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.

Task-based default mode network connectivity predicts cognitive impairment and negative symptoms in first-episode schizophrenia.

Individuals diagnosed with schizophrenia (SZ) demonstrate difficulty distinguishing between internally and externally generated stimuli. These aberrations in "source monitoring" have been theorized as contributing to symptoms of the disorder, including hallucinations and delusions. Altered connectivity within the default mode network (DMN) of the brain has been proposed as a mechanism through which discrimination between self-generated and externally generated events is disrupted. Source monitoring abnormalities in SZ have additionally been linked to impairments in selective attention and inhibitory processing, which are reliably observed via the N100 component of the event-related brain potential elicited during an auditory paired-stimulus paradigm. Given overlapping constructs associated with DMN connectivity and N100 in SZ, the present investigation evaluated relationships between these measures of disorder-related dysfunction and sought to clarify the nature of task-based DMN function in SZ. DMN connectivity and N100 measures were assessed using EEG recorded from SZ during their first episode of illness (N = 52) and demographically matched healthy comparison participants (N = 25). SZ demonstrated less evoked theta-band connectivity within DMN following presentation of pairs of identical auditory stimuli than HC. Greater DMN connectivity among SZ was associated with better performance on measures of sustained attention (p = .03) and working memory (p = .09), as well as lower severity of negative symptoms, though it was not predictive of N100 measures. Together, present findings provide EEG evidence of lower task-based connectivity among first-episode SZ, reflecting disruptions of DMN functions that support cognitive processes. Attentional processes captured by N100 appear to be supported by different neural mechanisms.

Developmental trajectories of premorbid functioning predict cognitive remediation treatment response in first-episode schizophrenia.

BACKGROUND: Cognitive development after schizophrenia onset can be shaped by interventions such as cognitive remediation, yet no study to date has investigated whether patterns of early behavioral development may predict later cognitive changes following intervention. We therefore investigated the extent to which premorbid adjustment trajectories predict cognitive remediation gains in schizophrenia. METHODS: In a total sample of 215 participants (170 first-episode schizophrenia participants and 45 controls), we classified premorbid functioning trajectories from childhood through late adolescence using the Cannon-Spoor Premorbid Adjustment Scale. For the 62 schizophrenia participants who underwent 6 months of computer-assisted, bottom-up cognitive remediation interventions, we identified MATRICS Consensus Cognitive Battery scores for which participants demonstrated mean changes after intervention, then evaluated whether developmental trajectories predicted these changes. RESULTS: Growth mixture models supported three premorbid functioning trajectories: stable-good, deteriorating, and stable-poor adjustment. Schizophrenia participants demonstrated significant cognitive remediation gains in processing speed, verbal learning, and overall cognition. Notably, participants with stable-poor trajectories demonstrated significantly greater improvements in processing speed compared to participants with deteriorating trajectories. CONCLUSIONS: This is the first study to our knowledge to characterize the associations between premorbid functioning trajectories and cognitive remediation gains after schizophrenia onset, indicating that 6 months of bottom-up cognitive remediation appears to be sufficient to yield a full standard deviation gain in processing speed for individuals with early, enduring functioning difficulties. Our findings highlight the connection between trajectories of premorbid and postmorbid functioning in schizophrenia and emphasize the utility of considering the lifespan developmental course in personalizing therapeutic interventions.

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.

Aerobic exercise enhances cognitive training effects in first-episode schizophrenia: randomized clinical trial demonstrates cognitive and functional gains.

