Neurophysiological indices of face processing in people with psychosis and their siblings: An event-related potential study.

People with schizophrenia experience difficulties with social interactions. One contributor to these social deficits is dysfunction in processing facial features and facial emotional expressions. However, it is not known whether face processing deficits are evident in those with other psychotic disorders or in those genetically at-risk for psychosis (i.e., first-degree relatives of those with psychosis). We assessed event-related potentials (ERPs) during a facial and emotion processing task in 100 people with a diagnosis of schizophrenia or another psychotic condition (PSY), 32 of their siblings (SIB) and 45 healthy comparison participants (CTL). In separate blocks, participants identified the sex (male or female) or emotion (happy, angry, neutral) of faces. In a comparison condition, participants indicated whether buildings had one or two floors. ERPs were examined in two stages. First, we compared ERPs across the emotion, sex and building identification conditions. Second, we compared ERPs among the three different facial emotions. PSY exhibited significantly lower amplitudes over parietal-occipital regions between 111 and 151 ms when viewing faces but not buildings than CTL, consistent with a face-selective N170 ERP component deficit. The SIB group was intermediate for faces, but not significantly different than PSY or CTL. During emotion identification, all three groups showed increased N170 amplitudes to angry and happy versus neutral expressions, with no group differences. In follow up analyses, we examined differences between PSY with or without affective psychosis, and differences between those with schizophrenia versus other psychotic disorders; there were no significant differences in these analyses. Face processing deficits assessed with ERPs were observed in a group of diverse psychotic disorders, though deficits were not seen to be modulated by facial emotion expression. Additionally, N170 deficits are not evident in siblings of those with PSY.

Clarifying directional dependence among measures of early auditory processing and cognition in schizophrenia: leveraging Gaussian graphical models and Bayesian networks.

BACKGROUND: Research using latent variable models demonstrates that pre-attentive measures of early auditory processing (EAP) and cognition may initiate a cascading effect on daily functioning in schizophrenia. However, such models fail to account for relationships among individual measures of cognition and EAP, thereby limiting their utility. Hence, EAP and cognition may function as complementary and interacting measures of brain function rather than independent stages of information processing. Here, we apply a data-driven approach to identifying directional relationships among neurophysiologic and cognitive variables. METHODS: Using data from the Consortium on the Genetics of Schizophrenia 2, we estimated Gaussian Graphical Models and Bayesian networks to examine undirected and directed connections between measures of EAP, including mismatch negativity and P3a, and cognition in 663 outpatients with schizophrenia and 630 control participants. RESULTS: Chain structures emerged among EAP and attention/vigilance measures in schizophrenia and control groups. Concerning differences between the groups, object memory was an influential variable in schizophrenia upon which other cognitive domains depended, and working memory was an influential variable in controls. CONCLUSIONS: Measures of EAP and attention/vigilance are conditionally independent of other cognitive domains that were used in this study. Findings also revealed additional causal assumptions among measures of cognition that could help guide statistical control and ultimately help identify early-stage targets or surrogate endpoints in schizophrenia.

Social cognition and social motivation in schizophrenia and bipolar disorder: are impairments linked to the disorder or to being socially isolated?

BACKGROUND: People with schizophrenia on average are more socially isolated, lonelier, have more social cognitive impairment, and are less socially motivated than healthy individuals. People with bipolar disorder also have social isolation, though typically less than that seen in schizophrenia. We aimed to disentangle whether the social cognitive and social motivation impairments observed in schizophrenia are a specific feature of the clinical condition v. social isolation generally. METHODS: We compared four groups (clinically stable patients with schizophrenia or bipolar disorder, individuals drawn from the community with self-described social isolation, and a socially connected community control group) on loneliness, social cognition, and approach and avoidance social motivation. RESULTS: Individuals with schizophrenia (n = 72) showed intermediate levels of social isolation, loneliness, and social approach motivation between the isolated (n = 96) and connected control (n = 55) groups. However, they showed significant deficits in social cognition compared to both community groups. Individuals with bipolar disorder (n = 48) were intermediate between isolated and control groups for loneliness and social approach. They did not show deficits on social cognition tasks. Both clinical groups had higher social avoidance than both community groups. CONCLUSIONS: The results suggest that social cognitive deficits in schizophrenia, and high social avoidance motivation in both schizophrenia and bipolar disorder, are distinct features of the clinical conditions and not byproducts of social isolation. In contrast, differences between clinical and control groups on levels of loneliness and social approach motivation were congruent with the groups' degree of social isolation.

