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.

Perception of social inclusion/exclusion and response inhibition in adolescents with past suicide attempt: a multidomain task-based fMRI study.

The occurrence of suicidal behaviors increases during adolescence. Hypersensitivity to negative social signals and deficits in cognitive control are putative mechanisms of suicidal behaviors, which necessitate confirmation in youths. Multidomain functional neuroimaging could enhance the identification of patients at suicidal risk beyond standard clinical measures. Three groups of adolescents (N = 96; 78% females, age = 11.6-18.1) were included: patients with depressive disorders and previous suicide attempts (SA, n = 29); patient controls with depressive disorders but without any suicide attempt history (PC, n = 35); and healthy controls (HC, n = 32). We scanned participants with 3T-MRI during social inclusion/exclusion (Cyberball Game) and response inhibition (Go-NoGo) tasks. Neural activation was indexed by the blood-oxygenation-level dependent (BOLD) of the hemodynamic response during three conditions in the Cyberball Game ("Control condition", "Social Inclusion", and "Social Exclusion"), and two conditions in Go-NoGo task ("Go" and "NoGo" blocks). ANCOVA-style analysis identified group effects across three whole-brain contrasts: 1) NoGo vs. Go, 2) Social inclusion vs. control condition, 3) Social exclusion vs. control condition. We found that SA had lower activation in the left insula during social inclusion vs. control condition compared to PC and HC. Moreover, SA compared to PC had higher activity in the right middle prefrontal gyrus during social exclusion vs. control condition, and in bilateral precentral gyri during NoGo vs. Go conditions. Task-related behavioral and self-report measures (Self-reported emotional reactivity in the Cyberball Game, response times and number of errors in the Go-NoGo Task) did not discriminate groups. In conclusion, adolescent suicidal behaviors are likely associated with neural alterations related to the processing of social perception and response inhibition. Further research, involving prospective designs and diverse cohorts of patients, is necessary to explore the potential of neuroimaging as a tool in understanding the emergence and progression of suicidal behaviors.

Effects of metacognitive training (MCT) on social cognition for schizophrenia spectrum and related psychotic disorders: a systematic review and meta-analysis.

BACKGROUND: Individuals with schizophrenia spectrum and related psychotic disorders (SSD) experience significant impairments in social cognition that impede functioning. Social cognition is a multidimensional construct consisting of four domains: 1. theory of mind, 2. emotion processing, 3. attributional style and 4. social perception. Metacognitive training (MCT) is an intervention designed to target cognitive biases in psychosis containing two modules addressing social cognition. METHODS: A systematic review and meta-analysis was conducted to investigate the effects of MCT on social cognition and two of its domains: theory of mind and emotion processing. Ten electronic databases were scoured from 2007 to 1 February 2022 for MCT studies reporting social cognition outcomes for people with SSD (1050 identified, 282 assessed). Effect sizes were calculated using Cohen's d in R. RESULTS: Nine studies were included in the meta-analysis (nMCT = 212, ncontrol = 194). MCT had a small but positive effect on global social cognition (d = 0.28 [95% CI 0.07-0.49]) and theory of mind (d = 0.27 [95% CI 0.01-0.52]). MCT showed no evidence of an effect on emotion processing (d = 0.03 [95% CI -0.26 to 0.32]). CONCLUSION: MCT has a small but significant effect on social cognition for people with SSD. Our results add to other recent meta-analyses showing significant effects of MCT on clinically relevant outcomes such as positive symptoms, cognitive biases and cognitive insight. We recommend that future studies on MCT report outcomes on all four domains of social cognition. TRIAL REGISTRATION: PROSPERO (in the process of registration) available at https://www.crd.york.ac.uk/prospero/#recordDetails.

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.

Manualized group cognitive behavioral therapy for social anxiety in first-episode psychosis: a randomized controlled trial.