BACKGROUND: Cognitive training (CT) and aerobic exercise both show promising moderate impact on cognition and everyday functioning in schizophrenia. Aerobic exercise is hypothesized to increase brain-derived neurotrophic factor (BDNF) and thereby synaptic plasticity, leading to increased learning capacity. Systematic CT should take advantage of increased learning capacity and be more effective when combined with aerobic exercise. METHODS: We examined the impact of a 6-month program of cognitive training & exercise (CT&E) compared to cognitive training alone (CT) in 47 first-episode schizophrenia outpatients. All participants were provided the same Posit Science computerized CT, 4 h/week, using BrainHQ and SocialVille programs. The CT&E group also participated in total body circuit training exercises to enhance aerobic conditioning. Clinic and home-based exercise were combined for a target of 150 min per week. RESULTS: The MATRICS Consensus Cognitive Battery Overall Composite improved significantly more with CT&E than with CT alone (p = 0.04), particularly in the first 3 months (6.5 v. 2.2 T-score points, p < 0.02). Work/school functioning improved substantially more with CT&E than with CT alone by 6 months (p < 0.001). BDNF gain tended to predict the amount of cognitive gain but did not reach significance. The cognitive gain by 3 months predicted the amount of work/school functioning improvement at 6 months. The amount of exercise completed was strongly associated with the degree of cognitive and work/school functioning improvement. CONCLUSIONS: Aerobic exercise significantly enhances the impact of CT on cognition and functional outcome in first-episode schizophrenia, apparently driven by the amount of exercise completed.

A randomized controlled trial of cognitive remediation and long-acting injectable risperidone after a first episode of schizophrenia: improving cognition and work/school functioning.

BACKGROUND: Cognitive deficits at the first episode of schizophrenia are predictive of functional outcome. Interventions that improve cognitive functioning early in schizophrenia are critical if we hope to prevent or limit long-term disability in this disorder. METHODS: We completed a 12-month randomized controlled trial of cognitive remediation and of long-acting injectable (LAI) risperidone with 60 patients with a recent first episode of schizophrenia. Cognitive remediation involved programs focused on basic cognitive processes as well as more complex, life-like situations. Healthy behavior training of equal treatment time was the comparison group for cognitive remediation, while oral risperidone was the comparator for LAI risperidone in a 2 × 2 design. All patients were provided supported employment/education to encourage return to work or school. RESULTS: Both antipsychotic medication adherence and cognitive remediation contributed to cognitive improvement. Cognitive remediation was superior to healthy behavior training in the LAI medication condition but not the oral medication condition. Cognitive remediation was also superior when medication adherence and protocol completion were covaried. Both LAI antipsychotic medication and cognitive remediation led to significantly greater improvement in work/school functioning. Effect sizes were larger than in most prior studies of first-episode patients. In addition, cognitive improvement was significantly correlated with work/school functional improvement. CONCLUSIONS: These results indicate that consistent antipsychotic medication adherence and cognitive remediation can significantly improve core cognitive deficits in the initial period of schizophrenia. When combined with supported employment/education, cognitive remediation and LAI antipsychotic medication show separate significant impact on improving work/school functioning.

Cognitive heterogeneity in first-episode psychosis and its relationship with premorbid developmental adjustment.

BACKGROUND: Patients with schizophrenia spectrum disorders have been increasingly recognised to form cognitive subgroups with differential levels of impairment. Using cluster analytical techniques, this study sought to identify cognitive clusters in a sample of first-episode psychosis (FEP) patients and examine clinical and developmental differences across the resultant groups. METHODS: In total, 105 FEP patients in the University of California Los Angeles Aftercare Research Program were assessed for cognition, symptoms and premorbid developmental adjustment. Hierarchical cluster analysis with Ward's method and squared Euclidean distance was conducted, confirmed by discriminant function analysis and optimised with k-means clustering. The stability of the solution was evaluated through split-sample (random, 80 and 70% samples) and alternate method (average linkage method) replication via Cohen's κ analysis. Controlling for multiple comparisons, one-way analysis of variances examined group differences in symptom severity and premorbid adjustment. RESULTS: Three groups were identified: severely impaired (n = 27), moderately impaired (n = 41) and relatively intact (n = 37). There were no significant differences in symptom severity across the groups. Significant differences were observed for scholastic performance at three different developmental stages: childhood, early adolescence and late adolescence, with the relatively intact group demonstrating significantly better scholastic performance at all three stages than both the moderately impaired and severely impaired groups (who did not significantly differ from each other). CONCLUSIONS: The findings add to growing evidence that cognitive clusters in FEP mirror that of later-stage schizophrenia. They also suggest that premorbid scholastic performance may not just be a risk factor for developing schizophrenia, but is also related to cognitive impairment severity and potentially to prognosis.