Stress-related gene regulation: Do isolated and connected individuals differ?

BACKGROUND: Social isolation and loneliness (known as social disconnection, collectively) lead to serious downstream health effects, including shortening of lifespan and higher risk for cardiac disease. We must better understand how isolation and loneliness lead to these negative health outcomes. Previous literature has demonstrated that social motivation and social ability are contributors to the likelihood of social isolation and loneliness. We examined the effect of the above social factors on immune gene expression in socially-connected and -isolated individuals. METHODS: Recruitment occurred via two online advertisements, one for socially isolated individuals and another for general research participants. Participants (n = 102) were separated into groups (isolated versus connected) based on which ad they responded to, and provided data on isolation, loneliness, social motivation, and social ability. The Conserved Transcriptional Response to Adversity (CTRA) stress gene regulation program was assessed with genome-wide transcriptional profiling. RESULTS: CTRA gene expression patterns were reversed between connected and isolated groups across several variables. Social isolation was associated with higher CTRA levels in the connected group, but lower levels in the isolated group. Social approach was associated with lower CTRA levels in the connected group, but higher in the isolated group, and the converse was true for social avoidance. CTRA levels were minimally affected by social ability measures. CONCLUSION: Prior work on social isolation and loneliness has focused on loneliness and has identified many negative downstream health effects. In this study we demonstrate that objective social isolation may not be associated with the same negative downstream health effects, and in fact, social interaction may be more stressful than social isolation for some socially-isolated individuals.

The impact of psychological strengths on Veteran populations' mental health trajectories during the COVID-19 pandemic.

PURPOSE: Mental health trajectories during the COVID-19 pandemic have been examined in Veterans with tenuous social connections, i.e., those with recent homelessness (RHV) or a psychotic disorder (PSY), and in control Veterans (CTL). We test potential moderating effects on these trajectories by psychological factors that may help individuals weather the socio-emotional challenges associated with the pandemic (i.e., 'psychological strengths'). METHODS: We assessed 81 PSY, 76 RHV, and 74 CTL over 5 periods between 05/2020 and 07/2021. Mental health outcomes (i.e., symptoms of depression, anxiety, contamination concerns, loneliness) were assessed at each period, and psychological strengths (i.e., a composite score based on tolerance of uncertainty, performance beliefs, coping style, resilience, perceived stress) were assessed at the initial assessment. Generalized models tested fixed and time-varying effects of a composite psychological strengths score on clinical trajectories across samples and within each group. RESULTS: Psychological strengths had a significant effect on trajectories for each outcome (ps < 0.05), serving to ameliorate changes in mental health symptoms. The timing of this effect varied across outcomes, with early effects for depression and anxiety, later effects for loneliness, and sustained effects for contamination concerns. A significant time-varying effect of psychological strengths on depressive symptoms was evident in RHV and CTL, anxious symptoms in RHV, contamination concerns in PSY and CTL, and loneliness in CTL (ps < 0.05). CONCLUSION: Across vulnerable and non-vulnerable Veterans, presence of psychological strengths buffered against exacerbations in clinical symptoms. The timing of the effect varied across outcomes and by group.

The relationship between sex and functional outcome in first-episode schizophrenia: the role of premorbid adjustment and insight.

BACKGROUND: Studies that examined sex differences in first-episode patients consistently show that males compared to females have poor premorbid adjustment, earlier age of onset, worse clinical characteristics, and poorer outcomes. However, little is known about potential mediators that could explain these sex differences. METHODS: Our sample consisted of 137 individuals with first episode schizophrenia (males, n = 105; 77%) with a mean age of 22.1(s.d. = 4.1) years and mean education of 12.5(s.d. = 1.7) years. At entry, patients were within 2 years of their first psychotic episode onset. Baseline assessments were conducted for premorbid adjustment, symptoms, cognitive functioning, insight, and at 6-months for role and social functioning. RESULTS: Males as compared to females had poorer premorbid adjustment across several key developmental periods (p < 0.01), an earlier age of onset [M = 20.3(3.3) v. 22.8(5.6), p = 0.002], more negative symptoms (p = 0.044), poorer insight (p = 0.031), and poorer baseline and 6-month role (p = 0.002) and social functioning (p = 0.034). Several of these variables in which males showed impairment were significant predictors of 6-month role and social functioning. Premorbid adjustment and insight mediated the relationship between sex and role and social functioning at 6-months, but not negative symptoms. DISCUSSION: Males compared to females were at lower levels across several key premorbid and clinical domains which are strongly associated with functional outcome supporting the hypothesis that males might have a more disabling form of schizophrenia. The relationship between sex with role and social functioning was mediated through premorbid adjustment and insight suggesting pathways for understanding why females might have a less disabling form of schizophrenia.

