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Neuroimaging studies point to neurostructural abnormalities in youth with anxiety disorders. Yet, findings are based on small-scale studies, often with small effect sizes, and have limited generalizability and clinical relevance. These issues have prompted a paradigm shift in the field towards highly powered (i.e., big data) individual-level inferences, which are data-driven, transdiagnostic, and neurobiologically informed. Here, we built and validated neurostructural machine learning (ML) models for individual-level inferences based on the largest-ever multi-site neuroimaging sample of youth with anxiety disorders (age: 10-25 years, N=3,343 individuals from 32 global sites), as compiled by three ENIGMA Anxiety Working Groups: Panic Disorder (PD), Generalized Anxiety Disorder (GAD), and Social Anxiety Disorder (SAD). ML classifiers were trained on MRI-derived regional measures of cortical thickness, surface area, and subcortical volumes to classify patients and healthy controls (HC) for each anxiety disorder separately and across disorders (transdiagnostic classification). Modest, yet robust, classification performance was achieved for PD vs. HC (AUC=0.62), but other disorder-specific and transdiagnostic classifications were not significantly different from chance. However, above chance-level transdiagnostic classifications were obtained in exploratory subgroup analyses of male patients vs. male HC, unmedicated patients vs. HC, and patients with low anxiety severity vs. HC (AUC 0.59-0.63). The above chance-level classifications were based on plausible and specific neuroanatomical features in fronto-striato-limbic and temporo-parietal regions. This study provides a realistic estimate of classification performance in a large, ecologically valid, multi-site sample of youth with anxiety disorders, and may as such serve as a benchmark.

Cognitive reappraisal is associated with reduced emotional distress; however, little is known about the nature of this relationship in autism. This study tested whether autistic traits moderate reappraisal success (i.e., the negative correlation between reappraisal use and emotional symptom severity). Emotional symptoms were assessed using measures of depression, anxiety, and stress. It was hypothesized that more severe autistic traits would be associated with weaker reappraisal success across all scales. Data were collected from 377 adults using an on-line survey. Structural equation models found moderation effects for depression and anxiety, but not stress. Contrary to hypotheses, more severe autistic traits were associated with stronger reappraisal success. These preliminary results support including reappraisal in emotion regulation treatments for individuals with autistic traits.

Intrinsic neural timescales (INT) reflect the duration for which brain areas store information. A posterior – anterior hierarchy of increasingly longer INT has been revealed in both typically developed individuals (TD), as well as patients diagnosed with autism spectrum disorder (ASD) and schizophrenia (SZ), though INT are, overall, shorter in both patient groups. In the present study, we attempted to replicate previously reported group differences by comparing INT of TD to ASD and SZ. We replicated the previously reported result showing reduced INT in the left lateral occipital gyrus and the right post-central gyrus in SZ compared to TD. For the first time, we also directly compared the INT of the two patient groups and found that these same two areas show significantly reduced INT in SZ compared to ASD. In ASD, significant correlations were found between INT and their clinical and phenotypic characteristics. Our results point to the left lateral occipital gyrus and the right post-central gyrus as holding potential for further diagnostic refinement of SZ.

The dynamics of the human brain span multiple spatial scales, from connectivity associated with a specific region/network to the global organization, each representing different brain mechanisms. Yet brain reconfigurations at different spatial scales are seldom explored and whether they are associated with the neural aspects of brain disorders is far from understood. In this study, we introduced a dynamic measure called step‐wise functional network reconfiguration (sFNR) to characterize how brain configuration rewires at different spatial scales. We applied sFNR to two independent datasets, one includes 160 healthy controls (HCs) and 151 patients with schizophrenia (SZ) and the other one includes 314 HCs and 255 individuals with autism spectrum disorder (ASD). We found that both SZ and ASD have increased whole‐brain sFNR and sFNR between cerebellar and subcortical/sensorimotor domains. At the ICN level, the abnormalities in SZ are mainly located in ICNs within subcortical, sensory, and cerebellar domains, while the abnormalities in ASD are more widespread across domains. Interestingly, the overlap SZ‐ASD abnormality in sFNR between cerebellar and sensorimotor domains was correlated with the reasoning‐problem‐solving performance in SZ (r = −.1652, p = .0058) as well as the Autism Diagnostic Observation Schedule in ASD (r = .1853, p = .0077). Our findings suggest that dynamic reconfiguration deficits may represent a key intersecting point for SZ and ASD. The investigation of brain dynamics at different spatial scales can provide comprehensive insights into the functional reconfiguration, which might advance our knowledge of cognitive decline and other pathophysiology in brain disorders., In this study, we found that both schizophrenia and autism have increased whole‐brain dynamic network reconfiguration and increased dynamic network reconfiguration associated with cerebellar and subcortical/sensorimotor domains. Interestingly, the diseases' overlapping abnormality in dynamic network reconfiguration between cerebellar and sensorimotor domains was correlated with the reasoning‐problem‐solving performance in schizophrenia as well as the Autism Diagnostic Observation Schedule in autism. Our findings suggest that dynamic functional connectivity deficits may represent a key intersecting point for schizophrenia and autism.

