior to supplement primary analyses. Overall, we believe that our work makes a critical theoretical contribution to the field.

Substance Abuse in Emerging Adults: The Role of Neuromelanin and Ventral Striatal Response to Social and Monetary Rewards.

Perturbations in dopamine system function may increase risk of substance use disorder (SUD). We recently demonstrated that neuromelanin (NM) MRI signal in the substantia nigra, a non-invasive index of dopamine system function, is elevated in long term cocaine users (Cassidy et al., 2020). However, it is unclear whether elevated NM-MRI signal is linked to risk of SUD, or is a byproduct of long-term drug use. Our prior work failed to show relations between NM-MRI signal and functional engagement of ventral striatum during a monetary reward task. However, social experiences are commonly linked to drug use and relapse. Given that, NM-MRI signal may be more closely linked to ventral striatal engagement during social, rather than monetary reward processing. Emerging adults (n = 33, 21.88 ± 4.35 years) with varying levels of substance abuse, but without SUD, underwent NM-MRI and fMRI during social and monetary reward processing tasks. Voxelwise analysis within the substantia nigra (SN) demonstrated lower NM-MRI signal was associated with more severe substance abuse. Lower right ventral striatal engagement to social reward was also associated with more severe substance abuse. This relation was moderated by SN NM-MRI signal such that diminished striatal response to reward was associated with greater substance abuse among those with low NM-MRI signal, but lower substance abuse among those with high NM-MRI signal. Unexpectedly, higher right ventral striatal engagement during monetary reward was associated with more severe substance abuse. This relation was moderated by SN NM-MRI signal such that greater striatal response to reward was associated with greater substance abuse among those with low NM-MRI signal. Taken together, we provide preliminary evidence that, in emerging adults, low rather than high dopamine system function may increase risk of substance abuse, and strengthen the association between substance use and the brain's sensitivity to social and monetary outcomes in different ways.

Sex differences in neural mechanisms of social and non-social threat monitoring.

Adolescent males and females differ in their responses to social threat. Yet, threat processing is often probed in non-social contexts using the error-related negativity (ERN; Flanker EEG Task), which does not yield sex-specific outcomes. fMRI studies show inconsistent patterns of sex-specific neural engagement during threat processing. Thus, the relation between threat processing in non-social and social contexts across sexes and the effects perceived level of threat on brain function are unclear. We tested the interactive effect of non-social threat-vigilance (ERN), sex (N = 69; Male=34; 11-14-year-olds), and perceived social threat on brain function while anticipating feedback from 'unpredictable', 'nice', or 'mean' purported peers (fMRI; Virtual School Paradigm). Whole-brain analyses revealed differential engagement of precentral and inferior frontal gyri, putamen, anterior cingulate cortex, and insula. Among males with more threat-vigilant ERNs, greater social threat was associated with increased activation when anticipating unpredictable feedback. Region of interest analyses revealed this same relation in females in the amygdala and anterior hippocampus when anticipating mean feedback. Thus, non-social threat vigilance relates to neural engagement depending on perceived social threat, but peer-based social contexts and brain regions engaged, differ across sexes. This may partially explain divergent psychosocial outcomes in adolescence.

Nonverbal Behavioral Patterns Predict Social Rejection Elicited Aggression.

Peer-based aggression following social rejection is a costly and prevalent problem for which existing treatments have had little success. This may be because aggression is a complex process influenced by current states of attention and arousal, which are difficult to measure on a moment to moment basis via self report. It is therefore crucial to identify nonverbal behavioral indices of attention and arousal that predict subsequent aggression. We used Support Vector Machines (SVMs) and eye gaze duration and pupillary response features, measured during positive and negative peer-based social interactions, to predict subsequent aggressive behavior towards those same peers. We found that eye gaze and pupillary reactivity not only predicted aggressive behavior, but performed better than models that included information about the participant's exposure to harsh parenting or trait aggression. Eye gaze and pupillary reactivity models also performed equally as well as those that included information about peer reputation (e.g. whether the peer was rejecting or accepting). This is the first study to decode nonverbal eye behavior during social interaction to predict social rejection-elicited aggression.