Linking social motivation, general motivation, and social cognition to interpersonal functioning in schizophrenia: insights from exploratory graph analysis.

Motivation in general, and social motivation in particular are important for interpersonal functioning in individuals with schizophrenia. Still, their roles after accounting for social cognition, are not well understood. The sample consisted of 147 patients with schizophrenia. General motivation was measured using the Behavioral inhibition/activation scale (BIS/BAS). Social motivation was measured by Passive social withdrawal and Active social avoidance items from PANSS. Interpersonal functioning was evaluated with Birchwood's Social Functioning Scale (SFS). We used Exploratory Graph Analysis for network estimation and community detection. Active social avoidance, passive social withdrawal, and social withdrawal/engagement (from SFS) were the most important nodes. In addition, three distinct communities were identified: Social cognition, Social motivation, and Interpersonal functioning. Notably, the BIS and BAS measures of general motivation were not part of any community. BAS showed stronger links to functioning than BIS. Passive social withdrawal was more strongly linked to interpersonal functioning than social cognitive abilities. Results suggest that social motivation, especially social approach, is more closely related to interpersonal functioning in schizophrenia than general motivation. In contrast, we found that general motivation was largely unrelated to social motivation. This pattern highlights the importance of type of motivation for understanding variability in interpersonal difficulties in schizophrenia.

Acceptability of a mobile sensing application to characterize community integration among homeless-experienced veterans.

Mobile sensing applications that collect active, Ecological Momentary Assessment data, and passive, Global Positioning System data provide reliable, longitudinal assessments of community integration. Ensuring their acceptability by vulnerable populations is warranted. Acceptability-related perceptions of a mobile sensing application were gathered via focus groups with homeless-experienced Veterans with serious mental illness (n = 19) and individual interviews with providers (n = 5) to inform subsequent application tailoring and testing. Rapid assessment generated structured summaries and matrix analyses integrated participant data. Active data collection was deemed noninvasive, with more concerns of passive data "ending up in the wrong hands." Providers recommended clear descriptions and promotion of choice to navigate privacy concerns and guardedness. Participants felt the application possessed clinical value for enhancing patient-provider interactions and community integration efforts. Overall, participants found application features acceptable and expressed Veterans' willingness to engage in research using mobile sensing technology. Recommendations to enhance acceptability are discussed.

Motivational and cognitive factors linked to community integration in homeless veterans: study 1 - individuals with psychotic disorders.

BACKGROUND: Little is known about the determinants of community integration (i.e. recovery) for individuals with a history of homelessness, yet such information is essential to develop targeted interventions. METHODS: We recruited homeless Veterans with a history of psychotic disorders and evaluated four domains of correlates of community integration: perception, non-social cognition, social cognition, and motivation. Baseline assessments occurred after participants were engaged in supported housing services but before they received housing, and again after 12 months. Ninety-five homeless Veterans with a history of psychosis were assessed at baseline and 53 returned after 12 months. We examined both cross-sectional and longitudinal relationships with 12-month community integration. RESULTS: The strongest longitudinal association was between a baseline motivational measure and social integration at 12 months. We also observed cross-sectional associations at baseline between motivational measures and community integration, including social, work, and independent living. Cross-lagged panel analyses did not suggest causal associations for the motivational measures. Correlations with perception and non-social cognition were weak. One social cognition measure showed a significant longitudinal correlation with independent living at 12 months that was significant for cross-lagged analysis, consistent with a causal relationship and potential treatment target. CONCLUSIONS: The relatively selective associations for motivational measures differ from what is typically seen in psychosis, in which all domains are associated with community integration. These findings are presented along with a partner paper (Study 2) to compare findings from this study to an independent sample without a history of psychotic disorders to evaluate the consistency in findings regarding community integration across projects.