Evidence of shared familial factors influencing neurocognitive endophenotypes in adult- and childhood-onset schizophrenia.

BACKGROUND: The aggregation of neurocognitive deficits among the non-psychotic first-degree relatives of adult- and childhood-onset schizophrenia patients suggests that there may be a common etiology for these deficits in childhood- and adult-onset illness. However, there is considerable heterogeneity in the presentation of neurobiological abnormalities, and whether there are differences in the extent of familial transmission for specific domains of cognitive function has not been systematically addressed. METHODS: We employed variance components analysis, as implemented in SOLAR-Eclipse, to evaluate the evidence of familial transmission for empirically derived composite scores representing attention, working memory, verbal learning, verbal retention, and memory for faces. We contrast estimates for adult- and childhood-onset schizophrenia families and matched community control pedigrees, and compare our findings to previous reports based on analogous neurocognitive assessments. RESULTS: We observed varying degrees of familial transmission; attention and working memory yielded comparable, significant estimates for adult-onset and community control pedigrees; verbal learning was significant for childhood-onset and community control pedigrees; and facial memory demonstrated significant familial transmission only for childhood-onset schizophrenia. Model-fitting analyses indicated significant differences in familiality between adult- and childhood-onset schizophrenia for attention, working memory, and verbal learning. CONCLUSIONS: By comprehensively assessing a wide range of neurocognitive domains in adult- and childhood-onset schizophrenia families, we provide additional support for specific neurocognitive domains as schizophrenia endophenotypes. Whereas comparable estimates of familial transmission for certain dimensions of cognitive functioning support a shared etiology of adult- and childhood-onset neurocognitive function, observed differences may be taken as preliminary evidence of partially divergent multifactorial architectures.

Enhancing return to work or school after a first episode of schizophrenia: the UCLA RCT of Individual Placement and Support and Workplace Fundamentals Module training.

BACKGROUND: This study evaluated in a rigorous 18-month randomized controlled trial the efficacy of an enhanced vocational intervention for helping individuals with a recent first schizophrenia episode to return to and remain in competitive work or regular schooling. METHODS: Individual Placement and Support (IPS) was adapted to meet the goals of individuals whose goals might involve either employment or schooling. IPS was combined with a Workplace Fundamentals Module (WFM) for an enhanced, outpatient, vocational intervention. Random assignment to the enhanced integrated rehabilitation program (N = 46) was contrasted with equally intensive clinical treatment at UCLA, including social skills training groups, and conventional vocational rehabilitation by state agencies (N = 23). All patients were provided case management and psychiatric services by the same clinical team and received oral atypical antipsychotic medication. RESULTS: The IPS-WFM combination led to 83% of patients participating in competitive employment or school in the first 6 months of intensive treatment, compared with 41% in the comparison group (p < 0.005). During the subsequent year, IPS-WFM continued to yield higher rates of schooling/employment (92% v. 60%, p < 0.03). Cumulative number of weeks of schooling and/or employment was also substantially greater with the IPS-WFM intervention (45 v. 26 weeks, p < 0.004). CONCLUSIONS: The results clearly support the efficacy of an enhanced intervention focused on recovery of participation in normative work and school settings in the initial phase of schizophrenia, suggesting potential for prevention of disability.

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.

Prefrontal and Hippocampal Brain Volume Deficits: Role of Low Physical Activity on Brain Plasticity in First-Episode Schizophrenia Patients.

UNLABELLED: Our objective in the present study was to conduct the first empirical study of the effects of regular physical activity habits and their relationship with brain volume and cortical thickness in patients in the early phase of schizophrenia. Relationships between larger brain volumes and higher physical activity levels have been reported in samples of healthy and aging populations, but have never been explored in first-episode schizophrenia patients. METHOD: We collected MRI structural scans in 14 first-episode schizophrenia patients with either self-reported low or high physical activity levels. We found a reduction in total gray matter volume, prefrontal cortex (PFC), and hippocampal gray matter volumes in the low physical activity group compared to the high activity group. Cortical thickness in the dorsolateral and orbitofrontal PFC were also significantly reduced in the low physical activity group compared to the high activity group. In the combined sample, greater overall physical activity levels showed a non-significant tendency with better performance on tests of verbal memory and social cognition. Together these pilot study findings suggest that greater amounts of physical activity may have a positive influence on brain health and cognition in first-episode schizophrenia patients and support the implementation of physical exercise interventions in this patient population to improve brain plasticity and cognitive functioning.