Alterations in white matter microstructure in individuals at persistent risk for psychosis.

Abnormalities in brain white matter (WM) are reported in youth at-risk for psychosis. Yet, the neurodevelopmental time course of these abnormalities remains unclear. Thus, longitudinal diffusion-weighted imaging (DWI) was used to investigate WM abnormalities in youth at-risk for psychosis. A subset of individuals from the Philadelphia Neurodevelopmental Cohort (PNC) completed two DWI scans approximately 20 months apart. Youths were identified through structured interview as having subthreshold persistent psychosis risk symptoms (n = 46), and were compared to healthy typically developing participants (TD; n = 98). Analyses were conducted at voxelwise and regional levels. Nonlinear developmental patterns were examined using penalized splines within a generalized additive model. Compared to TD, youth with persistent psychosis risk symptoms had lower whole-brain WM fractional anisotropy (FA) and higher radial diffusivity (RD). Voxelwise analyses revealed clusters of significant WM abnormalities within the temporal and parietal lobes. Lower FA within the cingulum bundle of hippocampus and cerebrospinal tracts were the most robust deficits in individuals with persistent psychosis symptoms. These findings were consistent over two visits. Thus, it appears that WM abnormalities are present early in youth with persistent psychosis risk symptoms, however, there is little evidence to suggest that these features emerge in late adolescence or early adulthood. Future studies should seek to characterize WM abnormalities in younger individuals and follow individuals as subthreshold psychotic symptoms emerge.

I Knew You Weren't Going to Like Me! Neural Response to Accurately Predicting Rejection Is Associated With Anxiety and Depression.

Anxiety and depression often emerge in adolescence. A normative increase in the desire for peer acceptance may be one of many contributing factors. These shifts occur during a phase of development in which neural reward networks, including structures such as the ventral striatum, undergo critical changes. Despite the salience of peer feedback during adolescence, neural responses to reward have largely been examined in the monetary domain, leaving many open questions about responses to social rewards. Moreover, most paradigms do not tease apart different aspects of reward processing (e.g., receiving feedback, being correct). Anxiety and depression are also associated with alterations in reward networks; however, little is known about how anxiety and depression in adolescence relate to differences in social vs. non-social reward processing. In this study, adolescents (n = 28) underwent fMRI while completing novel monetary and social feedback tasks, which tease apart reward domain (social/monetary), valence (positive/negative), and outcome (correct/incorrect). Participants were shown a pair of stimuli (doors/age-matched peers) and asked to indicate which stimulus would provide positive (win money/social like) or negative (lose money/social dislike) feedback. Participants then received feedback about the purported accuracy of their response. Region-of-interest analyses showed that left ventral striatum response varied by domain (social/monetary), valence (positive/negative), and outcome (correct/incorrect) of reward. Additionally, unique associations between anxiety, depression, and brain function were observed for correct, but not for incorrect trials, in the social, but not monetary task. Specifically, adolescents with high anxiety symptoms, but low depression, displayed greater left ventral striatum activation when correctly identifying peers who gave dislike (vs. like) feedback. Thus, anxious youth exhibited enhanced activation in a brain region implicated in reward processing when they accurately predicted someone was going to dislike them. Higher levels of both depression and anxiety symptoms were associated with greater striatal activation to correctly identifying peers who gave like (vs. dislike) feedback. These results suggest a neural mechanism by which negative prediction biases may be reinforced in anxious youth.

Reduced safety processing during aversive social conditioning in psychosis and clinical risk.