Individuals with generalized anxiety disorder (GAD) report poorer quality of life (QOL) than do nonanxious controls. Further, although positive affect (PA) and negative affect (NA) have been shown to predict QOL, no previous literature has tested this relationship in the context of individuals with GAD. In the present study, we evaluated the unique and interactive contributions of PA and NA on QOL within a sample of individuals diagnosed with GAD (N = 50). Specifically, a hierarchical regression was conducted to evaluate the unique contributions of PA, NA, and their interaction on QOL, over and above symptoms of depression. PA and depression symptoms were both significant predictors of QOL, whereas neither the main effect for NA nor the PA × NA interaction was statistically significant. Results suggest that, for those with GAD, PA uniquely contributes to QOL. Strategies to upregulate PA may be a useful treatment target for increasing QOL in individuals with GAD.

The excitation/inhibition (E/I) ratio has been shown to be elevated in both autism spectrum disorder (ASD) and schizophrenia (SZ), relative to neurotypical controls. However, the degree of E/I imbalance overlap and differentiation between SZ and ASD is not known. Our main objectives were therefore (1) to quantify group differences in the E/I ratio between controls, ASD and SZ, and (2) to assess the potential of the E/I ratio for differential diagnosis. We collected resting state fMRI (rsfMRI) and phenotypic data from 55 controls, 30 ASD, and 39 SZ, ages 18 to 35 (IQ>80). For each participant, we computed the Hurst exponent (H), an indicator of the E/I ratio, for the timecourses of 53 independent components covering the entire brain. Next, using Optimal Classification Trees (OCT), we ran a classification analysis on the two clinical groups using five incremental feature sets (i.e., models): (1) Positive and Negative Syndrome Scale (PANSS) and the Autism Diagnostic Observation Schedule (ADOS) only; (2) PANSS, ADOS, Bermond–Vorst Alexithymia Questionnaire (BVAQ), Empathy Quotient (EQ), and IQ; (3) H only; (4) H, PANSS and ADOS; (5) H, PANSS, ADOS, BVAQ, EQ and IQ. We observed decreased H (i.e., increase in E/I ratio) in ASD and SZ compared to controls, and in SZ compared to ASD in the Cerebellar, Sensorimotor, Visual and Cognitive Control networks. The OCT classification showed a consistent increase in discrimination accuracy across models between ASD and SZ, suggesting that the E/I ratio in combination with phenotypic measures can contribute to differential diagnosis in adults.

Background Autism spectrum disorder (ASD) is characterized by deficits in social functioning and is comorbid with internalizing disorders and symptoms. While personality is associated with these symptoms and social functioning in non-ASD samples, its role mediating the relationship between ASD traits and internalizing symptoms is not clear. Methods We studied the mediating effect of personality on the correlations between ASD traits and internalizing symptoms (i.e., depression, anxiety, stress) in two samples. Additionally, we explored the moderating effect of gender. Analyses were applied to a small (Study 1; N = 101) undergraduate sample. A broader sample recruited via an online crowdsourcing platform (Study 2; N = 371) was used to validate the results. Results Study 1’s mediation analyses revealed that neuroticism was the only significant mediator. Study 2 replicated these results by finding extraversion to be an additional mediator for anxiety and extraversion, openness, and agreeableness as additional mediators for stress. Moderation analyses revealed that gender was never a significant moderator. Conclusions These results support the effects of personality on the relationship between autism traits and internalizing symptoms. Future research should explore these effects in clinical samples to better understand the role of personality in symptomatology and the need to address it as part of intervention.

Autism spectrum disorder (ASD) and schizophrenia (SZ) are separate clinical entities but share deficits in social–emotional processing and static neural functional connectivity patterns. We compared patients’ dynamic functional network connectivity (dFNC) state engagement with typically developed (TD) individuals during social–emotional processing after initially characterizing such dynamics in TD. Young adults diagnosed with ASD (n = 42), SZ (n = 41), or TD (n = 55) completed three functional MRI runs, viewing social–emotional videos with happy, sad, or neutral content. We examined dFNC of 53 spatially independent networks extracted using independent component analysis and applied k-means clustering to windowed dFNC matrices, identifying four unique whole-brain dFNC states. TD showed differential engagement (fractional time, mean dwell time) in three states as a function of emotion. During Happy videos, patients spent less time than TD in a happy-associated state and instead spent more time in the most weakly connected state. During Sad videos, only ASD spent more time than TD in a sad-associated state. Additionally, only ASD showed a significant relationship between dFNC measures and alexithymia and social–emotional recognition task scores, potentially indicating different neural processing of emotions in ASD and SZ. Our results highlight the importance of examining temporal whole-brain reconfiguration of FNC, indicating engagement in unique emotion-specific dFNC states.

Cognitive reappraisal is associated with reduced emotional distress; however, little is known about the nature of this relationship in autism. This study tested whether autistic traits moderate reappraisal success (i.e., the negative correlation between reappraisal use and emotional symptom severity). Emotional symptoms were assessed using measures of depression, anxiety, and stress. It was hypothesized that more severe autistic traits would be associated with weaker reappraisal success across all scales. Data were collected from 377 adults using an on-line survey. Structural equation models found moderation effects for depression and anxiety, but not stress. Contrary to hypotheses, more severe autistic traits were associated with stronger reappraisal success. These preliminary results support including reappraisal in emotion regulation treatments for individuals with autistic traits.

