Longitudinal inference of multiscale markers in psychosis: from hippocampal centrality to functional outcome.

Multiscale neuroscience conceptualizes mental illness as arising from aberrant interactions across and within multiple biopsychosocial scales. We leverage this framework to propose a multiscale disease progression model of psychosis, in which hippocampal-cortical dysconnectivity precedes impairments in episodic memory and social cognition, which lead to more severe negative symptoms and lower functional outcome. As psychosis represents a heterogeneous collection of biological and behavioral alterations that evolve over time, we further predict this disease progression for a subtype of the patient sample, with other patients showing normal-range performance on all variables. We sampled data from two cross-sectional datasets of first- and multi-episode psychosis, resulting in a sample of 163 patients and 119 non-clinical controls. To address our proposed disease progression model and evaluate potential heterogeneity, we applied a machine-learning algorithm, SuStaIn, to the patient data. SuStaIn uniquely integrates clustering and disease progression modeling and identified three patient subtypes. Subtype 0 showed normal-range performance on all variables. In comparison, Subtype 1 showed lower episodic memory, social cognition, functional outcome, and higher negative symptoms, while Subtype 2 showed lower hippocampal-cortical connectivity and episodic memory. Subtype 1 deteriorated from episodic memory to social cognition, negative symptoms, functional outcome to bilateral hippocampal-cortical dysconnectivity, while Subtype 2 deteriorated from bilateral hippocampal-cortical dysconnectivity to episodic memory and social cognition, functional outcome to negative symptoms. This first application of SuStaIn in a multiscale psychiatric model provides distinct disease trajectories of hippocampal-cortical connectivity, which might underlie the heterogeneous behavioral manifestations of psychosis.

Sex differences in cognition and structural covariance-based morphometric connectivity: evidence from 28,000+ UK Biobank participants.

There is robust evidence for sex differences in domain-specific cognition, where females typically show an advantage for verbal memory, whereas males tend to perform better in spatial memory. Sex differences in brain connectivity are well documented and may provide insight into these differences. In this study, we examined sex differences in cognition and structural covariance, as an index of morphometric connectivity, of a large healthy sample (n = 28,821) from the UK Biobank. Using T1-weighted magnetic resonance imaging scans and regional cortical thickness values, we applied jackknife bias estimation and graph theory to obtain subject-specific measures of structural covariance, hypothesizing that sex-related differences in brain network global efficiency, or overall covariance, would underlie cognitive differences. As predicted, females demonstrated better verbal memory and males showed a spatial memory advantage. Females also demonstrated faster processing speed, with no observed sex difference in executive functioning. Males showed higher global efficiency, as well as higher regional covariance (nodal strengths) in both hemispheres relative to females. Furthermore, higher global efficiency in males mediated sex differences in verbal memory and processing speed. Findings contribute to an improved understanding of how biological sex and differences in cognition are related to morphometric connectivity as derived from graph-theoretic methods.

Effects of Anticholinergic Burden on Verbal Memory Performance in First-Episode Psychosis.

OBJECTIVES: Antipsychotics are widely used to treat first-episode psychosis but may have an anticholinergic burden, that is, a cumulative effect of medications that block the cholinergic system. Studies suggest that a high anticholinergic burden negatively affects memory in psychosis, where cognitive deficits, particularly those in verbal memory, are a core feature of the disease. The present study sought to replicate this in a large cohort of well-characterized first-episode psychosis patients. We expected that patients in the highest anticholinergic burden group would exhibit the poorest verbal memory compared to those with low anticholinergic burden and healthy controls at baseline (3 months following admission). We further hypothesized that over time, at month 12, patients' verbal memory performance would improve but would remain inferior to controls. METHODS: Patients (n = 311; low anticholinergic burden [n = 241] and high anticholinergic burden [n = 70], defined by a Drug Burden Index cut-off of 1) and healthy controls (n = 128) completed a clinical and neurocognitive battery including parts of the Wechsler Memory Scale at months 3 and 12. RESULTS: Cross-sectionally, using an analysis of variance, patients in the highest anticholinergic burden group had the poorest performance in verbal memory when compared to the other groups at month 3, F(2,430) = 52.33, P < 0.001. Longitudinally, using a Generalized Estimating Equation model, the verbal memory performance of all groups improved over time. However, patients' performance overall remained poorer than the controls. CONCLUSION: These findings highlight the importance of considering the anticholinergic burden when prescribing medications in the early stages of the disease.

