Intrinsic neural timescales in autism spectrum disorder and schizophrenia. A replication and direct comparison study.

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 persons diagnosed with autism spectrum disorder (ASD) and schizophrenia (SZ), though INT are, overall, shorter in both patient groups. In the present study, we aimed to replicate previously reported group differences by comparing INT of TD to ASD and SZ. We partially 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. 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. Previously reported correlations between INT and symptom severity were not replicated in the current project. Our findings serve to circumscribe the brain areas that can potentially play a determinant role in observed sensory peculiarities in ASD and SZ.

Factors Related to Passive Social Withdrawal and Active Social Avoidance in Schizophrenia.

ABSTRACT: Social withdrawal in schizophrenia may be a result of "passive" motivation (reduced drive to engage) or "active" motivation (increased drive to avoid). We conducted a cross-sectional, between-subjects study using self-report measures and social cognition tasks to evaluate the relationships between motivational subtypes, social abilities, and social functioning in schizophrenia spectrum (n = 52, ages 19-34). Regression models showed significant differences in passive and active withdrawal. Passive, but not active, motivation predicted social functioning as measured by a clinical interview. This suggests that motivation, especially passive type, plays an important role in social withdrawal in schizophrenia. However, on a self-report measure of social functioning, neither passive nor active motivation predicted outcomes, suggesting a potential disconnect between observer versus self-report measures when assessing social motivation. Furthermore, performance on tasks of social abilities did not predict motivation, which supports the idea that motivation is distinct from social ability and should be specifically addressed in treatment.

Personality as a mediator of autistic traits and internalizing symptoms in two community samples.

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.

Atypical Dynamic Functional Network Connectivity State Engagement during Social-Emotional Processing in Schizophrenia and Autism.

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.

Predictors of social functioning and quality of life in schizophrenia and autism spectrum disorder.

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; p<0.01), and only in ASD, IQ predicted QL, the higher the IQ the higher QL (t = 2.1; p<0.05). In ASD only, negative symptoms predicted SF, the greater negative symptoms the worse SF (t=-3.45; p<0.01), and communication deficits predicted SF, the higher deficits, the higher SF (t = 2.9; p<0.01). Negative symptoms but not empathy were the shared predictors of functioning across ASD and SZ.

Default mode network modulation by mentalizing in young adults with autism spectrum disorder or schizophrenia.

Schizophrenia and autism spectrum disorder (ASD) are nosologically distinct neurodevelopmental disorders with similar deficits in social cognition, including the ability to form mental representations of others (i.e., mentalizing). However, the extent of patient deficit overlap in underlying neural mechanisms is unclear. Our goal was to examine deficits in mentalizing task-related (MTR) activity modulation in schizophrenia and ASD and the relationship of such deficits with social functioning and psychotic symptoms in patients. Adults, ages 18-34, diagnosed with either ASD or schizophrenia, and typically developed controls (n = 30/group), performed an interactive functional MRI Domino task. Using independent component analysis, we analyzed game intervals known to stimulate mentalizing in the default mode network (DMN), i.e., medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC), precuneus, and temporoparietal junction (TPJ), for group differences in MTR activity and associations between MTR activity and social and psychosis measures. Compared to controls, both schizophrenia and ASD groups showed MTR activity deficits in PCC and TPJ. In TPJ and MPFC, MTR activity modulation was associated with social communication impairments only in ASD. In precuneus, MTR activity was associated with increased self-reported fantasizing only in schizophrenia. In schizophrenia, we found no indication of over-mentalizing activity or an association between MTR activity and psychotic symptoms. Results suggest shared neural deficits between ASD and schizophrenia in mentalizing-associated DMN regions; however, neural organization might correspond to different dimensional social deficits. Our results therefore indicate the importance of examining both categorical-clinical diagnosis and social functioning dimensional constructs when examining neural deficits in schizophrenia and ASD.

Dynamic functional connectivity in schizophrenia and autism spectrum disorder: Convergence, divergence and classification.