We present an exploratory cross-sectional analysis of the effect of season and weather on Freesurfer-derived brain volumes from a sample of 3,279 healthy individuals collected on two MRI scanners in Hartford, CT, USA over a 15 year period. Weather and seasonal effects were analyzed using a single linear regression model with age, sex, motion, scan sequence, time-of-day, month of the year, and the deviation from average barometric pressure, air temperature, and humidity, as covariates. FDR correction for multiple comparisons was applied to groups of non-overlapping ROIs. Significant negative relationships were found between the left- and right-cerebellum cortex and pressure (t = −2.25, p = 0.049; t = −2.771, p = 0.017). Significant positive relationships were found between left- and right-cerebellum cortex and white matter between the comparisons of January/June and January/September. Significant negative relationships were found between several subcortical ROIs for the summer months compared to January. An opposing effect was observed between the supra- and infra-tentorium, with opposite effect directions in winter and summer. Cohen’s d effect sizes from monthly comparisons were similar to those reported in recent psychiatric big-data publications, raising the possibility that seasonal changes and weather may be confounds in large cohort studies. Additionally, changes in brain volume due to natural environmental variation have not been reported before and may have implications for weather-related and seasonal ailments.

Schizophrenia (SZ) and Autism Spectrum Disorder (ASD) show overlap in social cognitive and functioning impairments. Proposed predictors of social functioning (SF) and quality of life (QL) have been symptom severity, IQ and social cognition. Empathy has rarely been compared between ASD and SZ and its predictive power on functional outcomes is unclear. We investigated general, affective, and cognitive empathy in 46 SZ, 30 ASD and 51 healthy controls (HC) and examined their relationship to SF and QL in addition to IQ and symptoms. SZ and ASD shared deficits in general and cognitive empathy, and personal distress, but only SZ showed deficits in affective empathy. Both groups showed lower performance-based empathy scores and only ASD showed slower responses compared to HC. Negative symptoms predicted QL in both groups, the more negative symptoms the worse QL (ASD t=-3.22; SZ t= -3.43; p0.01), and only in ASD, IQ predicted QL, the higher the IQ the higher QL (t = 2.1; p0.05). In ASD only, negative symptoms predicted SF, the greater negative symptoms the worse SF (t=-3.45; p0.01), and communication deficits predicted SF, the higher deficits, the higher SF (t = 2.9; p0.01). Negative symptoms but not empathy were the shared predictors of functioning across ASD and SZ.

Despite over 400 peer-reviewed structural MRI publications documenting neuroanatomic abnormalities in bipolar disorder and schizophrenia, the confounding effects of head motion and the regional specificity of these defects are unclear. Using a large cohort of individuals scanned on the same research dedicated MRI with broadly similar protocols, we observe reduced cortical thickness indices in both illnesses, though less pronounced in bipolar disorder. While schizophrenia (n = 226) was associated with wide-spread surface area reductions, bipolar disorder (n = 227) and healthy comparison subjects (n = 370) did not differ. We replicate earlier reports that head motion (estimated from time-series data) influences surface area and cortical thickness measurements and demonstrate that motion influences a portion, but not all, of the observed between-group structural differences. Although the effect sizes for these differences were small to medium, when global indices were covaried during vertex-level analyses, between-group effects became nonsignificant. This analysis raises doubts about the regional specificity of structural brain changes, possible in contrast to functional changes, in affective and psychotic illnesses as measured with current imaging technology. Given that both schizophrenia and bipolar disorder showed cortical thickness reductions, but only schizophrenia showed surface area changes, and assuming these measures are influenced by at least partially unique sets of biological factors, then our results could indicate some degree of specificity between bipolar disorder and schizophrenia. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.

Cognitive models of generalized anxiety disorder (GAD) propose that cognitive control, broadly construed, and inhibition specifically, play a role in the maintenance of GAD symptoms. However, few studies have explicitly investigated inhibition, and in particular “cold” (non-emotional) inhibition, and its relation to worry and anxiety severity in GAD. Adults with GAD (n = 35) and healthy controls (n = 21) completed computerized Stroop and Go/NoGo tasks, two widely-used tests of inhibition. GAD status predicted significantly worse (slower and less accurate) performance on the Stroop but not the Go/NoGo task. Clinician-rated anxiety severity predicted slower and less accurate Stroop performance over and above the effect of GAD diagnosis but did not predict Go/NoGo performance. Trait worry did not incrementally predict performance on either task. These findings provide qualified support for theoretical models of inhibition impairments in GAD and suggest that inhibition could be a promising target for novel neurocognitive interventions.

Generalized anxiety disorder (GAD) is characterized by emotion regulation difficulties, which are associated with abnormalities in neural circuits encompassing fronto-limbic regions including the dorsolateral prefrontal cortex (DLPFC). The aim of this study was to determine whether DLPFC neuromodulation improves emotion regulation in patients with GAD. This is a secondary analysis from a randomized-controlled trial comparing 30 sessions of low-frequency right-sided active (n=13) versus sham (n=12, sham coil) repetitive transcranial magnetic stimulation (rTMS) at the right DLPFC in patients with GAD. Results indicated statistically significant improvements in self-reported emotion regulation difficulties at posttreatment and 3-month follow-up in the active group only. Improvements were found primarily in the domains of goal-directed behaviors and impulse control and were significantly associated with a global clinician rating of improvement. These preliminary results support rTMS as a treatment for GAD and suggest improved emotion regulation as a possible mechanism of change.