Hallucination- and speech-specific hypercoupling in frontotemporal auditory and language networks in schizophrenia using combined task-based fMRI data: An fBIRN study.

Hypercoupling of activity in speech-perception-specific brain networks has been proposed to play a role in the generation of auditory-verbal hallucinations (AVHs) in schizophrenia; however, it is unclear whether this hypercoupling extends to nonverbal auditory perception. We investigated this by comparing schizophrenia patients with and without AVHs, and healthy controls, on task-based functional magnetic resonance imaging (fMRI) data combining verbal speech perception (SP), inner verbal thought generation (VTG), and nonverbal auditory oddball detection (AO). Data from two previously published fMRI studies were simultaneously analyzed using group constrained principal component analysis for fMRI (group fMRI-CPCA), which allowed for comparison of task-related functional brain networks across groups and tasks while holding the brain networks under study constant, leading to determination of the degree to which networks are common to verbal and nonverbal perception conditions, and which show coordinated hyperactivity in hallucinations. Three functional brain networks emerged: (a) auditory-motor, (b) language processing, and (c) default-mode (DMN) networks. Combining the AO and sentence tasks allowed the auditory-motor and language networks to separately emerge, whereas they were aggregated when individual tasks were analyzed. AVH patients showed greater coordinated activity (deactivity for DMN regions) than non-AVH patients during SP in all networks, but this did not extend to VTG or AO. This suggests that the hypercoupling in AVH patients in speech-perception-related brain networks is specific to perceived speech, and does not extend to perceived nonspeech or inner verbal thought generation.

Impairment in subcortical suppression in schizophrenia: Evidence from the fBIRN Oddball Task.

Schizophrenia patients show widespread impairments in brain activity during oddball tasks, which involve responding to infrequent target stimuli while refraining from responding during continuous non-target stimuli. In a network-based investigation comparing schizophrenia or schizoaffective patients to healthy controls, we sought to clarify which networks were specifically associated with target detection using a multivariate analysis technique that identifies task-specific functional brain networks. We acquired data from the publicly available function biomedical informatics research network collaboration, including 58 patients and 50 controls. Two task-based functional brain networks were identified: (1) a response modulation network including bilateral temporal pole, supramarginal gyrus, striatum, and thalamus, on which patients showed decreased activity relative to controls; and (2) an auditory-motor response activation network, on which patients showed a slower return to baseline than controls, but no difference in peak activation. For both groups, baseline to peak activation of the response modulation network correlated negatively with peak to baseline activity in the response activation network, suggesting a role in suppressing the motor response following targets. Patients' impaired activity in the response modulation network, and subsequent longer return to baseline in the response activation network, correspond with their later and less accurate behavioral performance, suggesting that impairment in suppression of the auditory-motor response activation network could underlie oddball task deficits in schizophrenia. In addition, the magnitude of the activity in the response modulation network was correlated with intensity of delusions of reference, supporting the notion that increased referential ideation is associated with hyperactivity within the subcortical striatal-limbic network. Hum Brain Mapp 37:4640-4653, 2016. © 2016 Wiley Periodicals, Inc.

Functional brain networks underlying detection and integration of disconfirmatory evidence.