The RAISE Connection Program for Early Psychosis: Secondary Outcomes and Mediators and Moderators of Improvement.

The aims of this study were to explore secondary outcomes of a coordinated specialty care program for persons with early psychosis, including quality of life and recovery, as well as to explore mediators and moderators of improvement in occupational and social functioning and symptoms. Sixty-five individuals across two sites were enrolled and received services for up to 2 years. Trajectories for individuals' outcomes over time were examined using linear and quadratic mixed-effects models with repeated measures. In addition, baseline prognostic factors of participant improvement in social and occupational functioning were explored based on previous literature and expert opinion of the analytic team. Results demonstrate that the program was effective in improving quality of life and recovery over time. Furthermore, processing speed was identified as a significant moderator of improvement in occupational Global Assessment of Function, and treatment fidelity, engagement, and family involvement were identified as mediators of improvement in social and occupational functioning.

Neural substrates of visual masking by object substitution in schizophrenia.

Despite a well-known behavioral finding of visual backward masking impairment in schizophrenia, its underlying neural mechanism remains obscure. This study examined neural correlates of a distinct type of visual backward masking, object substitution masking (OSM), in schizophrenia. Twenty schizophrenia patients and 26 healthy controls completed a 4-Dot OSM task and three functional localizer tasks for the lateral occipital (LO), human motion-sensitive (hMT+), and retinotopic areas in the scanner. In 4-dot masking, subjects detected a target that was followed by a mask consisting of 4 dots that surrounded a target. Stimulus-onset asynchrony (SOA) between target and mask was varied to examine the modulation of masking: (1) within three visual processing areas regions of interest (ROI) (i.e., ROI analysis) and (2) in brain regions outside the three visual processing areas (i.e., whole brain analysis). In the ROI analyses, LO and retinotopic areas showed increased peak amplitude when SOA become longer in both patients and controls. There was also an effect of ROI in that both groups showed higher activation in LO and hMT+ compared with the retinotopic areas. The whole brain analyses revealed a significantly activated area for longer SOAs vs. a short SOA in the occipital cortex in controls only, but the group contrast was not significant. Overall, this study did not find strong evidence for neural abnormalities of OSM in schizophrenia, suggesting that neural substrates of OSM in schizophrenia are not as compromised as those involved in the more common masking methods that rely on disruption of object formation.

Intrinsic motivation predicts cognitive and functional gains during coordinated specialty care for first-episode schizophrenia.

Coordinated Specialty Care (CSC) and embedded group therapeutic interventions have been effective in improving outcomes for individuals experiencing recent first-episode schizophrenia, including cognitive performance and functioning. Treatment response varies substantially, with some patients experiencing limited or no improvement. Motivation has emerged as a key determinant of treatment engagement and efficacy. However, the impact of intrinsic and extrinsic aspects of motivation has not been directly examined with treatment outcomes in first-episode schizophrenia. This study investigated whether baseline levels of intrinsic and extrinsic motivation predicted cognitive and functional gains over 6 and 12 months in CSC. Forty participants with first-episode schizophrenia completed a 12-month CSC treatment period. Baseline measures of intrinsic and extrinsic motivation were obtained for group therapeutic interventions and work/school, as well as measures of cognition and functioning (role and social) at baseline, 6 months, and 12 months. Results revealed that higher baseline scores of intrinsic motivation for group therapeutic interventions were significantly predictive of greater cognitive gains at 12 months, and a similar tendency was observed at 6 months. Additionally, baseline scores of intrinsic motivation for work/school predicted role gains at 6 months, with a similar tendency observed at 12 months. Extrinsic motivation did not consistently impact treatment outcomes, except for work/school-related extrinsic motivation, which was linked to greater social functioning gains at 12 months. These findings provide insight into the factors influencing treatment outcomes for individuals with first-episode schizophrenia and highlight the importance of intrinsic motivation as a modifiable personal variable that can enhance response to CSC.