BackgroundRepetitive transcranial magnetic stimulation (rTMS) holds promise for treating generalised anxiety disorder (GAD) but has only been studied in uncontrolled research.AimsThis is the first randomised controlled trial (clinicaltrials.gov: NCT01659736) to investigate the efficacy and neural correlates of rTMS in GAD.MethodTwenty five participants (activen= 13; sham,n= 12) enrolled. rTMS was targeted at the right dorsolateral prefrontal cortex (DLPFC, 1 Hz, 90% resting motor threshold).ResultsResponse and remission rates were higher in the activev.sham groups and there were significant group × time interactions for anxiety, worry and depressive symptoms, favouring activev.sham. In addition, right DLPFC activation during a decision-making gambling task increased at post-treatment for active rTMS only, and changes in neuroactivation correlated significantly with changes in worry symptoms.ConclusionsFindings provide preliminary evidence that rTMS may improve GAD symptoms in association with modifying neural activity in the stimulation site.

Emerging research highlights the potential cognitive benefits of physical exercise (PE) programs for schizophrenia (SCZ). The few recent efficacy studies that examined augmenting cognitive training (CT) with PE suggest superior effects of the combination. The next step is to consider strategies to enhance adherence in real-world settings if this type of combined treatment is going to be effective. We present the first community effectiveness data for PE and CT that included a motivationally-enhancing, self-determined approach to exercise, in lieu of participant payment. Eighty-five outpatients with schizophrenia attending an intensive outpatient program were randomized to 18 h of either (A) self-determined PE regimen with choice from a menu of different activities; (B) tablet-based neurofeedback CT focused on processing speed (PS) and working memory (WM), or (C) a time-matched combination of PE and CT. Assessments were conducted at baseline, post, and follow-up (2 mo). All groups improved in WM from baseline to post, with greatest gains in the PE only group. At follow-up, cognitive gains originally observed in the PE-only group disappeared, while the PE + CT group evidenced improvements in WM and psychotic symptoms. Notably, attrition for PE was only 7%. Our data shows that combining PE and CT leads to lasting effects that are superior to those of either intervention alone. The low PE drop-out rate suggests a self-determined approach to the exercise regimen was tolerable, and may be an important component of future community implementation efforts. Keywords: Schizophrenia, Motivation, Physical exercise, Cognitive training

The ability to attribute mental states to others, or “mentalizing,” is posited to involve specific subnetworks within the overall default mode network (DMN), but this question needs clarification. To determine which default mode (DM) subnetworks are engaged by mentalizing processes, we assessed task-related recruitment of DM subnetworks. Spatial independent component analysis (sICA) applied to fMRI data using relatively high-order model (75 components). Healthy participants (n = 53, ages 17–60) performed two fMRI tasks: an interactive game involving mentalizing (Domino), a semantic memory task (SORT), and a resting state fMRI scan. sICA of the two tasks split the DMN into 10 subnetworks located in three core regions: medial prefrontal cortex (mPFC; five subnetworks), posterior cingulate/precuneus (PCC/PrC; three subnetworks), and bilateral temporoparietal junction (TPJ). Mentalizing events increased recruitment in five of 10 DM subnetworks, located in all three core DMN regions. In addition, three of these five DM subnetworks, one dmPFC subnetwork, one PCC/PrC subnetwork, and the right TPJ subnetwork, showed reduced recruitment by semantic memory task events. The opposing modulation by the two tasks suggests that these three DM subnetworks are specifically engaged in mentalizing. Our findings, therefore, suggest the unique involvement of mentalizing processes in only three of 10 DM subnetworks, and support the importance of the dmPFC, PCC/PrC, and right TPJ in mentalizing as described in prior studies. Hum Brain Mapp 36:3047–3063, 2015. © 2015 Wiley Periodicals, Inc.

Background Recent evidence suggests that repetitive transcranial magnetic stimulation (rTMS) might be effective in treating generalized anxiety disorder (GAD). Cognitive models of GAD highlight the role of intolerance of uncertainty (IU) in precipitating and maintaining worry, and it has been hypothesized that patients with GAD exhibit decision‐making deficits under uncertain conditions. Improving understanding of the neural mechanisms underlying cognitive deficits associated with IU may lead to the identification of novel rTMS treatment targets and optimization of treatment parameters. The current report describes two interrelated studies designed to identify and verify a potential neural target for rTMS treatment of GAD. Methods Study I explored the integrity of prefrontal cortex (PFC) and amygdala neural networks, which underlie decision making under conditions of uncertainty, in GAD. Individuals diagnosed with GAD (n = 31) and healthy controls (n = 20) completed a functional magnetic resonance imaging (fMRI) gambling task that manipulated uncertainty using high versus low error rates. In a subsequent randomized‐controlled trial (Study II), a subset of the GAD sample (n = 16) completed the fMRI gambling task again after 30 sessions of active versus sham rTMS (1 Hz, right dorsolateral prefrontal cortex) to investigate the modulation of functional networks and symptoms. Results In Study I, participants with GAD demonstrated impairments in PFC‐PFC and PFC‐amygdala functional connectivity (FC) mostly during the high uncertainty condition. In Study II, one region of interest pair, dorsal anterior cingulate (ACC) – subgenual ACC, showed “normalization” of FC following active, but not sham, rTMS, and neural changes were associated with improvement in worry symptoms. Conclusions These results outline a possible treatment mechanism of rTMS in GAD, and pave the way for future studies of treatment optimization.

