Assessing Trial-by-Trial Electrophysiological and Behavioral Markers of Attentional Control and Sensory Precision in Psychotic and Mood Disorders.

BACKGROUND AND HYPOTHESIS: The current study investigated the extent to which changes in attentional control contribute to performance on a visual perceptual discrimination task, on a trial-by-trial basis in a transdiagnostic clinical sample. STUDY DESIGN: Participants with schizophrenia (SZ; N = 58), bipolar disorder (N = 42), major depression disorder (N = 51), and psychiatrically healthy controls (N = 92) completed a visual perception task in which stimuli appeared briefly. The design allowed us to estimate the lapse rate and the precision of perceptual representations of the stimuli. Electroencephalograms (EEG) were recorded to examine pre-stimulus activity in the alpha band (8-13 Hz), overall and in relation to behavior performance on the task. STUDY RESULTS: We found that the attention lapse rate was elevated in the SZ group compared with all other groups. We also observed group differences in pre-stimulus alpha activity, with control participants showing the highest levels of pre-stimulus alpha when averaging across trials. However, trial-by-trial analyses showed within-participant fluctuations in pre-stimulus alpha activity significantly predicted the likelihood of making an error, in all groups. Interestingly, our analysis demonstrated that aperiodic contributions to the EEG signal (which affect power estimates across frequency bands) serve as a significant predictor of behavior as well. CONCLUSIONS: These results confirm the elevated attention lapse rate that has been observed in SZ, validate pre-stimulus EEG markers of attentional control and their use as a predictor of behavior on a trial-by-trial basis, and suggest that aperiodic contributions to the EEG signal are an important target for further research in this area, in addition to alpha-band activity.

Over 30 years of STEP: The Pittsburgh experience with first-episode psychosis.

AIMS: For over 30 years, combined research and treatment settings in the US have been critical to conceptualizing care for first-episode psychosis (FEP). Here we describe an early example of such a context, the Services for the Treatment of Early Psychosis (STEP) clinic, which is affiliated with the University of Pittsburgh. METHODS: We describe STEP's historical roots and establishment in the early 1990s; STEP's research and treatment contributions, alongside its growth and ongoing leadership. RESULTS: Research-based clinics, like STEP, preceded and helped pave the way for the Recovery After an Initial Schizophrenia Episode project in the US and the ensuing Coordinated Specialty Care (CSC) approach, now widely adopted in the US. Early clinic-based research at STEP helped establish protocols for psychopharmacology, the relevance of effective early treatment, including psychosocial approaches, and highlighted disparities in treatment outcomes across race/ethnicity. Multidisciplinary collaboration and dialogue with consumers contributed to early treatment, combining psychosocial and pharmacological approaches. STEP adopted CSC and is situated within a bi-state Learning Health System. STEP has retained a relatively unique 5-year treatment model and exists within continuum of care ideally suited to studying psychotic illness and treatment outcomes. CONCLUSIONS: STEP remains the largest academic FEP clinic in Pennsylvania. Academic FEP clinics like STEP will have a critical role within Learning Health Systems nationally to model participatory approaches, sustain early intervention treatment quality and ongoing treatment developments.

Association of neurotransmitter pathway polygenic risk with specific symptom profiles in psychosis.

A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 205 demographically diverse cases with a psychotic disorder who underwent comprehensive psychiatric and neurological phenotyping and 115 matched controls. Following genotyping, we calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if overall genetic risk can be partitioned into affected neurotransmitter pathways, we calculated pathway PGSs (pPGSs) for SZ risk affecting each of four major neurotransmitter systems: glutamate, GABA, dopamine, and serotonin. Psychosis subjects had elevated SZ PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association within psychosis cases between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were moderately associated with specific endophenotypes; notably, glutamate was associated with SZ diagnosis and with deficits in cognitive control during task-based fMRI, while dopamine was associated with global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. All clusters showed strong genome-wide risk. Cluster 2, characterized by deficits in cognitive control and negative symptoms, additionally showed specific risk concentrated in glutamatergic and GABAergic pathways. Due to the intensive characterization of our subjects, the present study was limited to a relatively small cohort. As such, results should be followed up with additional research at the population and mechanism level. Our study suggests pathway-based PGS analysis may be a powerful path forward to study genetic mechanisms driving psychiatric endophenotypes.