Exercise behaviours and motivation after a first psychotic episode: A digital intervention.

AIM: Research has demonstrated that participation in aerobic exercise can have significant beneficial effects across both physical and mental health domains for individuals who are in the early phase of schizophrenia. Despite these notable benefits of exercise, deficits in motivation and a lack of methods to increase engagement are significant barriers for exercise participation, limiting these potentially positive effects. Fortunately, digital health tools have the potential to improve adherence to an exercise program. The present study examined the role of motivation for exercise and the effects of an automated digital text messaging program on participation in an aerobic exercise program. METHODS: A total of 46 first-episode psychosis participants from an ongoing 12-month randomized clinical trial (Enhancing Cognitive Training through Exercise Following a First Schizophrenia Episode (CT&E-RCT)) were included in an analysis to examine the efficacy of motivational text messaging. Personalized motivational text message reminders were sent to participants with the aim of increasing engagement in the exercise program. RESULTS: We found that participants with higher levels of intrinsic motivation to participate in a text messaging program and in an exercise intervention completed a higher proportion of individual, at-home exercise sessions. In a between groups analysis, participants who received motivational text messages, compared to those who did not, completed a higher proportion of at-home exercise sessions. CONCLUSION: These results indicate the importance of considering a person's level of motivation for exercise and the potential utility of using individualized and interactive mobile text messaging reminders to increase engagement in aerobic exercise in the early phase of psychosis. We emphasize the need for understanding how individualized patient preferences and needs interplay between intrinsic motivation and digital health interventions for young adults.

Defeatist performance beliefs in individuals with recent-onset schizophrenia: Relationships with cognition and negative symptoms.

BACKGROUND: The cognitive model of negative symptoms of schizophrenia suggests that defeatist performance beliefs (DPB), or overgeneralized negative beliefs about one's performance, are an intermediary variable along the pathway from impaired neurocognitive performance to negative symptoms and functioning in daily life. Although reliable associations between these variables have been established in chronic schizophrenia, less is known about the nature of these relationships in recent-onset schizophrenia (ROSz). This current study tested the associations between DPB and variables in the cognitive model (neurocognitive performance, negative symptoms, functioning) as well as mediation by DPB of the association between neurocognitive performance and negative symptoms in ROSz. METHODS: A total of 52 participants (32 adults with ROSz and 20 non-psychiatric healthy comparators; HC) completed in-lab measures of neurocognitive performance, self-reported defeatist performance beliefs, and clinician administered measures of negative symptoms and functional outcome. Bivariate relationships among these variables were tested with Pearson correlations. Bootstrapped regression analyses were conducted to test the strength of the indirect effect of neurocognitive performance on negative symptoms through DPB. RESULTS: Defeatist performance beliefs were significantly elevated in ROSz, and were associated with neurocognitive performance, negative symptoms, and functional outcome as predicted by the cognitive model. There was a significant indirect effect of neurocognition on experiential negative symptoms through DPB, indicating DPB are a partial mediator of the relationship between neurocognitive performance and negative symptoms. CONCLUSION: These findings are consistent with the cognitive model of negative symptoms and extend previous findings in both ROSz and established schizophrenia. Specifically, these data demonstrate that DPB are elevated among ROSz and the associations with neurocognition and clinical outcomes (e.g., negative symptoms and functioning) are of similar magnitude to those reported in chronic schizophrenia. DPB may therefore be a viable treatment target in the early course of illness.

Statistical shape analysis of the corpus callosum in Schizophrenia.

We present a statistical shape-analysis framework for characterizing and comparing morphological variation of the corpus callosum. The midsagittal boundary of the corpus callosum is represented by a closed curve and analyzed using an invariant shape representation. The shape space of callosal curves is endowed with a Riemannian metric. Shape distances are given by the length of shortest paths (geodesics) that are invariant to shape-confounding transformations. The statistical framework enables computation of shape averages and covariances on the shape space in an intrinsic manner (unique to the shape space). The statistical framework makes use of the tangent principal component approach to achieve dimension reduction on the space of corpus callosum shapes. The advantages of this approach are - it is fully automatic, invariant, and avoids the use of landmarks to define shapes. We applied our method to determine the effects of sex, age, schizophrenia and schizophrenia-related genetic liability on callosal shape in a large sample of patients and controls and their first-degree relatives (N=218). Results showed significant age, sex, and schizophrenia effects on both global and local callosal shape structure.