Social impairment occurs across the psychosis spectrum, but its pathophysiology remains poorly understood. Here we tested the hypothesis that reduced differential responses (aversive vs. neutral) in neural circuitry underpinning aversive conditioning of social stimuli characterizes the psychosis spectrum. Participants age 10-30 included a healthy control group (HC, analyzed n = 36) and a psychosis spectrum group (PSY, n = 71), including 49 at clinical risk for psychosis and 22 with a frank psychotic disorder. 3T fMRI utilized a passive aversive conditioning paradigm, with neutral faces as conditioned stimuli (CS) and a scream as the unconditioned stimulus. fMRI conditioning was indexed as the activation difference between aversive and neutral trials. Analysis focused on amygdala, ventromedial prefrontal cortex, and anterior insula, regions previously implicated in aversive and social-emotional processing. Ventromedial prefrontal cortex activated more to neutral than aversive CS; this "safety effect" was driven by HC and reduced in PSY, and correlated with subjective emotional ratings following conditioning. Insula showed the expected aversive conditioning effect, and although no group differences were found, its activation in PSY correlated with anxiety severity. Unexpectedly, amygdala did not show aversive conditioning; its activation trended greater for neutral than aversive CS, and did not differ significantly based on group or symptom severity. We conclude that abnormalities in social aversive conditioning are present across the psychosis spectrum including clinical risk, linked to a failure of safety processing. Aversive and safety learning provide translational paradigms yielding insight into pathophysiology of psychosis risk, and providing potential targets for therapeutic and preventative interventions.

Connecting Childhood Wariness to Adolescent Social Anxiety through the Brain and Peer Experiences.

Wariness in early childhood manifests as shy, inhibited behavior in novel social situations and is associated with increased risk for developing social anxiety. In youth with childhood wariness, exposure to a potent social stressor, such as peer victimization, may potentiate brain-based sensitivity to unpredictable social contexts, thereby increasing risk for developing social anxiety. To test brain-based associations between early childhood wariness, self-reported peer victimization, and current social anxiety symptoms, we quantified neural responses to different social contexts in low- and high-victimized pre-adolescents with varying levels of early childhood wariness. Measures of early childhood wariness were obtained annually from ages 2-to-7-years. At age 11, participants were characterized as having low (N = 20) or high (N = 27) peer victimization. To index their neural responses to peer evaluation, participants completed an fMRI-based Virtual School paradigm (Jarcho et al. Developmental Cognitive Neuroscience, 13, 21-31, 2013a). In highly victimized, relative to low-victimized participants, wariness was differentially related to right amygdala response based on the valence and predictability of peer evaluation. More specifically, in highly victimized participants, wariness was associated with greater right amygdala response to unpredictably positive peer evaluation. Effects of wariness were not observed in participants who reported low levels of victimization. Moreover, in victimized participants, high wariness and right amygdala response to unpredictably positive peer evaluation was associated with more severe social anxiety symptoms. Results can be interpreted using a diathesis-stress model, which suggests that neural response to unexpectedly positive social feedback is a mechanism by which exposure to peer victimization potentiates the risk for developing social anxiety in individuals exhibiting high levels of early childhood wariness.

Quantitative assessment of structural image quality.

Data quality is increasingly recognized as one of the most important confounding factors in brain imaging research. It is particularly important for studies of brain development, where age is systematically related to in-scanner motion and data quality. Prior work has demonstrated that in-scanner head motion biases estimates of structural neuroimaging measures. However, objective measures of data quality are not available for most structural brain images. Here we sought to identify quantitative measures of data quality for T1-weighted volumes, describe how these measures relate to cortical thickness, and delineate how this in turn may bias inference regarding associations with age in youth. Three highly-trained raters provided manual ratings of 1840 raw T1-weighted volumes. These images included a training set of 1065 images from Philadelphia Neurodevelopmental Cohort (PNC), a test set of 533 images from the PNC, as well as an external test set of 242 adults acquired on a different scanner. Manual ratings were compared to automated quality measures provided by the Preprocessed Connectomes Project's Quality Assurance Protocol (QAP), as well as FreeSurfer's Euler number, which summarizes the topological complexity of the reconstructed cortical surface. Results revealed that the Euler number was consistently correlated with manual ratings across samples. Furthermore, the Euler number could be used to identify images scored "unusable" by human raters with a high degree of accuracy (AUC: 0.98-0.99), and out-performed proxy measures from functional timeseries acquired in the same scanning session. The Euler number also was significantly related to cortical thickness in a regionally heterogeneous pattern that was consistent across datasets and replicated prior results. Finally, data quality both inflated and obscured associations with age during adolescence. Taken together, these results indicate that reliable measures of data quality can be automatically derived from T1-weighted volumes, and that failing to control for data quality can systematically bias the results of studies of brain maturation.