Factors associated with recovery from homelessness among veterans in permanent supportive housing.

AIMS: We sought to identify person- and program-level factors distinguishing permanent supportive housing (PSH) residents with higher versus lower social integration; and higher versus lower instrumental functioning. METHODS: Among 60 PSH residents at Los Angeles' VA, surveys and medical records captured person-level factors. Using a median split, we dichotomized participants with higher versus lower social integration; and higher versus lower instrumental functioning. Recursive partitioning (RP) identified variables that best-differentiated these subgroups. Interviews with 26 participants captured their perceptions on social integration and instrumental functioning. RESULTS: Using RP, health-related quality of life, psychiatric symptoms and case management frequency best-differentiated the social integration subgroups. Few perceived that PSH affected social integration. RP did not yield a stable model to differentiate the instrumental functioning subgroups; participants perceived that PSH addressed most functional deficits. CONCLUSIONS: Services that enhance social integration may benefit PSH residents with poor health; existing services may adequately address instrumental functioning.

Motivational and cognitive factors linked to community integration in homeless veterans: Study 2 - clinically diverse sample.

BACKGROUND: In an initial study (Study 1), we found that motivation predicted community integration (i.e. functional recovery) 12 months after receiving housing in formerly homeless Veterans with a psychotic disorder. The current study examined whether the same pattern would be found in a broader, more clinically diverse, homeless Veteran sample without psychosis. METHODS: We examined four categories of variables as potential predictors of community integration in non-psychotic Veterans: perception, non-social cognition, social cognition, and motivation at baseline (after participants were engaged in a permanent supported housing program but before receiving housing) and a 12-month follow-up. A total of 82 Veterans had a baseline assessment and 41 returned for testing after 12 months. RESULTS: The strongest longitudinal association was between an interview-based measure of motivation (the motivation and pleasure subscale from the Clinical Assessment Interview for Negative Symptoms) at baseline and measures of social integration at 12 months. In addition, cross-lagged panel analyses were consistent with a causal influence of general psychiatric symptoms at baseline driving social integration at 12 months, and reduced expressiveness at baseline driving independent living at 12 months, but there were no significant causal associations with measures of motivation. CONCLUSIONS: The findings from this study complement and reinforce those in Veterans with psychosis. Across these two studies, our findings suggest that motivational factors are associated at baseline and at 12 months and are particularly important for understanding and improving community integration in recently-housed Veterans across psychiatric diagnoses.

Social cognition in schizophrenia.

Individuals with schizophrenia exhibit impaired social cognition, which manifests as difficulties in identifying emotions, feeing connected to others, inferring people's thoughts and reacting emotionally to others. These social cognitive impairments interfere with social connections and are strong determinants of the degree of impaired daily functioning in such individuals. Here, we review recent findings from the fields of social cognition and social neuroscience and identify the social processes that are impaired in schizophrenia. We also consider empathy as an example of a complex social cognitive function that integrates several social processes and is impaired in schizophrenia. This information may guide interventions to improve social cognition in patients with this disorder.

Exploring Community Integration Among Formerly Homeless Veterans in Project-Based Versus Tenant-Based Supportive Housing.

Community integration-an individual's embeddedness in his/her community-impacts mental and physical health. This study aimed to understand factors affecting community integration among Veterans in the Department of Housing and Urban Development-VA Supportive Housing (HUD-VASH) program. Semi-structured interviews and focus groups were conducted with HUD-VASH staff (n = 14) and persons residing in project-based (n = 9) and tenant-based (n = 9) housing at VA Greater Los Angeles. Participants identified neighborhood safety concerns as a limitation to community integration. Participants were reluctant to connect with HUD-VASH peers living nearby because they wanted to focus on their own recovery (e.g., from substance use); and many were dissatisfied with the location of their apartments. Staff valued community integration but saw it as secondary to housing retention. Increased access to safe neighborhoods (e.g., through relationship building with landlords) and the addition of staff dedicated to improving community integration (e.g., peer-support specialists) would enhance community integration in the HUD-VASH program.

Linking resting-state networks and social cognition in schizophrenia and bipolar disorder.