Theory of mind (ToM) is the ability to understand mental states of others and it is crucial for building sensitivity to other persons or events. Measuring ToM is important for understanding and rehabilitating social cognitive impairments in persons with schizophrenia. The Social Attribution Task-Multiple Choice (SAT-MC) has been successfully employed to measure ToM between individuals with schizophrenia (SZ) and healthy controls (HC) in North America. Given that the SAT-MC uses geometric shapes, is nonverbal and less culturally loaded than other social cognition measures, it may serve for measuring ToM in schizophrenia across cultures. A total of 120 participants (30 per group; Korean SZ; Korean HC; North American SZ; North American HC) were selected from existing databases to examine the reliability and validity of the SAT-MC. Internal consistency, factor structure, measurement invariance, discriminant validity, and convergent/divergent validity were examined. The SAT-MC had good internal consistency regardless of the clinical and cultural group as evidence by Cronbach's α ≥ 0.78 in all groups. Confirmatory factor analysis confirmed the one-factor model with a good model fit (χ2 = 188.122, TLI = 0.958, CFI = 0.963, RMSEA = 0.045). The SAT-MC was sensitive to detect individual differences in ToM of SZ and HC, regardless of culture (p The SAT-MC is a reliable measure for evaluating ToM in both Koreans and North Americans with or without schizophrenia, supporting its potential utility in diverse language and cultures for schizophrenia research.

Generalized anxiety disorder (GAD) and social anxiety disorder (SAD) are currently considered distinct diagnostic categories. Accumulating data suggest the study of anxiety disorders may benefit from the use of dimensional conceptualizations. One such dimension of shared dysfunction is emotion regulation (ER). The current study evaluated dimensional (ER) and categorical (diagnosis) neurocorrelates of resting-state functional connectivity (rsFC) in participants with GAD and SAD and healthy controls (HC). Functional magnetic resonance imaging (fMRI) rsFC was estimated between all regions of the default mode network (DMN), salience network (SN), and bilateral amygdala (N = 37: HC-19; GAD-10; SAD-8). Thereafter, rsFC was predicted by both ER, (using the Difficulties in Emotion Regulation Scale [DERS]), and diagnosis (DSM-5) within a single unified analysis of covariance (ANCOVA). For the ER dimension, there was a significant association between impaired ER abilities and anticorrelated rsFC of amygdala and DMN (L.amygdala-ACC: p = 0.011, beta = -0.345), as well as amygdala and SN (L.amygdala-posterior cingulate cortex [PCC]: p = 0.032, beta = -0.409). Diagnostic status was significantly associated with rsFC differences between the SAD and HC groups, both within the DMN (PCC-MPFC: p = 0.009) and between the DMN and SN (R.LP-ACC: p = 0.010). Although preliminary, our results exemplify the potential contribution of the dimensional approach to the study of GAD and SAD and support a combined categorical and dimensional model of rsFC of anxiety disorders.

Despite over 400 peer-reviewed structural MRI publications documenting neuroanatomic abnormalities in bipolar disorder and schizophrenia, the confounding effects of head motion and the regional specificity of these defects are unclear. Using a large cohort of individuals scanned on the same research dedicated MRI with broadly similar protocols, we observe reduced cortical thickness indices in both illnesses, though less pronounced in bipolar disorder. While schizophrenia (n = 226) was associated with wide-spread surface area reductions, bipolar disorder (n = 227) and healthy comparison subjects (n = 370) did not differ. We replicate earlier reports that head motion (estimated from time-series data) influences surface area and cortical thickness measurements and demonstrate that motion influences a portion, but not all, of the observed between-group structural differences. Although the effect sizes for these differences were small to medium, when global indices were covaried during vertex-level analyses, between-group effects became nonsignificant. This analysis raises doubts about the regional specificity of structural brain changes, possible in contrast to functional changes, in affective and psychotic illnesses as measured with current imaging technology. Given that both schizophrenia and bipolar disorder showed cortical thickness reductions, but only schizophrenia showed surface area changes, and assuming these measures are influenced by at least partially unique sets of biological factors, then our results could indicate some degree of specificity between bipolar disorder and schizophrenia. Hum Brain Mapp 38:3757-3770, 2017. © 2017 Wiley Periodicals, Inc.