Structural anomalies of the peripheral olfactory system in psychosis high-risk subjects.

BACKGROUND: Olfactory impairments are prominent in both schizophrenia and the preceding at-risk state. Their presence prior to illness predicts poor functional outcome. In schizophrenia, these impairments reflect peripheral olfactory structural abnormalities, which are hypothesized to arise during early embryonic development. If this is correct, then similar structural anomalies should be apparent among clinical high-risk subjects. METHODS: Thirty-nine clinical high-risk (CR) subjects (24M/15F) were compared to 36 low-risk (LR) subjects (19M/17F). Olfactory measures derived from 3T MRI scans included olfactory bulb volume, primary olfactory cortical gray matter volume, and the depth of the olfactory sulcus overlying the bulb. Additionally, nasal cavity volumes were assessed with acoustic rhinometry. RESULTS: Male CR subjects exhibited bilateral reductions in olfactory bulb volume and abnormal asymmetries of the posterior nasal cavities and olfactory sulci (left reduced relative to right). Post-hoc contrasts also indicated reduced left, but not right, olfactory cortical gray matter volume. Female CRs had no significant abnormalities, although they exhibited similar trend effects. Left olfactory bulb volume correlated, across all CR subjects, with negative, but not positive, symptoms. In a classification analysis, with 80% target specificity, olfactory measurements distinguished male CR from male LR subjects with 93% sensitivity. Among females, the comparable sensitivity was 69%. CONCLUSION: Psychosis-risk youths exhibit an array of sexually dimorphic and laterally asymmetric anomalies of the peripheral olfactory system. These are consistent with a developmental disruption primarily affecting male fetuses. These structural biomarkers may enhance the identification of at-risk subjects with poor prognosis, before their clinical trajectory is apparent.

Modular Segregation of Structural Brain Networks Supports the Development of Executive Function in Youth.

The human brain is organized into large-scale functional modules that have been shown to evolve in childhood and adolescence. However, it remains unknown whether the underlying white matter architecture is similarly refined during development, potentially allowing for improvements in executive function. In a sample of 882 participants (ages 8-22) who underwent diffusion imaging as part of the Philadelphia Neurodevelopmental Cohort, we demonstrate that structural network modules become more segregated with age, with weaker connections between modules and stronger connections within modules. Evolving modular topology facilitates global network efficiency and is driven by age-related strengthening of hub edges present both within and between modules. Critically, both modular segregation and network efficiency are associated with enhanced executive performance and mediate the improvement of executive functioning with age. Together, results delineate a process of structural network maturation that supports executive function in youth.

Temporal Lobe Volume Decrements in Psychosis Spectrum Youths.