Processing evidence that disconfirms a prior interpretation is a fundamental aspect of belief revision, and has clear social and clinical relevance. This complex cognitive process requires (at minimum) an alerting stage and an integration stage, and in the current functional magnetic resonance imaging (fMRI) study, we used multivariate analysis methodology on two datasets in an attempt to separate these sequentially-activated cognitive stages and link them to distinct functional brain networks. Thirty-nine healthy participants completed one of two versions of an evidence integration experiment involving rating two consecutive animal images, both of which consisted of two intact images of animal faces morphed together at different ratios (e.g., 70/30 bird/dolphin followed by 10/90 bird/dolphin). The two versions of the experiment differed primarily in terms of stimulus presentation and timing, which facilitated functional interpretation of brain networks based on differences in the hemodynamic response shapes between versions. The data were analyzed using constrained principal component analysis for fMRI (fMRI-CPCA), which allows distinct, simultaneously active task-based networks to be separated, and these were interpreted using both temporal (task-based hemodynamic response shapes) and spatial (dominant brain regions) information. Three networks showed increased activity during integration of disconfirmatory relative to confirmatory evidence: (1) a network involved in alerting to the requirement to revise an interpretation, identified as the salience network (dorsal anterior cingulate cortex and bilateral insula); (2) a sensorimotor response-related network (pre- and post-central gyri, supplementary motor area, and thalamus); and (3) an integration network involving rostral prefrontal, orbitofrontal and posterior parietal cortex. These three networks were staggered in their peak activity (alerting, responding, then integrating), but at certain time points (e.g., 17s after trial onset) the hemodynamic responses associated with all three networks were simultaneously active. These findings highlight distinct cognitive processes and corresponding functional brain networks underlying stages of disconfirmatory evidence integration, and demonstrate the power of multivariate and multi-experiment methodology in cognitive neuroscience.

Reduced functional connectivity during controlled semantic integration in schizophrenia: A multivariate approach.

Impairment in controlled semantic association is a central feature of schizophrenia, and the goal of the current functional magnetic resonance imaging study was to identify the neural correlates of this impairment. Thirty people with schizophrenia and 30 healthy age- and gender-matched control subjects performed a task requiring participants to match word pairs that varied in semantic distance (distant vs. close). A whole-brain multivariate connectivity analysis revealed three functional brain networks of primary interest engaged by the task: two configurations of a multiple demands network, in which brain activity did not differ between groups, and a semantic integration network, in which coordinated activity was reduced in schizophrenia patients relative to healthy controls, for distantly relative to closely related word pairs. The hypoactivity during controlled semantic integration in schizophrenia reported here, combined with hyperactivity in automatic semantic association reported in the literature, suggests an imbalance between controlled integration and automatic association. This provides a biological basis for Bleuler's concept of schizophrenia as a "split mind" arising from an impaired ability to form coherent associations between semantic concepts.

Transdiagnostic cognitive biases in psychiatric disorders: A systematic review and network meta-analysis.

Psychiatric disorders are characterized by cognitive deficits, which have been proposed as a transdiagnostic feature of psychopathology ("C" factor). Similarly, cognitive biases (e.g., in attention, memory, and interpretation) represent common tendencies in information processing that are often associated with psychiatric symptoms. However, the question remains whether cognitive biases are also transdiagnostic or are specific to certain psychiatric disorders/symptoms. The current systematic review sought to address whether the proposed "C" factor of transdiagnostic cognitive dysfunction in psychopathology can be extended to cognitive biases. Overall, 31 studies comprising 4401 participants (2536 patients, 1865 non-clinical controls) met inclusion criteria, assessing 19 cognitive biases across 20 diagnostic categories, with most studies focusing on interpretation (k = 22) and attention (k = 11) biases and only 2 assessing memory biases. Traditional meta-analyses found a moderate effect size (g = 0.32) for more severe cognitive biases in all patients relative to non-clinical controls, as well as small but significant associations between interpretation biases and transdiagnostic symptom categories (general psychopathology: r = 0.20, emotion dysfunction: r = 0.17, psychotic symptoms: r = 0.25). Network meta-analyses revealed significant patient versus non-clinical control differences on attention and interpretation biases across diagnoses, as well as significant differences between diagnoses, with highest severity in panic disorder for attention biases and obsessive-compulsive disorder for interpretation biases. The current findings extend the big "C" interpretation of transdiagnostic cognitive dysfunction in psychiatric disorders to cognitive biases and transdiagnostic symptom dimensions. Results also suggest that while the presence of cognitive biases is transdiagnostic, bias severity differs across diagnoses, as in traditional neurocognitive deficits.

Overlap between individual differences in cognition and symptoms of schizophrenia.