We examined performance and functional magnetic resonance imaging activity in participants (n = 235) aged 17-81 years on a nonverbal recognition memory task, figural memory. Reaction time, error rate, and response bias measures indicated that the youngest and oldest participants were faster, made fewer errors, and showed a more conservative response bias than participants in the median age ranges. Encoding and Recognition phases activated a distributed bilateral network encompassing prefrontal, subcortical, lateral, and medial temporal and occipital regions. Activation during Encoding phase did not correlate with age. During Recognition, task-related activation for correctly identified targets (Hit-Targets) correlated linearly positively with age; nontask related activity correlated negative quadratically with age. During correctly identified distractors (Hit-Distractors) activity in task-related regions correlated positive linearly with age, nontask activity showed positive and negative quadratic relationships with age. Missed-Targets activity did not correlate with age. We concluded that figural memory performance and functional magnetic resonance imaging activity during Recognition but not Encoding was affected both by continued maturation of the brain in the early 20s and compensatory recruitment of additional brain regions during recognition memory in old age.

Trauma-related psychopathology has been associated with an intense emotional reaction to stressful event. Emotional responses have evolved to signal the presence of risks to be avoided or of rewards to be approached in the environment. Thus, individuals' sensitivity to signals of risk and reward may affect the level of stress vulnerability. Stress, however, can modify these sensitivities as well. In the current functional magnetic resonance imaging (fMRI) study, we prospectively probed the neural correlates of such sensitivities in 24 healthy soldiers by using an interactive game that encompasses risky and rewarding intervals both pre-exposure and post-exposure to stressful military service. As expected, risky and rewarding intervals elicited selective responses in the amygdala and nucleus accumbens (Nacc), respectively. Furthermore, increased post-traumatic stress disorder symptoms post-exposure (i.e., stress vulnerability) corresponded to greater amygdala's response to risk both pre-exposure and post-exposure and to decreased NAcc response to reward only post-exposure. By combining these regional responsivities post-exposure, we accurately identified all the most vulnerable soldiers. Imbalanced neural responsivity to risk and reward following exposure to stress may therefore constitute a marker for stress vulnerability. Such identification of vulnerability biomarkers can aid future diagnostic and therapeutic efforts by allowing early detection of vulnerability as well as follow up on patient's treatment progression.

Studies demonstrating selective brain networks subserving motivation and mentalization (i.e. attributing states of mind to others) during social interactions have not investigated their mutual independence. We report the results of two fMRI studies using a competitive game requiring players to use implicit ‘on-line’ mentalization simultaneously with motivational processes of gains and losses in playing against a human or a computer opponent. We delineate a network, consisting of bilateral temporoparietal junction, temporal pole (TP), medial prefrontal cortex (MPFC) and right fusiform gyrus, which is sensitive to the opponent's response (challenging>not challenging the player) and opponent type (human>computer). This network is similar to a known explicit ‘off-line’ mentalization circuit, suggesting its additional involvement in implicit ‘on-line’ mentalization, a process more applicable to real-life social interactions. Importantly, only MPFC and TP were selective to mentalization compared to motivation, highlighting their specific operation in attributing states of mind to others during social interactions.

Error-related brain activity has become an increasingly important focus of cognitive neuroscience research utilizing both event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI). Given the significant time and resources required to collect these data, it is important for researchers to plan their experiments such that stable estimates of error-related processes can be achieved efficiently. Reliability of error-related brain measures will vary as a function of the number of error trials and the number of participants included in the averages. Unfortunately, systematic investigations of the number of events and participants required to achieve stability in error-related processing are sparse, and none have addressed variability in sample size. Our goal here is to provide data compiled from a large sample of healthy participants (n = 180) performing a Go/NoGo task, resampled iteratively to demonstrate the relative stability of measures of error-related brain activity given a range of sample sizes and event numbers included in the averages. We examine ERP measures of error-related negativity (ERN/Ne) and error positivity (Pe), as well as event-related fMRI measures locked to false alarms. We find that achieving stable estimates of ERP measures required four to six error trials and approximately 30 participants; fMRI measures required six to eight trials and approximately 40 participants. Fewer trials and participants were required for measures where additional data reduction techniques (i.e., principal component analysis and independent component analysis) were implemented. Ranges of reliability statistics for various sample sizes and numbers of trials are provided. We intend this to be a useful resource for those planning or evaluating ERP or fMRI investigations with tasks designed to measure error-processing.

Background: Implicit theory of mind (iToM) is part of early social development (Schneider et al, 2012). It is crucial for building sensitivity to the other person or event (Apperly and Butterfill, 2009) and for tracking the other’s mental states. This process occurs without conscious awareness (Low and Perner, 2012). Measuring iToM may be important for understanding and rehabilitating social cognitive impairments in people with schizophrenia. The Social Attribution Task–Multiple Choice (SAT-MC), which was first developed for studying people with autism, has been successfully employed to distinguishing individuals with schizophrenia (SZ) from healthy controls (HC) in iToM in western countries (Bell et al, 2010). Because it uses geometric shapes enacting a social drama, the stimuli are nonverbal and does not include culturally loaded materials compared to other social cognition measures. We therefore hypothesized that the SAT-MC would be valid for use in schizophrenia research across cultures.