Identification of distinct clinical profiles and trajectories in individuals at high risk of developing psychosis: A latent profile analysis of the north American prodrome longitudinal study consortium-3 dataset.

AIM: People at clinical high risk (CHR) for psychosis are a heterogeneous population in regard to clinical presentation and outcome. It is unclear, however, if their baseline clinical characteristics can be used to construct orthogonal subgroups that differ in their clinical trajectory to provide early identification of individuals in need of tailored interventions. METHODS: We used latent profile analysis (LPA) to determine the number of distinct clinical profiles within the CHR population using the NAPLS-3 dataset, focusing on the clinical features incorporated in the NAPLS psychosis risk calculator (including age, unusual thought content and suspiciousness, processing speed, verbal learning and memory function, social functioning decline, life events, childhood trauma, and family history of psychosis). We then conducted a between-profile comparisons of clinical trajectories based on psychotic and depressive symptoms as well as substance use disorder (SUD) related features over time. RESULTS: Two distinct profiles emerged. One profile, comprising approximately 25% of the sample, was significantly older, displayed better cognitive performance, experienced more types of traumatic and undesirable life events, exhibited a greater decline in functioning in the past year, and was more likely to have relatives with psychosis. This group showed worse positive symptoms and SUD-related features over time, although groups did not differ in the proportion of individuals who developed psychosis. CONCLUSIONS: LPA results suggest CHRs can be segregated into two profiles with different clinical trajectories. Characterizing individuals within these clinical profiles may help understand the divergent outcomes of this population and ultimately facilitate the development of specialized interventions.

The diagnostic accuracy of screening for psychosis spectrum disorders in behavioral health clinics integrated into primary care.

Screening for psychosis spectrum disorders in primary care could improve early identification and reduce the duration of untreated psychosis. However, the accuracy of psychosis screening in this setting is unknown. To address this, we conducted a diagnostic accuracy study of screening for psychosis spectrum disorders in eight behavioral health services integrated into primary care clinics. Patients attending an integrated behavioral health appointment at their primary care clinic completed the Prodromal Questionnaire - Brief (PQ-B) immediately prior to their intake assessment. This was compared to a diagnostic phone interview based on the Structured Interview for Psychosis Risk Syndromes (SIPS). In total, 145 participants completed all study procedures, of which 100 screened positive and 45 negative at a provisional PQ-B threshold of ≥20. The PQ-B was moderately accurate at differentiating psychosis spectrum from no psychosis spectrum disorders; a PQ-B distress score of ≥27 had a sensitivity and specificity of 71.2 % and 57.0 % respectively. In total, 66 individuals (45.5 %) met criteria for a psychosis spectrum disorder and 24 (16.7 %) were diagnosed with full psychosis, indicating a high prevalence of psychosis in the sample. Overall, screening for psychosis spectrum disorders in an IBH primary care setting identified a relatively high number of individuals and may identify people that would otherwise be missed. The PQ-B performed slightly less well than in population-based screening in community mental health settings. However, the findings suggest this may represent an effective way to streamline the pathway between specialty early psychosis programs and primary care clinics for those in need.

Greater Choline-Containing Compounds and Myo-inositol in Treatment-Resistant Versus Responsive Schizophrenia: A 1H-Magnetic Resonance Spectroscopy Meta-analysis.