BACKGROUND: Neurocognitive impairment is a core feature of schizophrenia spectrum disorders (SSDs), and the relationship between cognition and symptoms in SSDs has been widely researched. Negative symptoms are related to a wide range of cognitive impairments; however, the aspects of negative symptoms that underpin this relationship have yet to be specified. STUDY DESIGN: We used iterative Constrained Principal Component Analysis (iCPCA) to explore the relationship between 18 cognitive measures (including processing speed, attention, working, spatial and verbal memory and executive functions) and 46 symptoms in schizophrenia at the individual item level while minimizing the risk of Type I errors. ICPCA was conducted on a sample of SSD patients in the early stages of psychiatric treatment (n = 121) to determine the components of cognition overlapping with symptoms measured by the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS). RESULTS: We found that a verbal memory component was associated with items from SANS and SAPS related to impoverished and disorganized emotional communication, language, and thought. In contrast, a working memory component was associated with SANS items related to motor system impoverishment. CONCLUSIONS: The iCPCA allowed us to explore the associations between individual items, optimized to understand the overlap between symptoms and cognition. The specific symptoms linked to verbal and working memory impairments imply distinct brain networks, which further investigation may lead to our deeper understanding of the illness and the development of treatment methods.

Speech markers to predict and prevent recurrent episodes of psychosis: A narrative overview and emerging opportunities.

Preventing relapse in schizophrenia improves long-term health outcomes. Repeated episodes of psychotic symptoms shape the trajectory of this illness and can be a detriment to functional recovery. Despite early intervention programs, high relapse rates persist, calling for alternative approaches in relapse prevention. Predicting imminent relapse at an individual level is critical for effective intervention. While clinical profiles are often used to foresee relapse, they lack the specificity and sensitivity needed for timely prediction. Here, we review the use of speech through Natural Language Processing (NLP) to predict a recurrent psychotic episode. Recent advancements in NLP of speech have shown the ability to detect linguistic markers related to thought disorder and other language disruptions within 2-4 weeks preceding a relapse. This approach has shown to be able to capture individual speech patterns, showing promise in its use as a prediction tool. We outline current developments in remote monitoring for psychotic relapses, discuss the challenges and limitations and present the speech-NLP based approach as an alternative to detect relapses with sufficient accuracy, construct validity and lead time to generate clinical actions towards prevention.

C-Reactive protein and cognition: Mediation analyses with brain morphology in the UK Biobank.

Cognitive impairments and abnormal immune activity are both associated with various clinical disorders. The association between C-Reactive protein (CRP), a marker associated with inflammation, and cognitive performance remains unclear. Further, mechanisms potentially linking CRP to cognition are not yet established. Brain structure may well mediate this relationship: immune processes play crucial roles in shaping and maintaining brain structure, with brain structure and function driving cognition. The United Kingdom Biobank (UKBB) is a large cohort study with extensive assessments, including high-sensitivity serum CRP levels, brain imaging, and various cognitive tasks. With data from 39,200 UKBB participants, we aimed first to determine the relationship between CRP and cognitive performance, and second, to assess metrics of brain morphology as potential mediators in this relationship. Participants were aged 40 to 70 at initial assessment and were mostly Caucasian. After accounting for potential covariates (e.g., age, sex, medical diagnoses, use of selective-serotonin reuptake inhibitors), we found CRP levels to have small, negative associations with fluid intelligence (b = -0.03, 95%CI[-0.05,-0.02], t(14381) = -3.62, pcor = .004), and numeric memory (b = -0.03, 95%CI[-0.05,-0.01], t(14366) = -3.31, pcor = .007). We found no evidence of brain morphology mediating these relationships (all |ab| < 0.001, all pcor > .55). Our findings from this large sample suggest that serum-assessed CRP is of marginal importance for cognitive performance in mid-to-late aged Caucasians; the small effect sizes of statistically significant associations provide context to previous inconsistent results. The seeming lack of involvement of brain morphology suggests that other brain metrics (e.g., connectivity, functional activation) may be more pertinent to this relationship. Future work should also consider CRP levels measured in the central nervous system and/or other cytokines that may better predict cognitive performance in this population.