Individuals with schizophrenia and bipolar disorder show alterations in functional neural connectivity during rest. However, resting-state network (RSN) disruptions have not been systematically compared between the two disorders. Further, the impact of RSN disruptions on social cognition, a key determinant of functional outcome, has not been studied. Forty-eight individuals with schizophrenia, 46 with bipolar disorder, and 48 healthy controls completed resting-state functional magnetic resonance imaging. An atlas-based approach was used to examine functional connectivity within nine RSNs across the cortex. RSN connectivity was assessed via nonparametric permutation testing, and associations with performance on emotion perception, mentalizing, and emotion management tasks were examined. Group differences were observed in the medial and lateral visual networks and the sensorimotor network. Individuals with schizophrenia demonstrated reduced connectivity relative to healthy controls in all three networks. Individuals with bipolar disorder demonstrated reduced connectivity relative to controls in the medial visual network and connectivity within this network was significantly positively correlated with emotion management. In healthy controls, connectivity within the medial and lateral visual networks positively correlated with mentalizing. No significant correlations were found for either visual network in schizophrenia. Results highlight the role of altered early visual processing in social cognitive deficits in both schizophrenia and bipolar disorder. However, individuals with bipolar disorder appear to compensate for disrupted visual network connectivity on social cognitive tasks, whereas those with schizophrenia do not. The current study adds clarity on the neurophysiology underlying social cognitive deficits that result in impaired functioning in serious mental illness.

fMRI evidence of aberrant neural adaptation for objects in schizophrenia and bipolar disorder.

Functional magnetic resonance imaging (fMRI) adaptation (also known as fMRI repetition suppression) has been widely used to characterize stimulus selectivity in vivo, a fundamental feature of neuronal processing in the brain. We investigated whether SZ patients and BD patients show aberrant fMRI adaptation for object perception. About 52 SZ patients, 55 BD patients, and 53 community controls completed an object discrimination task with three conditions: the same object presented twice, two exemplars from the same category, and two exemplars from different categories. We also administered two functional localizer tasks. A region of interest analysis was employed to evaluate a priori hypotheses about the lateral occipital complex (LOC) and early visual cortex (EVC). An exploratory whole brain analysis was also conducted. In the LOC and EVC, controls showed the expected reduced fMRI responses to repeated presentation of the same objects compared with different objects (i.e., fMRI adaptation for objects, p < .001). SZ patients showed an adaptation effect that was significantly smaller compared with controls. BD patients showed a lack of fMRI adaptation. The whole brain analyses showed enhanced fMRI responses to repeated presentation of the same objects only in BD patients in several brain regions including anterior cingulate cortex. This study was the first to employ fMRI adaptation for objects in SZ and BD. The current findings provide empirical evidence of aberrant fMRI adaptation in the visual cortex in SZ and BD, but in distinctly different ways.

Parsing components of auditory predictive coding in schizophrenia using a roving standard mismatch negativity paradigm.

BACKGROUND: Mismatch negativity (MMN) is an event-related potential (ERP) component reflecting auditory predictive coding. Repeated standard tones evoke increasing positivity ('repetition positivity'; RP), reflecting strengthening of the standard's memory trace and the prediction it will recur. Likewise, deviant tones preceded by more standard repetitions evoke greater negativity ('deviant negativity'; DN), reflecting stronger prediction error signaling. These memory trace effects are also evident in MMN difference wave. Here, we assess group differences and test-retest reliability of these indices in schizophrenia patients (SZ) and healthy controls (HC). METHODS: Electroencephalography was recorded twice, 2 weeks apart, from 43 SZ and 30 HC, during a roving standard paradigm. We examined ERPs to the third, eighth, and 33rd standards (RP), immediately subsequent deviants (DN), and the corresponding MMN. Memory trace effects were assessed by comparing amplitudes associated with the three standard repetition trains. RESULTS: Compared with controls, SZ showed reduced MMNs and DNs, but normal RPs. Both groups showed memory trace effects for RP, MMN, and DN, with a trend for attenuated DNs in SZ. Intraclass correlations obtained via this paradigm indicated good-to-moderate reliabilities for overall MMN, DN and RP, but moderate to poor reliabilities for components associated with short, intermediate, and long standard trains, and poor reliability of their memory trace effects. CONCLUSION: MMN deficits in SZ reflected attenuated prediction error signaling (DN), with relatively intact predictive code formation (RP) and memory trace effects. This roving standard MMN paradigm requires additional development/validation to obtain suitable levels of reliability for use in clinical trials.