BACKGROUND: The neurobiology of treatment-resistant schizophrenia (TRS) is poorly understood, and meta-analytic consensus regarding magnetic resonance spectroscopic profiles of glutamate, choline-containing compounds, myo-inositol, and other metabolites in the condition is lacking. METHODS: In this meta-analysis, we examined published findings for N-acetylaspartate, choline-containing compounds (phosphocholine+glycerophosphocholine), myo-inositol, creatine+phosphocreatine, glutamate, and glutamate+glutamine in the anterior cingulate cortex and dorsal striatum in people with TRS versus non-TRS as well as TRS versus healthy control participants (HCs) and TRS versus ultra TRS (i.e., TRS with clozapine resistance). A MEDLINE search revealed 9 articles including 239 people with pooled TRS and ultra TRS, 59 with ultra TRS, 175 with non-TRS, and 153 (HCs) that met meta-analytic criteria. RESULTS: Significant effects included higher anterior cingulate cortex phosphocholine+glycerophosphocholine and myo-inositol in the pooled TRS and ultra TRS group than in both the non-TRS group and HCs as well as higher dorsal striatal phosphocholine+glycerophosphocholine in ultra TRS versus HCs, but no differences in other regional metabolites. CONCLUSIONS: The observed metabolite profile in TRS (higher phosphocholine+glycerophosphocholine and myo-inositol signal) is consistent with the hypothesis that TRS has a neuroinflammatory component, although this meta-analysis is not a critical test of that hypothesis. A similar profile is seen in healthy aging, which is known to involve increased neuroinflammation and glial activation. Because the overall number of datasets was low, however, results should be considered preliminary and highlight the need for additional studies of brain metabolites in TRS and their possible association with inflammatory processes.

A Transdiagnostic Study of Effort-Cost Decision-Making in Psychotic and Mood Disorders.

BACKGROUND: Research suggests that effort-cost decision-making (ECDM), the estimation of work required to obtain reward, may be a relevant framework for understanding motivational impairment in psychotic and mood pathology. Specifically, research has suggested that people with psychotic and mood pathology experience effort as more costly than controls, and thus pursue effortful goals less frequently. This study examined ECDM across psychotic and mood pathology. HYPOTHESIS: We hypothesized that patient groups would show reduced willingness to expend effort compared to controls. STUDY DESIGN: People with schizophrenia (N = 33), schizoaffective disorder (N = 28), bipolar disorder (N = 39), major depressive disorder (N = 40), and controls (N = 70) completed a physical ECDM task. Participants decided between completing a low-effort or high-effort option for small or larger rewards, respectively. Reward magnitude, reward probability, and effort magnitude varied trial-by-trial. Data were analyzed using standard and hierarchical logistic regression analyses to assess the subject-specific contribution of various factors to choice. Negative symptoms were measured with a clinician-rated interview. STUDY RESULTS: There was a significant effect of group, driven by reduced choice of high-effort options in schizophrenia. Hierarchical logistic regression revealed that reduced choice of high-effort options in schizophrenia was driven by weaker contributions of probability information. Use of reward information was inversely associated with motivational impairment in schizophrenia. Surprisingly, individuals with major depressive disorder and bipolar disorder did not differ from controls. CONCLUSIONS: Our results provide support for ECDM deficits in schizophrenia. Additionally, differences between groups in ECDM suggest a seemingly similar behavioral phenotype, reduced motivation, could arise from disparate mechanisms.

Recreational cannabis use over time in individuals at clinical high risk for psychosis: Lack of associations with symptom, neurocognitive, functioning, and treatment patterns.

Recreational cannabis use has recently gained considerable interest as an environmental risk factor that triggers the onset of psychosis. To date, however, the evidence that cannabis is associated with negative outcomes in individuals at clinical high risk (CHR) for psychosis is inconsistent. The present study tracked cannabis usage over a 2-year period and examined its associations with clinical and neurocognitive outcomes, along with medication rates. CHR youth who continuously used cannabis had higher neurocognition and social functioning over time, and decreased medication usage, relative to non-users. Surprisingly, clinical symptoms improved over time despite the medication decreases.

Extracellular free water elevations are associated with brain volume and maternal cytokine response in a longitudinal nonhuman primate maternal immune activation model.

Maternal infection has emerged as an important environmental risk factor for neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Animal model systems of maternal immune activation (MIA) suggest that the maternal immune response plays a significant role in the offspring's neurodevelopment and behavioral outcomes. Extracellular free water is a measure of freely diffusing water in the brain that may be associated with neuroinflammation and impacted by MIA. The present study evaluates the brain diffusion characteristics of male rhesus monkeys (Macaca mulatta) born to MIA-exposed dams (n = 14) treated with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the end of the first trimester (n = 10) or were untreated (n = 4). Offspring underwent diffusion MRI scans at 6, 12, 24, 36, and 45 months. Offspring born to MIA-exposed dams showed significantly increased extracellular free water in cingulate cortex gray matter starting as early as 6 months of age and persisting through 45 months. In addition, offspring gray matter free water in this region was significantly correlated with the magnitude of the maternal IL-6 response in the MIA-exposed dams. Significant correlations between brain volume and extracellular free water in the MIA-exposed offspring also indicate converging, multimodal evidence of the impact of MIA on brain development. These findings provide strong evidence for the construct validity of the nonhuman primate MIA model as a system of relevance for investigating the pathophysiology of human neurodevelopmental psychiatric disorders. Elevated free water in individuals exposed to immune activation in utero could represent an early marker of a perturbed or vulnerable neurodevelopmental trajectory.