Structural brain abnormalities have been amply demonstrated in schizophrenia. These include volume decrements in the perirhinal/entorhinal regions of the ventromedial temporal lobe, which comprise the primary olfactory cortex. Olfactory impairments, which are a hallmark of schizophrenia, precede the onset of illness, distinguish adolescents experiencing prodromal symptoms from healthy youths, and may predict the transition from the prodrome to frank psychosis. We therefore examined temporal lobe regional volumes in a large adolescent sample to determine if structural deficits in ventromedial temporal lobe areas were associated, not only with schizophrenia, but also with a heightened risk for psychosis. Seven temporal lobe regional volumes (amygdala [AM], hippocampus, inferior temporal gyrus, parahippocampal gyrus, superior temporal gyrus, temporal pole, and entorhinal cortex [EC]) were measured in 386 psychosis spectrum adolescents, 521 adolescents with other types of psychopathology, and 359 healthy adolescents from the Philadelphia Neurodevelopment Cohort. Total intracranial and left EC volumes, which were both smallest among the psychosis spectrum, were the only measures that distinguished all 3 groups. Left AM was also smaller in psychosis spectrum compared with healthy subjects. EC volume decrement was strongly correlated with impaired cognition and less robustly associated with heightened negative/disorganized symptoms. AM volume decrement correlated with positive symptoms (persecution/special abilities). Temporal lobe volumes classified psychosis spectrum youths with very high specificity but relatively low sensitivity. These MRI measures may therefore serve as important confirmatory biomarkers denoting a worrisome preclinical trajectory among at-risk youths, and the specific pattern of deficits may predict specific symptom profiles.

Odor Identification Screening Improves Diagnostic Classification in Incipient Alzheimer's Disease.

BACKGROUND: Measurements of olfaction may serve as useful biomarkers of incipient dementia. Here we examine the improvement in diagnostic accuracy of Alzheimer's disease (AD) and mild cognitive impairment (MCI) when assessing both cognitive functioning and odor identification. OBJECTIVE: To determine the utility of odor identification as a supplementary screening test in incipient AD. METHODS: Sniffin' Sticks Odor Identification Test (SS-OIT) and the Montreal Cognitive Assessment (MoCA) were administered in 262 AD, 174 MCI [150 amnestic (aMCI), and 24 non-amnestic (naMCI)], and 292 healthy older adults (HOA). RESULTS: Odor identification scores were higher in HOA relative to MCI or AD groups, and MCI outperformed AD. Odor identification scores were higher in aMCI single domain than aMCI multiple domain. Complementing MoCA scores with the SS-OIT significantly improved diagnostic accuracy of individuals with AD and MCI, including within MCI subgroups. DISCUSSION: Odor identification is a useful supplementary screening tool that provides additional information relevant for clinical categorization of AD and MCI, including those who are at highest risk to convert to AD.

Within-Individual Variability: An Index for Subtle Change in Neurocognition in Mild Cognitive Impairment.

BACKGROUND: The transition from mild cognitive impairment (MCI) to Alzheimer's disease is characterized by a decline in cognitive performance in many domains. Cognitive performance profiles in MCI are heterogeneous, however, and additional insights into markers of incipient dementia are needed. Typically, studies focus on average or mean performance, but ignore consistency of performance across domains. WIV (within-individual variability) provides an index of this consistency and is a potential marker of cognitive decline. OBJECTIVE: To use neurocognitive data from the Alzheimer's Disease Neuroimaging Initiative cohort to measure neurocognitive variability. METHODS: The utility of WIV was measured, in addition to global neurocognitive performance (GNP), for identifying AD and MCI. In addition, the association between changes in neurocognitive variability and diagnostic transition over 12 months was measured. RESULTS: As expected, variability was higher in AD and MCI as compared to healthy controls; GNP was lower in both groups as compared to healthy subjects. Global neurocognitive performance alone best distinguished those with dementia from healthy older adults. Yet, for individuals with MCI, including variability along with GNP improved diagnostic classification. Variability was higher at baseline in individuals transitioning from MCI to AD over a 12-month period. CONCLUSION: We conclude that variability offers complementary information about neurocognitive performance in dementia, particularly in individuals with MCI, and may provide beneficial information about disease transition.

The impact of quality assurance assessment on diffusion tensor imaging outcomes in a large-scale population-based cohort.