Background: Emerging research highlights the potential cognitive benefits of physical fitness programs for schizophrenia. Physical exercise (PE) is a safe, nonstigmatizing, and side effect-free intervention that has the potential to mitigate neurocognitive dysfunction in psychosis. To date, only two recent studies have explored the possibility of combining PE and cognitive training therapy (CT). While both studies found a signal showing that combining PE and CT may improve cognition more than CT alone, the conclusions were limited by lack of randomization, no examination of biological factors, no study arm with PE only, low power due to small sample size (N < 22), or significant attrition during the physical exercise intervention (i.e., only 75% completed the PE regimen). Methods: In our randomized pilot with 82 outpatients, we examined the individual and synergistic effects of PE and/or CT using treatments designed to improve motivation for treatment and retain patients for the entire PE (and CT) intervention. This 3-arm study employed a self-determined PE regimen intended to improve motivation for exercising and neurofeedback-aided CT that monitored a biophysiologic gauge of motivation to maximize cognitive gains. Participants were allocated to 18 hours of either: (A) PE regimen where patients chose from a menu of activities for 12 weeks with each activity designed so participants would reach volitional exhaustion—a commonly accepted physiological gauge of strenuous exercise—at least twice per week; (B) tablet-based neurofeedback CT focused on processing speed and working memory, or (C) a combination of PE and CT, matched for total duration and treatment time. Assessments of cognition and symptoms were conducted at baseline, post (3 months), and follow-up (5 montha). Results: At post, all three groups showed significant improvements in working memory, with the PE group surpassing the other two in working memory and processing speed improvements. However, at 2-month follow-up, gains in the PE only group disappeared, and it was the PE+CT group that showed significant improvements in both cognition and negative symptoms. Notably, attrition for all three groups was only 4%–7% and even those with low baseline motivation attended as many sessions as those with high motivation while both saw improvements in cognition and negative symptoms. Conclusion: This pilot is the first study to show that combining PE and CT leads to lasting effects that are superior to those of either intervention alone. Moreover, our approach to PE and CT was well tolerated, and the low dropout rate may have further maximized the benefits of both types of interventions.

Background: Social cognitive deficits play an important role in social functioning in adults with established psychosis (schizophrenia), young adults recently diagnosed with schizophrenia in the last 2 years (first episode psychosis; FEP), and teenagers at clinical high risk for developing psychosis (CHR). In particular, the ability to infer other people’s mental states has been shown to be compromised in those with psychosis, albeit less so in earlier stages. Recent studies have shown that processing speed (PS) may be upstream to social cognitive abilities in psychosis. If such were the case, remediating PS may in turn have beneficial effects on social cognition. This study examined whether improving PS would lead to subsequent improvements in social cognition in individuals with schizophrenia, FEP, and/or CHR. We examined whether (a) improving PS was related to improvements in social cognition, and (b) if so, whether these social cognitive improvements would in turn lead to fewer symptoms and better social function.

Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE) - a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) (http://fcon-1000.projects. nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies. © 2014 Macmillan Publishers Limited.

Background The Semantic Object Retrieval Task (SORT) requires participants to indicate whether word pairs recall a third object. Schizophrenia individuals (SZ) tend to report associations between nonassociated word pairs; this overretrieval is related to formal thought disorder (FTD). Since semantic memory impairments and psychosis are also found in bipolar disorder (BP), we examined whether SORT impairments and their relationship to symptoms are also present in BP. Methods Participants ( n = 239; healthy control subjects [HC] = 133; BP=32; SZ=74) completed SORT while undergoing functional magnetic resonance imaging (fMRI) scanning. Results Retrieval accuracy negatively correlated with negative symptoms and no-retrieval accuracy negatively correlated with FTD severity in SZ but not BP. Retrieval versus no-retrieval trials activated a distributed fronto-parieto-temporal network; bilateral inferior parietal lobule (IPL) activity was larger in HC versus SZ and HC versus BP, with no difference in SZ versus BP. Right IPL activity positively correlated with positive and general psychosis symptoms in SZ but not BP. Conclusions SZ reported more associations between unrelated word pairs than HC; this overretrieval increased with FTD severity. Schizophrenia individuals were also more likely to fail to find associations between related word pairs; this underretrieval increased with negative symptom severity. fMRI symptom correlations in IPL in SZ are consistent with arguments that IPL abnormality relates to loosening of associations in SZ. By comparison, BP showed intermediate impairments on SORT, uncorrelated with symptoms, suggesting that the relationship between SORT performance, fMRI activity, and psychotic symptoms is schizophrenia-specific.

(2011). Effect of Exercise Training on Hippocampal Volume in Humans. Research Quarterly for Exercise and Sport: Vol. 82, No. 3, pp. 585-591.

Autism spectrum disorders (ASDs) are characterized by deficits in social and communication processes. Recent data suggest that altered functional connectivity (FC), i.e. synchronous brain activity, might contribute to these deficits. Of specific interest is the FC integrity of the default mode network (DMN), a network active during passive resting states and cognitive processes related to social deficits seen in ASD, e.g. Theory of Mind. We investigated the role of altered FC of default mode sub-networks (DM-SNs) in 16 patients with high-functioning ASD compared to 16 matched healthy controls of short resting fMRI scans using independent component analysis (ICA). ICA is a multivariate data-driven approach that identifies temporally coherent networks, providing a natural measure of FC. Results show that compared to controls, patients showed decreased FC between the precuneus and medial prefrontal cortex/anterior cingulate cortex, DMN core areas, and other DM-SNs areas. FC magnitude in these regions inversely correlated with the severity of patients' social and communication deficits as measured by the Autism Diagnostic Observational Schedule and the Social Responsiveness Scale. Importantly, supplemental analyses suggest that these results were independent of treatment status. These results support the hypothesis that DM-SNs under-connectivity contributes to the core deficits seen in ASD. Moreover, these data provide further support for the use of data-driven analysis with resting-state data for illuminating neural systems that differ between groups. This approach seems especially well suited for populations where compliance with and performance of active tasks might be a challenge, as it requires minimal cooperation.