BACKGROUND: Over the recent years there has been a growing debate regarding the extent and nature of the overlap in neuropathology between schizophrenia (SZ) and autism spectrum disorder (ASD). Dynamic functional network connectivity (dFNC) is a recent analysis method that explores temporal patterns of functional connectivity (FC). We compared resting-state dFNC in SZ, ASD and healthy controls (HC), characterized the associations between temporal patterns and symptoms, and performed a three-way classification analysis based on dFNC indices. METHODS: Resting-state fMRI was collected from 100 young adults: 33 SZ, 33 ASD, 34 HC. Independent component analysis (ICA) was performed, followed by dFNC analysis (window = 33 s, step = 1TR, k-means clustering). Temporal patterns were compared between groups, correlated with symptoms, and classified via cross-validated three-way discriminant analysis. RESULTS: Both clinical groups displayed an increased fraction of time (FT) spent in a state of weak, intra-network connectivity [p < .001] and decreased FT in a highly-connected state [p < .001]. SZ further showed decreased number of transitions between states [p < .001], decreased FT in a widely-connected state [p < .001], increased dwell time (DT) in the weakly-connected state [p < .001], and decreased DT in the highly-connected state [p = .001]. Social behavior scores correlated with DT in the widely-connected state in SZ [r = 0.416, p = .043], but not ASD. Classification correctly identified SZ at high rates (81.8%), while ASD and HC at lower rates. CONCLUSIONS: Results indicate a severe and pervasive pattern of temporal aberrations in SZ (specifically, being "stuck" in a state of weak connectivity), that distinguishes SZ participants from both ASD and HC, and is associated with clinical symptoms.

Measuring theory of mind in schizophrenia research: Cross-cultural validation.

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 < 0.001), and significantly correlated with other social cognition tasks (Hinting and Reading the Mind in the Eyes Test) among Korean and North American patients. 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.

Cognitive remediation for adults with schizophrenia: Does age matter?

Cognitive remediation (CR), a novel behavioral intervention designed to improve cognitive deficits through repeated task practice and/or strategy acquisition has gained increasing empirical support in people with schizophrenia, but substantial individual differences in treatment response remain (Wykes et al., 2011). The role of age on response to CR in schizophrenia remains understudied. We evaluated the role of three age ranges in treatment response to CR relative to a closely-matched computer skills control intervention in a blinded, randomized control trial (RCT) with 112 adults with schizophrenia divided into three groups: an early-stage group (ES; 25 years or younger, mean=3.4 years of illness; n=45), an early-chronic group (EC; 26-39, mean=7.6 years of illness; n=31) and a late-chronic group (LC; 40 and over, mean=18.2 years of illness; n=36). With respect to cognitive outcomes, early-stage and early-chronic individuals with schizophrenia showed greater improvement in response to CR on a working memory measure at a trend level, relative to late-chronic clients. These findings were confirmed in analyses of a subsample of clients who received an adequate dose of treatment. These findings emphasize the need for adaptations of currently-existing CR programs to more effectively address the needs of older client populations.

Baseline Predictors for Success Following Strategy-Based Cognitive Remediation Group Training in Schizophrenia.

Our aim was to examine predictive variables associated with the improvement in cognitive, clinical, and functional outcomes after outpatient participation in REPYFLEC strategy-based Cognitive Remediation (CR) group training. In addition, we investigated which factors might be associated with some long-lasting effects at 6 months' follow-up. Predictors of improvement after CR were studied in a sample of 29 outpatients with schizophrenia. Partial correlations were computed between targeted variables and outcomes of response to explore significant associations. Subsequently, we built linear regression models for each outcome variable and predictors of improvement. The improvement in negative symptoms at posttreatment was linked to faster performance in the Trail Making Test B. Disorganization and cognitive symptoms were related to changes in executive function at follow-up. Lower levels of positive symptoms were related to durable improvements in life skills. Levels of symptoms and cognition were associated with improvements following CR, but the pattern of resulting associations was nonspecific.

Social skills training and computer-assisted cognitive remediation in schizophrenia.