Episodic Memory and Schizophrenia: From Characterization of Relational Memory Impairments to Neuroimaging Biomarkers.

Episodic memory research in schizophrenia has a long history already which has clearly established significant impairments and strong associations with brain measures and functional outcome. The purpose of this chapter is not to make an exhaustive review of the recent literature but to highlight some relatively recent developments in the cognitive neuroscience field of episodic memory and schizophrenia. Hence, we present a contemporary view focusing specifically of relational memory which represents a form of episodic memory that refers to associations or binding among items or elements presented together. We describe the major tasks used and illustrate how their combination with brain imaging has: (1) favored the use of experimental memory tasks to isolate specific processes with specific neural correlates, (2) led to a distributed view of the neural correlates of memory impairments in schizophrenia where multiple regions are contributing, and (3) made possible the identification of fMRI biomarkers specific to episodic memory. We then briefly propose what we see as the next steps for memory research in schizophrenia so that the impact of this work can be maximized.

Exploring the Relationship Between Suicidality and Persistent Negative Symptoms Following a First Episode of Psychosis.

BACKGROUND AND HYPOTHESIS: Suicide is a leading cause of death in first-episode psychosis (FEP), with an elevated risk during the first year following illness onset. The association between negative symptoms and suicidality remains contentious. Some studies suggest that negative symptoms may be associated with lower suicidality, while others fail to find an association between the two. No previous studies have specifically investigated suicidality in Persistent Negative Symptoms (PNS) and its associated subgroups. STUDY DESIGN: In a large cohort of FEP patients (n = 515) from an early intervention service, we investigated suicidality in those with PNS, secondary PNS (ie, sPNS; PNS with clinical-level positive, depressive, or extrapyramidal symptoms), and non-PNS (all other patients) over 24 months. Patients were categorized into PNS groups based on symptoms from month 6 to month 12, and suicidality was evaluated using the Brief Psychiatric Rating Scale (BPRS). STUDY RESULTS: Covarying for age and sex, we found that sPNS had higher suicidality relative to PNS and non-PNS throughout the 24-month period, but PNS and non-PNS did not differ. These differences were maintained after adjusting for depressive symptoms. CONCLUSION: We observed that PNS did not significantly differ from non-PNS. However, we identified sPNS as a group with elevated suicidality above and beyond depression, suggesting that sPNS would benefit from targeted intervention and that PNS categorization identifies a subgroup for whom negative symptoms are not associated with lower suicidality.

Dimensions of beliefs without strong supporting evidence and reasons for holding them.

Beliefs without strong supporting evidence (BWSSE) are commonplace, such as religious beliefs and conspiracy theories. The goals of the current study were to identify dimensions of BWSSE in the general public and study how reasons for holding each dimension depend on the strength of the belief. Participants completed a BWSSE questionnaire online, and principal component analysis suggested that the questionnaire captured 6 dimensions of beliefs that range in strength: New Age Spiritual, Traditional Spiritual, Nonconformist, Science, Mythical, and Conspiracy Theory. Mixed-model analyses of variance showed that while high-strength believers in both New Age and Traditional Spiritual shifted their reasons-for-belief away from 'just believe' and towards personal experience, only Traditional Spiritual shifted away from 'just believe' to culture. In contrast, for Conspiracy Theory and Mythical, the dominant reason for belief was media, but for Conspiracy Theory only, there was a shift from media to education/personal research for high-strength believers. This demonstrates that although spiritual beliefs are strengthened by personal experience, conspiracy theory beliefs are strengthened by information gathering. Understanding the source of an existing belief is important for debiasing attempts to move people towards beliefs with strong supporting evidence, including greater acceptance of evidence provided by experts, a likely requirement for negotiating global humanitarian emergencies in the not-so-distant future. Statement of Relevance. Beliefs without strong supporting evidence (BWSSE) have been gaining attention in mainstream society; particularly, the sources of information that may contribute to their formation and resistance to correction. Understanding the source of an existing belief is important for debiasing attempts to move people towards beliefs with strong supporting evidence, including greater acceptance of evidence provided by experts, a likely requirement for negotiating global humanitarian emergencies in the not-so-distant future.