Association of neurotransmitter pathway polygenic risk with specific symptom profiles in psychosis.

A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 206 demographically diverse cases with a psychotic disorder who underwent comprehensive psychiatric and neurological phenotyping and 115 matched controls. Following genotyping, we calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if overall genetic risk can be partitioned into affected neurotransmitter pathways, we calculated pathway PGSs (pPGSs) for SZ risk affecting each of four major neurotransmitter systems: glutamate, GABA, dopamine, and serotonin. Psychosis subjects had elevated SZ PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association within psychosis cases between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were moderately associated with specific endophenotypes; notably, glutamate was associated with SZ diagnosis and with deficits in cognitive control during task-based fMRI, while dopamine was associated with global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. All clusters showed strong genome-wide risk. Cluster 2, characterized by deficits in cognitive control and negative symptoms, additionally showed specific risk concentrated in glutamatergic and GABAergic pathways. Due to the intensive characterization of our subjects, the present study was limited to a relatively small cohort. As such, results should be followed up with additional research at the population and mechanism level. Our study suggests pathway-based PGS analysis may be a powerful path forward to study genetic mechanisms driving psychiatric endophenotypes.

Altered Associations Between Task Performance and Dorsolateral Prefrontal Cortex Activation During Cognitive Control in Schizophrenia.

BACKGROUND: Dysfunctional cognitive control processes are now well understood to be core features of schizophrenia (SZ). A body of work suggests that the dorsolateral prefrontal cortex (DLPFC) plays a critical role in explaining cognitive control disruptions in SZ. Here, we examined relationships between DLPFC activation and drift rate (DR), a model-based performance measure that combines reaction time and accuracy, in people with SZ and healthy control (HC) participants. METHODS: One hundred fifty-one people with recent-onset SZ spectrum disorders and 118 HC participants performed the AX-Continuous Performance Task during functional magnetic resonance imaging scanning. Proactive cognitive control-associated activation was extracted from left and right DLPFC regions of interest. Individual behavior was fit using a drift diffusion model, allowing DR to vary between task conditions. RESULTS: Behaviorally, people with SZ showed significantly lower DRs than HC participants, particularly during high proactive control trial types ("B" trials). Recapitulating previous findings, the SZ group also demonstrated reduced cognitive control-associated DLPFC activation compared with HC participants. Furthermore, significant group differences were also observed in the relationship between left and right DLPFC activation with DR, such that positive relationships between DR and activation were found in HC participants but not in people with SZ. CONCLUSIONS: These results suggest that DLPFC activation is less associated with cognitive control-related behavioral performance enhancements in SZ. Potential mechanisms and implications are discussed.

Transdiagnostic Predictors of Everyday Functioning: Examining the Relationships of Depression and Reinforcement Learning.