The MATRICS Consensus Cognitive Battery: An Update.

Through a series of NIMH-supported consensus-building meetings of experts and empirical comparisons of candidate tests, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative developed a battery of standardized cognitive measures to allow reliable evaluation of results from clinical trials of promising interventions for core cognitive deficits in this disorder. Ten tests in seven cognitive domains were selected for the MATRICS Consensus Cognitive Battery (MCCB). The MCCB has now been translated into 39 languages/dialects and has been employed in more than 145 clinical trials. It has become the standard cognitive change measure for studies of both pharmacological and training-based interventions seeking to improve cognitive deficits in schizophrenia. We summarize its applications and its relationship to the subsequent development of the NIMH RDoC Matrix.

Treatment engagement in first-episode schizophrenia: Associations between intrinsic motivation and attendance during cognitive training and an aerobic exercise program.

Systematic cognitive training and aerobic exercise programs have emerged as promising interventions to improve cognitive deficits in first-episode schizophrenia, with successful outcomes closely linked with greater treatment engagement (e.g., higher attendance and homework completion rates). Unfortunately, treatment disengagement from these services remains a persistent issue. Intrinsic motivation, or the willingness to exert effort because a task is inherently interesting or meaningful, has emerged as a promising malleable personal factor to enhance treatment engagement. This study investigated whether early task-specific intrinsic motivation and its domains (e.g., interest, perceived competence, and value) predicted treatment engagement within the context of intensive cognitive training and aerobic exercise interventions over a 6-month period. Thirty-nine participants with first-episode schizophrenia were administered baseline measures of task-specific intrinsic motivation inventories, one for cognitive training and one for exercise, and completed a 6-month randomized clinical trial comparing a neuroplasticity-based cognitive training plus aerobic exercise program against the same cognitive training alone. Results indicated that higher baseline scores of intrinsic motivation for cognitive training, specifically early perceptions of task interest and value, were predictive of greater cognitive training and exercise group attendance. Scores for exercise-specific intrinsic motivation were generally unrelated to indices of exercise participation, with the exception that the gain over time in perceived choice for exercise was linked with greater exercise homework completion and a similar directional tendency for greater in-clinic exercise attendance. This study provides support for monitoring and enhancing motivation early during service delivery to maximize engagement and the likelihood of successful treatment outcomes.

Prospective, randomized, multicenter clinical trial evaluating longitudinal changes in brain function and microstructure in first-episode schizophrenia patients treated with long-acting injectable paliperidone palmitate versus oral antipsychotics.

Widespread anatomical alterations and abnormal functional connectivity have shown strong association with symptom severity in first-episode schizophrenia (FES) patients. Second-generation antipsychotic treatment might slow disease progression and possibly modify the cerebral plasticity in FES patients. However, whether a long-acting injectable antipsychotic (paliperidone palmitate [PP]), available in monthly and every-3-months formulations, is more effective than oral antipsychotics (OAP) in improving cerebral organization has been unclear. Therefore, in the current longitudinal study, we evaluated the differences in functional and microstructural changes of 68 FES patients in a randomized clinical trial of PP vs OAP. When compared to OAP treatment, PP treatment was more effective in decreasing abnormally high fronto-temporal and thalamo-temporal connectivity, as well as increasing fronto-sensorimotor and thalamo-insular connectivity. Consistent with previous studies, multiple white matter pathways showed larger changes in fractional anisotropy (FA) and mean diffusivity (MD) in response to PP compared with OAP treatment. These findings suggest that PP treatment might reduce regional abnormalities and improve cerebral connectivity networks compared with OAP treatment, and identified changes that may serve as reliable imaging biomarkers associated with medication treatment efficacy.