Ultra-high field neuroimaging in psychosis: A narrative review.

Schizophrenia and related psychoses are complex neuropsychiatric diseases representing dysconnectivity across multiple scales, through the micro (cellular), meso (brain network), manifest (behavioral), and social (interpersonal) levels. In vivo human neuroimaging, particularly at ultra-high field (UHF), offers unprecedented opportunity to examine multiscale dysconnectivity in psychosis. In this review, we provide an overview of the literature to date on UHF in psychosis, focusing on microscale findings from magnetic resonance spectroscopy (MRS), mesoscale studies on structural and functional magnetic resonance imaging (fMRI), and multiscale studies assessing multiple neuroimaging modalities and relating UHF findings to behavior. We highlight key insights and considerations from multiscale and longitudinal studies and provide recommendations for future research on UHF neuroimaging in psychosis.

Altered Surface Area Covariance in the Mentalizing Network in Schizophrenia: Insight Into Theory of Mind Processing.

BACKGROUND: Theory of mind (ToM), the cognitive capacity to attribute mental states to self and others, is robustly affected in schizophrenia. The neural substrates of ToM impairment have been largely studied with functional imaging, but little is known about structural abnormalities. We compared structural covariance (between-subjects correlations of brain regional measures) of magnetic resonance imaging-based cortical surface area between patients with schizophrenia and healthy control subjects and between schizophrenia subgroups based on the patients' ToM ability to examine ToM-specific effects on structural covariance in schizophrenia. METHODS: T1-weighted structural images were acquired on a 3T magnetic resonance imaging scanner, and ToM was assessed with the Hinting Task for 104 patients with schizophrenia and 69 healthy control subjects. The sum of surface area was computed for 12 regions of interest selected and compared between groups to examine structural covariance within the often reported mentalizing network: rostral and caudal middle frontal gyrus, inferior parietal lobule, precuneus, and middle and superior temporal gyrus. High and low ToM groups were defined using a median split on the Hinting Task. RESULTS: Cortical surface contraction was observed in the schizophrenia group, predominantly in temporoparietal regions. Patients with schizophrenia also exhibited significantly stronger covariance between the right rostral middle frontal gyrus and the right superior temporal gyrus than control subjects (r = 4.015; p < .001). Direct comparisons between high and low ToM subgroups revealed stronger contralateral frontotemporal covariances in the low ToM group. CONCLUSIONS: Our results provide evidence for structural changes underlying ToM impairments in schizophrenia that need to be confirmed to develop new therapeutic perspectives.

Dynamic Interplay Between Insight and Persistent Negative Symptoms in First Episode of Psychosis: A Longitudinal Study.

Persistent negative symptoms (PNS) are an important factor of first episode of psychosis (FEP) that present early on in the course of illness and have a major impact on long-term functional outcome. Lack of clinical insight is consistently associated with negative symptoms during the course of schizophrenia, yet only a few studies have explored its evolution in FEP. We sought to explore clinical insight change over a 24-month time period in relation to PNS in a large sample of FEP patients. Clinical insight was assessed in 515 FEP patients using the Scale to assess Unawareness of Mental Disorder. Data on awareness of illness, belief in response to medication, and belief in need for medication were analyzed. Patients were divided into 3 groups based on the presence of negative symptoms: idiopathic (PNS; n = 135), secondary (sPNS; n = 98), or absence (non-PNS; n = 282). Secondary PNS were those with PNS but also had clinically relevant levels of positive, depressive, or extrapyramidal symptoms. Our results revealed that insight improved during the first 2 months for all groups. Patients with PNS and sPNS displayed poorer insight across the 24-month period compared to the non-PNS group, but these 2 groups did not significantly differ. This large longitudinal study supported the strong relationship known to exist between poor insight and negative symptoms early in the course of the disorder and probes into potential factors that transcend the distinction between idiopathic and secondary negative symptoms.

Structural brain correlates of cognitive function in schizophrenia: A meta-analysis.