A growing body of research shows that cognitive remediation (COG REM), consisting of drill-and-practice and/or strategy training in neurocognitive functions, produces moderate improvements in neurocognition. These improvements generalize to functioning when COG REM is provided with other rehabilitation interventions (Wykes et al., 2011). The number of studies using COG REM as an adjunct to other behavioral-based rehabilitation interventions however remains small and consists of widely varying interventions with few active control conditions. This study compared the effects of an extended (6-month), standardized, computer-assisted cognitive remediation intervention, administered along with a standardized program of social skills-training (SST), with those of an active control condition that included participation in the same SST program and a computer skills training program (Computer Skills). Sixty-four individuals with schizophrenia recruited from two treatment sites were randomly assigned to one of two conditions and were assessed by blinded raters on neurocognitive measures, performance-based measures of social skill, and ratings of psychosocial function before and after treatment. Results revealed that the COG REM group improved significantly more in attention, working memory, and empathy than the Computer Skills group, but there were no differences between groups on other measures of psychosocial functioning or skills. Taken together, these findings suggest that COG REM used in the context of other evidence-based psychosocial interventions (SST) improves working memory in schizophrenia and suggests that this effect may generalize to improved empathy.

Increasing stimulus duration can normalize late-positive event related potentials in people with schizophrenia: Possible implications for understanding cognitive deficits.

This study determined whether increasing stimulus duration for patients with schizophrenia normalized late Event Related Potentials (ERPs) associated with modulation of response to emotion-evoking stimuli. These ERPs are decreased in patients versus healthy controls when both view stimuli of the same duration. Subjects viewed pictures of hands and judged whether the events depicted were painful or non-painful. Pictures were presented to patients for 500 or 800 ms and to healthy controls for 200 or 500 ms. Participants were 19 adult outpatients meeting DSM-IV criteria for schizophrenia or schizoaffective disorder and 18 healthy controls, as assessed by the Structured Clinical Interview. ERPs to neutral stimuli during a 350-900 ms window following stimulus onset were subtracted from ERPs during this same response window to pain stimuli. The area under this difference wave reflected the degree of pain-related positivity and was the dependent measure for analysis. Patient late-positive ERP responses following 500 and 800 ms stimuli were highly similar to responses in healthy controls following 200 and 500 ms stimuli respectively. Patients and controls differed significantly when responses to 500 ms stimuli were compared. People with schizophrenia are known to process information more slowly than healthy people. Our results indicate that slowed early processing of sensory input may limit engagement of higher cognitive and regulatory processes in patients with schizophrenia. This may be one reason that self-regulation is compromised in patients, and may help explain why measures of slowed information processing account for so much variance in other cognitive deficits in schizophrenia.

Neural activation abnormalities during self-referential processing in schizophrenia: an fMRI study.

Impairments in self-awareness contribute to disability in schizophrenia. Studies have revealed activation abnormalities in schizophrenia in cortical midline structures associated with self-reference. We used functional magnetic resonance imaging to compare activation throughout the brain in people with schizophrenia and healthy controls (Kelly et al., 2002) while they indicated whether trait adjectives described attributes of themselves, their mother or a former president of the United States. Blood oxygenation level dependent signal in each condition was compared to resting fixation. Patients were less likely and slower to endorse positive self-attributes, and more likely and quicker to endorse negative self-attributes than controls. Activation abnormalities reported previously in cortical midline structures were again noted. In addition, patients showed greater signal increases in frontal, temporal gyri and insula, and smaller signal decreases in posterior regions than healthy controls when thinking about themselves. Group differences were less evident when subjects were thinking about their mothers and tended to go in the opposite direction when thinking about a president. Many of the areas showing abnormality have been shown in other studies to differ between patients and controls in structure and with other activation paradigms. We suggest that general neuropathology in schizophrenia alters the neural system configurations associated with self-representation.

Emotion self-regulation and empathy depend upon longer stimulus exposure.

Observation of others in pain induces positive elevation (pain effect) in late event-related potentials (ERP). This effect is associated with top-down attention regulating processes. It has previously been shown that stimulus exposure duration can affect top-down attentional modulation of response to threat-related stimuli. We investigated the effect of exposure duration on ERP response to others in pain. Two late ERP components, P3 and late positive potentials (LPP), from 18 healthy people were measured while they viewed pictures of hands in painful or neutral situations for either 200 or 500 ms, during two task conditions (pain judgment and counting hands). P3 and LPP pain effects during the pain judgment condition were significantly greater with 500 ms than 200 ms stimulus presentation. Ours is the first study to suggest that engagement of empathy-related self-regulatory processes reflected in late potentials requires longer exposure to the pain-related stimulus. Although this is important information about the relationship between early sensory and subsequent brain processing, and about engagement of self-regulatory processes, the neural basis of this time-dependence remains unclear. It might be important to investigate the relationship between stimulus duration and empathic response in clinical populations where issues of self-regulation, empathic response and speed of information processing exist.