BACKGROUND: Diffusion tensor imaging (DTI) is applied in investigation of brain biomarkers for neurodevelopmental and neurodegenerative disorders. However, the quality of DTI measurements, like other neuroimaging techniques, is susceptible to several confounding factors (e.g., motion, eddy currents), which have only recently come under scrutiny. These confounds are especially relevant in adolescent samples where data quality may be compromised in ways that confound interpretation of maturation parameters. The current study aims to leverage DTI data from the Philadelphia Neurodevelopmental Cohort (PNC), a sample of 1601 youths with ages of 8-21 who underwent neuroimaging, to: 1) establish quality assurance (QA) metrics for the automatic identification of poor DTI image quality; 2) examine the performance of these QA measures in an external validation sample; 3) document the influence of data quality on developmental patterns of typical DTI metrics. METHODS: All diffusion-weighted images were acquired on the same scanner. Visual QA was performed on all subjects completing DTI; images were manually categorized as Poor, Good, or Excellent. Four image quality metrics were automatically computed and used to predict manual QA status: Mean voxel intensity outlier count (MEANVOX), Maximum voxel intensity outlier count (MAXVOX), mean relative motion (MOTION) and temporal signal-to-noise ratio (TSNR). Classification accuracy for each metric was calculated as the area under the receiver-operating characteristic curve (AUC). A threshold was generated for each measure that best differentiated visual QA status and applied in a validation sample. The effects of data quality on sensitivity to expected age effects in this developmental sample were then investigated using the traditional MRI diffusion metrics: fractional anisotropy (FA) and mean diffusivity (MD). Finally, our method of QA is compared with DTIPrep. RESULTS: TSNR (AUC=0.94) best differentiated Poor data from Good and Excellent data. MAXVOX (AUC=0.88) best differentiated Good from Excellent DTI data. At the optimal threshold, 88% of Poor data and 91% Good/Excellent data were correctly identified. Use of these thresholds on a validation dataset (n=374) indicated high accuracy. In the validation sample 83% of Poor data and 94% of Excellent data was identified using thresholds derived from the training sample. Both FA and MD were affected by the inclusion of poor data in an analysis of an age, sex and race matched comparison sample. In addition, we show that the inclusion of poor data results in significant attenuation of the correlation between diffusion metrics (FA and MD) and age during a critical neurodevelopmental period. We find higher correspondence between our QA method and DTIPrep for Poor data, but we find our method to be more robust for apparently high-quality images. CONCLUSION: Automated QA of DTI can facilitate large-scale, high-throughput quality assurance by reliably identifying both scanner and subject induced imaging artifacts. The results present a practical example of the confounding effects of artifacts on DTI analysis in a large population-based sample, and suggest that estimates of data quality should not only be reported but also accounted for in data analysis, especially in studies of development.

White matter microstructure in schizophrenia: associations to neurocognition and clinical symptomatology.

BACKGROUND: Diffusion tensor imaging (DTI) studies in schizophrenia report widespread aberrations in brain white matter (WM). These appear related to poorer neurocognitive performance and higher levels of negative and positive symptomatology. However, identification of the most salient WM aberrations to neurocognition and clinical symptoms is limited by relatively small samples with divergent results. METHODS: We examined 53 well-characterized patients with schizophrenia and 62 healthy controls. All participants were administered a computerized neurocognitive battery, which evaluated performance in several domains. Patients were assessed for negative and positive symptoms. Fractional anisotropy (FA) of WM cortical regions and WM fiber tracts were compared across the groups. FA values were also used to predict neurocognitive performance and symptoms. RESULTS: We confirm widespread aberrant WM microstructure in a relatively large sample of well-characterized patients with schizophrenia in comparison to healthy participants. Moreover, we illustrate the utility of FA measures in predicting global neurocognitive performance in healthy participants and schizophrenia patients, especially for reaction time. FA was less predictive of clinical symptomatology. CONCLUSIONS: Using a standardized computerized neurocognitive battery and diffusion tensor imaging we show that behavioral performance is moderated by a particular constellation of WM microstructure in healthy individuals that differs in schizophrenia.