Schizophrenia is characterized by cognitive impairments and widespread structural brain abnormalities. Brain structure-cognition associations have been extensively studied in schizophrenia, typically involving individual cognitive domains or brain regions of interest. Findings in overlapping and diffuse brain regions may point to structural alterations in large-scale brain networks. We performed a systematic review and meta-analysis examining whether brain structure-cognition associations can be explained in terms of biologically meaningful brain networks. Of 7,261 screened articles, 88 were included in a series of meta-analyses assessing publication bias, heterogeneity, and study quality. Significant associations were found between overall brain structure and eight MATRICS-inspired cognitive domains. Brain structure mapped onto the seven Yeo functionally defined networks and extraneous structures (amygdala, hippocampus, and cerebellum) typically showed associations with conceptually related cognitive domains, with higher-level domains (e.g., executive function, social cognition) associated with more networks. These findings synthesize the extensive literature on brain structure and cognition in schizophrenia from a contemporary network neuroscience perspective and suggest that brain structure-cognition associations in schizophrenia may follow functional network architecture.

Sex-specific associations in verbal memory brain circuitry in early psychosis.

Hippocampal circuitry and related cortical connections are altered in first episode psychosis (FEP) and are associated with verbal memory deficits, as well as positive and negative symptoms. There are robust sex differences in the clinical presentation of psychosis, including poorer verbal memory in male patients. Consideration of sex differences in hippocampal-cortical circuitry and their associations with different behavioral dimensions may be useful for understanding the underlying pathophysiology of verbal memory deficits and related symptomatology in psychosis. Here, we use a data-driven approach to simultaneously capture the complex links between sex, verbal memory, symptoms, and cortical-hippocampal brain metrics in FEP. Structural magnetic resonance imaging and behavioral data were acquired from 100 FEP patients (75 males, 25 females) and 87 controls (55 males, 32 females). Multivariate brain-behavior associations were examined in FEP using partial least squares to map sociodemographic, verbal memory, and clinical data onto brain morphometry. The analysis identified two sex-dependent patterns of verbal memory, symptoms, and brain structure. In male patients, verbal memory deficits and core psychotic symptoms were associated with both increased and decreased frontal and temporal cortical thickness and reductions in CA2/3 hippocampal subfield and fornix volumes. In female patients, fewer negative/depressive symptoms were associated with a more attenuated cortical thickness pattern and more diffuse reductions in hippocampal white matter regions. Taken together, the results contribute towards better understanding the underlying pathophysiology of psychosis by highlighting the unique contribution of specific hippocampal subfields and surrounding white matter and their connections with broader cortical networks in a sex-dependent manner.

Normal-range verbal memory in the first-episode of psychosis: Clinical and functional outcomes across 24 months and impact of estimated verbal memory decrement.

Verbal memory (VM) dysfunction is prevalent in first-episode psychosis (FEP) and has major impacts on long-term functional and clinical outcomes. Nevertheless, a substantial proportion of FEP patients have VM performance in the norm, called normal-range (NR) VM, and only a few studies have explored its relation to outcomes. Moreover, probable decrements between estimated premorbid and current cognitive performance could confuse the relationship between VM and clinical or functional outcomes in FEP patients. These potential interactions have not yet been considered in FEP, thus, we examined 1) the longitudinal relationship between VM performance (NR vs. below NR (BNR)) in FEP and clinical and functional outcomes over 24 months following admission to treatment, and 2) compared the clinical and functional status of NR patients with and without cognitive decrement at baseline and 12 months. A total of 271 patients (BNR = 114, NR = 157; 81 out of 105 NR with decrement) completed measures of psychosocial functioning and clinical symptoms at baseline, month 12, and month 24. Generalized Estimating Equations and unpaired t-tests were used to address the first and second aim, respectively. NR demonstrated better functioning and fewer negative symptoms when compared to BNR. Interestingly, NR patients with decrement reported significantly more negative symptoms at baseline compared to their counterparts without decrement. These findings document that a large proportion (57.9 %) of FEP patients have NR VM that appear to be functionally advantageous but that NR VM is nuanced by the presence or absence of a potential decrement early in the developmental course of the disorder.