Schizophrenia is a complex genetic disorder, with multiple putative risk genes and many reports of reduced cortical gray matter. Identifying the genetic loci contributing to these structural alterations in schizophrenia (and likely also to normal structural gray matter patterns) could aid understanding of schizophrenia's pathophysiology. We used structural parameters as potential intermediate illness markers to investigate genomic factors derived from single nucleotide polymorphism (SNP) arrays.We used research quality structural magnetic resonance imaging (sMRI) scans from European American subjects including 33 healthy control subjects and 18 schizophrenia patients. All subjects were genotyped for 367 SNPs. Linked sMRI and genetic (SNP) components were extracted to reveal relationships between brain structure and SNPs, using parallel independent component analysis, a novel multivariate approach that operates effectively in small sample sizes.We identified an sMRI component that significantly correlated with a genetic component (r = -.536, p.00005); components also distinguished groups. In the sMRI component, schizophrenia gray matter deficits were in brain regions consistently implicated in previous reports, including frontal and temporal lobes and thalamus (p.01). These deficits were related to SNPs from 16 genes, several previously associated with schizophrenia risk and/or involved in normal central nervous system development, including AKT, PI3K, SLC6A4, DRD2, CHRM2, and ADORA2A.Despite the small sample size, this novel analysis method identified an sMRI component including brain areas previously reported to be abnormal in schizophrenia and an associated genetic component containing several putative schizophrenia risk genes. Thus, we identified multiple genes potentially underlying specific structural brain abnormalities in schizophrenia.

Formal thought disorder (FTD) is a debilitating symptom that affects 90 percent of schizophrenic patients and undermines a patient's capacity to communicate. This chapter reviews the clinical and cognitive symptoms related to (FTD), the evidence available that supports different aspects of semantic impairments in FTD, and recent data suggesting that a far-spreading activation theory within the semantic system is the core, underlying deficit resulting in FTD. The Thought, Language and Communication Scale (TLC) provided the first standardized tool that quantified positive FTD severity which in turn enhanced FTD research. An early neuroimaging study used positron emission tomography (PET) to evaluate the relationship between regional blood flow and symptomatology of 30 schizophrenia patients during a resting state. Based on the suggested role of semantic memory dysfunction in the pathophysiology of FTD, the chapter examines whether a specific semantic memory operation is more relevant to this symptomatology.

The recall of an object from features is a specific operation in semantic memory in which the thalamus and pre-supplementary motor area (pre-SMA) are integrally involved. Other higher-order semantic cortices are also likely to be involved. We used the object-recall-from-features paradigm, with more sensitive scanning techniques and larger sample size, to replicate and extend our previous results. Eighteen right-handed healthy participants performed an object-recall task and an association semantic task, while undergoing functional magnetic resonance imaging. During object-recall, subjects determined whether words pairs describing object features combined to recall an object; during the association task they decided if two words were related. Of brain areas specifically involved in object recall, in addition to the thalamus and pre-SMA, other regions included the left dorsolateral prefrontal cortex, inferior parietal lobule, and middle temporal gyrus, and bilateral rostral anterior cingulate and inferior frontal gyri. These regions are involved in semantic processing, verbal working memory and response-conflict detection and monitoring. The thalamus likely helps to coordinate activity of these different brain areas. Understanding the circuit that normally mediates this process is relevant for schizophrenia, where many regions in this circuit are functionally abnormal and semantic memory is impaired.

Background The neural basis of formal thought disorder (FTD) is unknown. An influential theory is that FTD results from impaired semantic memory processing. We explored the neural correlates of semantic memory retrieval in schizophrenia using an imaging task assessing semantic object recall. Method Sixteen healthy control subjects and sixteen schizophrenia patients whose FTD symptoms were measured with the Thought Disorder Index completed a verbal object-recall task during functional magnetic resonance imaging. Participants viewed two words describing object features that either evoked (object recall) or did not evoke a semantic concept. Results Schizophrenia patients tended to overrecall objects for feature pairs that did not describe the same object. Functionally, rostral anterior cingulate cortex (ACC) activation in patients positively correlated with FTD severity during both correct recalled and overrecalled trials. Compared with control subjects, during object recalling, patients overactivated bilateral ACC, temporooccipital junctions, temporal poles and parahippocampi, right inferior frontal gyrus, and dorsolateral prefrontal cortex, but underactivated inferior parietal lobules. Conclusions Our results support impaired semantic memory retrieval as underlying FTD pathophysiology. Schizophrenia patients showed abnormal activations of brain areas involved in semantic memory, verbal working memory, and initiation and suppression of conflicting responses, which were associated with semantic overrecall and FTD.