BACKGROUND AND HYPOTHESIS: Impairments in function (ie, the ability to independently accomplish daily tasks) have been established in psychotic disorders. Identifying factors that contribute to these deficits is essential to developing effective interventions. The current study had several goals: examine potential differential relationships across domains of neurocognition, assess whether reinforcement learning is related to function, identify if predictors of function are transdiagnostic, determine whether depression and positive symptoms contribute to function, and to explore whether the modality of assessment impacts observed relationships. STUDY DESIGN: Data from 274 participants were examined with schizophrenia/schizoaffective disorder (SZ; n = 195) and bipolar disorder (BD; n = 79). To reduce dimensionality, a PCA was completed on neurocognitive tasks which resulted in 3 components. These components and clinical interview data were used to investigate predictors of functional domains across measures of function (self- and informant-report SLOF and UPSA). RESULTS: Two components, working memory/processing speed/episodic memory (ßs = 0.18-0.42), and negative/positive reinforcement learning (ß = -0.04), predicted different functional domains. Predictors of function were largely transdiagnostic with two exceptions: reinforcement learning had a positive association with self-reported interpersonal relationships for SZ and a negative association for BD (ß = 0.34), and the negative association between positive symptoms and self-reported social acceptability was stronger for BD than for SZ (ß = 0.93). Depression robustly predicted self-reported but not informant-reported function, and anhedonia predicted all domains of informant-reported function. CONCLUSIONS: These findings imply that reinforcement learning may differentially relate to function across disorders, traditional domains of neurocognition can be effective transdiagnostic targets for interventions, and positive symptoms and depression play a critical role in self-perceived functional impairments.

Managing EEG studies: How to prepare and what to do once data collection has begun.

In this paper, we provide guidance for the organization and implementation of EEG studies. This work was inspired by our experience conducting a large-scale, multi-site study, but many elements could be applied to any EEG project. Section 1 focuses on study activities that take place before data collection begins. Topics covered include: establishing and training study teams, considerations for task design and piloting, setting up equipment and software, development of formal protocol documents, and planning communication strategy with all study team members. Section 2 focuses on what to do once data collection has already begun. Topics covered include: (1) how to effectively monitor and maintain EEG data quality, (2) how to ensure consistent implementation of experimental protocols, and (3) how to develop rigorous preprocessing procedures that are feasible for use in a large-scale study. Links to resources are also provided, including sample protocols, sample equipment and software tracking forms, sample code, and tutorial videos (to access resources, please visit: https://osf.io/wdrj3/).

Cortical and subcortical brain morphometry abnormalities in youth at clinical high-risk for psychosis and individuals with early illness schizophrenia.

Neuroimaging studies have documented morphometric brain abnormalities in schizophrenia, but less is known about them in individuals at clinical high-risk for psychosis (CHR-P), including how they compare with those observed in early schizophrenia (ESZ). Accordingly, we implemented multivariate profile analysis of regional morphometric profiles in CHR-P (n = 89), ESZ (n = 93) and healthy controls (HC; n = 122). ESZ profiles differed from HC and CHR-P profiles, including 1) cortical thickness: significant level reduction and regional non-parallelism reflecting widespread thinning, except for entorhinal and pericalcarine cortex, 2) basal ganglia volume: significant level increase and regional non-parallelism reflecting larger caudate and pallidum, and 3) ventricular volume: significant level increase with parallel regional profiles. CHR-P and ESZ cerebellar profiles showed significant non-parallelism with HC profiles. Regional profiles did not significantly differ between groups for cortical surface area or subcortical volume. Compared to CHR-P followed for ≥18 months without psychosis conversion (n = 31), CHR-P converters (n = 17) showed significant non-parallel ventricular volume expansion reflecting specific enlargement of lateral and inferolateral regions. Antipsychotic dosage in ESZ was significantly correlated with frontal cortical thinning. Results suggest that morphometric abnormalities in ESZ are not present in CHR-P, except for ventricular enlargement, which was evident in CHR-P who developed psychosis.

Altered Associations Between Motivated Performance and Frontostriatal Functional Connectivity During Reward Anticipation in Schizophrenia.