Factor structure of social cognition in schizophrenia: is empathy preserved?

Social cognitive impairments are core features of schizophrenia and are closely associated with poor functional outcome. This study sought to identify specific aspects of social cognition and their relationships to measures of social function, quality of life, and neurocognition. Principal component analysis was performed using social cognitive measures in patients with schizophrenia and healthy matched controls and revealed three factors: Interpersonal Discomfort, Basic Social Cognition, and Empathy. Patients had higher scores on Interpersonal Discomfort and lower scores on Basic Social Cognition than controls, but the two groups were the same on Empathy. Lower social performance was significantly correlated with poor Basic Social Cognition in patients and with high Interpersonal Discomfort in controls. While neurocognition was significantly associated with Basic Social Cognition in both groups, it was not associated with Empathy. Social cognitive interventions should emphasize improving basic social cognitive processing deficits, managing Interpersonal Discomfort, and utilizing preserved capacity for empathy as a potential strength in social interactions.

Social cognitive impairments and negative symptoms in schizophrenia: are there subtypes with distinct functional correlates?

Social cognitive impairments and negative symptoms are core features of schizophrenia closely associated with impaired community functioning. However, little is known about whether these are independent dimensions of illness and if so, whether individuals with schizophrenia can be meaningfully classified based on these dimensions (SANS) and potentially differentially treated. Five social cognitive measures plus Scale for the Assessment of Negative Symptoms (SANS) and Positive and Negative Syndrome Scale (PANSS) scores in a sample of 77 outpatients produced 2 distinct factors--a social cognitive factor and a negative symptom factor. Factor scores were used in a cluster analysis, which yielded 3 well-defined groupings--a high negative symptom group (HN) and 2 low negative symptom groups, 1 with higher social cognition (HSC) and 1 with low social cognition (LSC). To make these findings more practicable for research and clinical settings, a rule of thumb for categorizing using only the Mayer-Salovey-Caruso Emotional Intelligence Test and PANSS negative component was created and produced 84.4% agreement with the original cluster groups. An additional 63 subjects were added to cross validate the rule of thumb. When samples were combined (N = 140), the HSC group had significantly better quality of life and Global Assessment of Functioning (GAF) scores, higher rates of marriage and more hospitalizations. The LSC group had worse criminal and substance abuse histories. With 2 common assessment instruments, people with schizophrenia can be classified into 3 subgroups that have different barriers to community integration and could potentially benefit from different treatments.

Empathy in electrodermal responsive and nonresponsive patients with schizophrenia.

Skin conductance response (SCR) to emotion-evoking stimuli has in previous studies suggested the existence of two subgroups of schizophrenia patients. One is characterized by absent SCR and the other by heightened or non-habituating SCR. These subgroups have also been shown to differ in symptoms, prognosis and social integration. The present project compared social cognition in the two subgroups. SCR from 28 patients with schizophrenia and 24 matched healthy controls was measured while they watched emotion-evoking and neutral video tapes. Assessments of symptoms, neurocognition, social cognition, and social function were also performed. Event related potentials (ERP) were recorded in response to pictures of people experiencing pain or not. Subjects were divided into "SCR non-responder" and "SCR responder" groups based on SCR frequency. Schizophrenia SCR responders had significantly higher self-reported personal distress in response to others in distress and lower P300 ERP responses to others in pain than schizophrenia SCR non-responders and healthy controls. SCR responsiveness is a potential marker of subgroups of patients with schizophrenia that differ in pathophysiology, function and prognosis.

Successful computer-based visual training specifically predicts visual memory enhancement over verbal memory improvement in schizophrenia.

We investigated whether improved early visual processing on cognitive remediation (CR) exercises generalizes to visual and auditory learning and information manipulation in schizophrenia. Fourteen participants received neuropsychological testing before and after CR consisting of visual, auditory and cognitive control training. Achievement on visual training exercises was strongly and significantly correlated with improved visual learning, but not improved verbal learning or increased ability to manipulate visual information. Improvement in training, not training time, predicted cognitive gain. Implications for improving cognitive outcomes from CR include ensuring the trained task is learned and providing exercises of multiple modalities.