Brain glutathione levels and age at onset of illness in chronic schizophrenia.

OBJECTIVE: Oxidative stress is implicated in the aetiology of schizophrenia, and the antioxidant defence system (AODS) may be protective in this illness. We examined the major antioxidant glutathione (GSH) in prefrontal brain and its correlates with clinical and demographic variables in schizophrenia. METHODS: GSH levels were measured in the dorsolateral prefrontal region of 28 patients with chronic schizophrenia using a magnetic resonance spectroscopy sequence specifically adapted for GSH. We examined correlations of GSH levels with age, age at onset of illness, duration of illness, and clinical symptoms. RESULTS: We found a negative correlation between GSH levels and age at onset (r = -0.46, p = 0.015), and a trend-level positive relationship between GSH and duration of illness (r = 0.34, p = 0.076). CONCLUSION: Our findings are consistent with a possible compensatory upregulation of the AODS with longer duration of illness and suggest that the AODS may play a role in schizophrenia.

Cortical Thickness of Functionally Defined Visual Areas in Schizophrenia and Bipolar Disorder.

Patients with schizophrenia show specific abnormalities in visual perception, and patients with bipolar disorder may have related perceptual deficits. During tasks that highlight perceptual dysfunction, patients with schizophrenia show abnormal activity in visual brain areas, including the lateral occipital complex (LOC) and early retinotopic cortex. It is unclear whether the anatomical structure of those visual areas is atypical in schizophrenia and bipolar disorder. In members of those two patient groups and healthy controls, we localized LOC and early retinotopic cortex individually for each participant using functional magnetic resonance imaging (MRI), then measured the thickness of those regions of interest using structural MRI scans. In both regions, patients with schizophrenia had the thinnest cortex, controls had the thickest cortex, and bipolar patients had intermediate cortical thickness. A control region, motor cortex, did not show this pattern of group differences. The thickness of each visual region of interest was significantly correlated with performance on a visual object masking task, but only in schizophrenia patients. These findings suggest an anatomical substrate for visual processing abnormalities that have been found with both neural and behavioral measures in schizophrenia and other severe mental illnesses.

Hallucinations, neuroplasticity, and prediction errors in schizophrenia.

Auditory hallucinations, a hallmark symptom of psychosis, are experienced by most people with a diagnosis of schizophrenia at some point in their illness. Auditory hallucinations can be understood as a failure in predictive coding, whereby abnormalities in sensory/perceptual processing combine with biased cognitive processes to result in a dampening of normal prediction error signaling. In this paper, we used a roving mismatch negativity (MMN) paradigm to optimize evaluation of prediction error signaling and short-term neuroplasticity in 30 people with schizophrenia (n = 16 with and n = 14 without recent auditory hallucinations) and 20 healthy comparison participants. The recent hallucinations group exhibited an abnormal roving MMN profile [F(2,27) = 3.98, p = 0.03], significantly reduced prediction error signaling [t(28) = -2.25, p = 0.03], and a trend for diminished short-term neuroplasticity [t(28) = 1.80, p = 0.08]. There were no statistically significant differences between the healthy comparison group and the combined schizophrenia group on any of the roving MMN indices. These findings are consistent with a predictive coding account of hallucinations in schizophrenia, which posits reduced prediction error signaling in those who are prone to hallucinations. These results also suggest that plasticity-mediated formation and online updating of predictive coding models may also be disrupted in individuals with recent hallucinations.

The effect of bilateral transcranial direct current stimulation on early auditory processing in schizophrenia: a preliminary study.

Transcranial direct current stimulation (tDCS) was applied bilaterally over the auditory cortex in 12 schizophrenia patients to modulate early auditory processing. Performance on a tone discrimination task (tone-matching task-TMT) and auditory mismatch negativity were assessed after counterbalanced anodal, cathodal, and sham tDCS. Cathodal stimulation improved TMT performance (p < 0.03) compared to sham condition. Post-hoc analyses revealed a stimulation condition by negative symptom interaction in which greater negative symptoms were associated with a better TMT performance after anodal tDCS.