BACKGROUND AND HYPOTHESIS: The neuronal mechanisms that underlie deficits in effort cost computation in schizophrenia (SZ) are poorly understood. Given the role of frontostriatal circuits in valence-oriented motivation, we hypothesized that these circuits are either dysfunctional in SZ or do not appropriately predict behavior in SZ when task conditions are difficult and good performance is rewarded. STUDY DESIGN: A total of 52 people with recent onset SZ-spectrum disorders and 48 healthy controls (HCs) performed a 3T fMRI task with 2 valence conditions (rewarded vs neutral) and 2 difficulty conditions. Frontostriatal connectivity was extracted during the cue (anticipatory) phase. Individual behavior was fit using a drift-diffusion model, allowing the performance parameter, drift rate (DR), to vary between task conditions. Three models were examined: A group × condition model of DR, a group × condition model of connectivity, and a regression model of connectivity predicting DR depending on group and condition. STUDY RESULTS: DRs showed the expected positive correlation with accuracy and a negative association with reaction time. The SZ group showed a deficit in DR but did not differ in overall connectivity or show a valence-specific deficit in connectivity. Significant group × valence × difficulty interactions, however, were observed on the relationship between right dorsolateral prefrontal (DLPFC)-striatal connectivity and DR (DLPFC-Caudate: F = 10.92, PFDR = .004; DLPFC-Putamen: F = 5.14, PFDR = .048) driven by more positive relationships between DR and connectivity during cues for the difficult-rewarded condition in HCs compared to SZ. CONCLUSIONS: These findings suggest that frontostriatal connectivity is less predictive of performance in SZ when task difficulty is increased and a reward incentive is applied.

Increased Striatal Presynaptic Dopamine in a Nonhuman Primate Model of Maternal Immune Activation: A Longitudinal Neurodevelopmental Positron Emission Tomography Study With Implications for Schizophrenia.

BACKGROUND: Epidemiological studies suggest that maternal immune activation (MIA) is a significant risk factor for future neurodevelopmental disorders, including schizophrenia (SZ), in offspring. Consistent with findings in SZ research and work in rodent systems, preliminary cross-sectional findings in nonhuman primates suggest that MIA is associated with dopaminergic hyperfunction in young adult offspring. METHODS: In this unique prospective longitudinal study, we used [18F]fluoro-l-m-tyrosine positron emission tomography to examine the developmental time course of striatal presynaptic dopamine synthesis in male rhesus monkeys born to dams (n = 13) injected with a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid [poly(I:C)], in the late first trimester. Striatal (caudate, putamen, and nucleus accumbens) dopamine from these animals was compared with that of control offspring born to dams that received saline (n = 10) or no injection (n = 4). Dopamine was measured at 15, 26, 38, and 48 months of age. Prior work with this cohort found decreased prefrontal gray matter volume in MIA offspring versus controls between 6 and 45 months of age. Based on theories of the etiology and development of SZ-related pathology, we hypothesized that there would be a delayed (relative to the gray matter decrease) increase in striatal fluoro-l-m-tyrosine signal in the MIA group versus controls. RESULTS: [18F]fluoro-l-m-tyrosine signal showed developmental increases in both groups in the caudate and putamen. Group comparisons revealed significantly greater caudate dopaminergic signal in the MIA group at 26 months. CONCLUSIONS: These findings are highly relevant to the known pathophysiology of SZ and highlight the translational relevance of the MIA model in understanding mechanisms by which MIA during pregnancy increases risk for later illness in offspring.

Altered dendritic morphology in dorsolateral prefrontal cortex of nonhuman primates prenatally exposed to maternal immune activation.

Women who contract a viral or bacterial infection during pregnancy have an increased risk of giving birth to a child with a neurodevelopmental or psychiatric disorder. The effects of maternal infection are likely mediated by the maternal immune response, as preclinical animal models have confirmed that maternal immune activation (MIA) leads to long lasting changes in offspring brain and behavior development. The present study sought to determine the impact of MIA-exposure during the first or second trimester on neuronal morphology in dorsolateral prefrontal cortex (DLPFC) and hippocampus from brain tissue obtained from MIA-exposed and control male rhesus monkey (Macaca mulatta) during late adolescence. MIA-exposed offspring display increased neuronal dendritic branching in pyramidal cells in DLPFC infra- and supragranular layers relative to controls, with no significant differences observed between offspring exposed to maternal infection in the first and second trimester. In addition, the diameter of apical dendrites in DLPFC infragranular layer is significantly decreased in MIA-exposed offspring relative to controls, irrespective of trimester exposure. In contrast, alterations in hippocampal neuronal morphology of MIA-exposed offspring were not evident. These findings demonstrate that a maternal immune challenge during pregnancy has long-term consequences for primate offspring dendritic structure, selectively in a brain region vital for socioemotional and cognitive development.

Effect of Technology-Enhanced Screening in Addition to Standard Targeted Clinician Education on the Duration of Untreated Psychosis: A Cluster Randomized Clinical Trial.

Importance: Reducing the duration of untreated psychosis (DUP) is essential to improving outcomes for people with first-episode psychosis (FEP). Current US approaches are insufficient to reduce DUP to international standards of less than 90 days. Objective: To determine whether population-based electronic screening in addition to standard targeted clinician education increases early detection of psychosis and decreases DUP, compared with clinician education alone. Design, Setting, and Participants: This cluster randomized clinical trial included individuals aged 12 to 30 years presenting for services between March 2015 and September 2017 at participating sites that included community mental health clinics and school support and special education services. Eligible participants were referred to the Early Diagnosis and Preventative Treatment (EDAPT) Clinic. Data analyses were performed in September and October 2019 for the primary and secondary analyses, with the exploratory subgroup analyses completed in May 2021. Interventions: All sites in both groups received targeted education about early psychosis for health care professionals. In the active screening group, clients also completed the Prodromal Questionnaire-Brief using tablets at intake; referrals were based on those scores and clinical judgment. In the group receiving treatment as usual (TAU), referrals were based on clinical judgment alone. Main Outcomes and Measures: Primary outcomes included DUP, defined as the period from full psychosis onset to the date of the EDAPT diagnostic telephone interview, and the number of individuals identified with FEP or a psychosis spectrum disorder. Exploratory analyses examined differences by site type, completion rates between conditions, and days from service entry to telephone interview. Results: Twenty-four sites agreed to participate, and 12 sites were randomized to either the active screening or TAU group. However, only 10 community clinics and 4 school sites were able to fully implement population screening and were included in the final analysis. The total potentially eligible population size within each study group was similar, with 2432 individuals entering at active screening group sites and 2455 at TAU group sites. A total of 303 diagnostic telephone interviews were completed (178 [58.7%] female individuals; mean [SD] age, 17.09 years [4.57]). Active screening sites reported a significantly higher detection rate of psychosis spectrum disorders (136 cases [5.6%], relative to 65 [2.6%]; P < .001) and referred a higher proportion of individuals with FEP and DUP less than 90 days (13 cases, relative to 4; odds ratio, 0.30; 95% CI, 0.10-0.93; P = .03). There was no difference in mean (SD) DUP between groups (active screening group, 239.0 days [207.4]; TAU group 262.3 days [170.2]). Conclusions and Relevance: In this cluster trial, population-based technology-enhanced screening across community settings detected more than twice as many individuals with psychosis spectrum disorders compared with clinical judgment alone but did not reduce DUP. Screening could identify people undetected in US mental health services. Significant DUP reduction may require interventions to reduce time to the first mental health contact. Trial Registration: ClinicalTrials.gov Identifier: NCT02841956.

Comparing the functional neuroanatomy of proactive and reactive control between patients with schizophrenia and healthy controls.

Cognitive control deficits are associated with impaired executive functioning in schizophrenia. The Dual Mechanisms of Control framework suggests that proactive control requires sustained dorsolateral prefrontal activity, whereas reactive control marshals a larger network. However, primate studies suggest these processes are maintained by dual-encoding regions. To distinguish between these theories, we compared the distinctiveness of proactive and reactive control functional neuroanatomy. In a reanalysis of data from a previous study, 47 adults with schizophrenia and 56 controls completed the Dot Pattern Expectancy task during an fMRI scan examining proactive and reactive control in frontoparietal and medial temporal regions. Areas suggesting specialized control or between-group differences were tested for association with symptoms and task performance. Elastic net models additionally explored these areas' predictive abilities regarding performance. Most regions were active in both reactive and proactive control. However, evidence of specialized proactive control was found in the left middle and superior frontal gyri. Control participants showed greater proactive control in the left middle and right inferior frontal gyri. Elastic net models moderately predicted task performance and implicated various frontal gyri regions in control participants, with additional involvement of anterior cingulate and posterior parietal regions for reactive control. Elastic nets for patient participants implicated the inferior and superior frontal gyri, and posterior parietal lobe. Specialized cognitive control was unassociated with either performance or schizophrenia symptomatology. Future work is needed to clarify the distinctiveness of proactive and reactive control, and its role in executive deficits in severe psychopathology.