BACKGROUND: Social anxiety (SA), a prevalent comorbid condition in psychotic disorders with a negative impact on functioning, requires adequate intervention relatively early. Using a randomized controlled trial, we tested the efficacy of a group cognitive-behavioral therapy intervention for SA (CBT-SA) that we developed for youth who experienced the first episode of psychosis (FEP). For our primary outcome, we hypothesized that compared to the active control of group cognitive remediation (CR), the CBT-SA group would show a reduction in SA that would be maintained at 3- and 6-month follow-ups. For secondary outcomes, it was hypothesized that the CBT-SA group would show a reduction of positive and negative symptoms and improvements in recovery and functioning. METHOD: Ninety-six patients with an FEP and SA, recruited from five different FEP programs in the Montreal area, were randomized to 13 weekly group sessions of either CBT-SA or CR intervention. RESULTS: Linear mixed models revealed that multiple measures of SA significantly reduced over time, but with no significant group differences. Positive and negative symptoms, as well as functioning improved over time, with negative symptoms and functioning exhibiting a greater reduction in the CBT-SA group. CONCLUSIONS: While SA decreased over time with both interventions, a positive effect of the CBT-SA intervention on measures of negative symptoms, functioning, and self-reported recovery at follow-up suggests that our intervention had a positive effect that extended beyond symptoms specific to SA.ClinicalTrials.gov identifier: NCT02294409.

Opening up mental health research.

Open science provides a compelling framework for accelerating global collaborations and enabling discoveries to understand and treat mental health disorders. Herein, we discuss the advantages and obstacles to adopting open science in mental health research, considering the particularities of sensitive and diverse data types, the potential of co-designing projects with research participants and the opportunity of amplifying open science by integration with mental health care. We present a practical example of how this landscape may be navigated to adopt open science across an entire research centre, in 5 steps, namely leadership committing to open science; finding models, resources and allies; identifying needs; defining open science principles; and putting principles into practice. We derive lessons learned that can be built upon by researchers and research organizations joining the open science movement in mental health.

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.

"The more things change "? Stability of delusional themes across 12 years of presentations to an early intervention service for psychosis.

PURPOSE: While the prevalence of delusional themes appears to be consistent across geographic contexts, little is known about the relative prevalence of such themes within a given setting over periods of time. We therefore investigated delusional themes across 12 years of presentation to a catchment-based early intervention service for first episode psychosis (FEP). METHODS: Systematically collected data from 500 patients at an early intervention service for FEP were analyzed. Four cohorts of 3 years each, from 2006 to 2017, were used to compare the frequency of delusion themes across cohorts. We also integrated into the analysis baseline sociodemographic factors such as gender, age, and highest level of education and clinical factors such as anxiety, depression, suicidality, hallucinations, and primary diagnosis (affective or non-affective psychosis). RESULTS: Sex and education level were stable across cohorts, while patient age varied (p = 0.047). Clinical anxiety, depression, and suicidality at entry were also stable. Across cohorts, the proportion of patients with affective versus non-affective diagnosis differed (p = 0.050), with no differences in global rating of delusion severity or theme prevalence except for delusions of guilt or sin (p = 0.001). This single theme difference was not correlated with age or diagnosis. CONCLUSION: Our study suggests relatively stable prevalence of delusion themes across cohorts of individuals experiencing FEP. This demonstrates the potential utility of studying thematic content both for understanding delusions in clinical populations and in research. Future explorations of the relationships between delusion themes and across individual patient episodes should be conducted.

Exploring the sociodemographic, clinical and neuropsychological factors associated with relational memory in schizophrenia.

INTRODUCTION: The Transverse Patterning (TP) task has been used to measure episodic relational memory (RM) deficits in clinical populations. Individuals with schizophrenia often fail to learn TP with standard, and sometimes extensive training. Identifying the differences between TP learners and non-learners can improve our understanding of successful TP performance and its underlying mechanisms, which may help improve interventions aimed at ameliorating RM performance. We investigated sociodemographic, clinical and neuropsychological factors associated with TP performance in schizophrenia. METHODS: Sixty-six participants with schizophrenia completed a semantically rich and a relational-binding dependent version of the TP task and reported on their task awareness and strategy use. RESULTS: Twenty-six participants failed to learn the task rules after extensive training. Learners had superior verbal, visual and working memory, executive functions and overall cognitive functioning compared to non-learners. Learners also had superior awareness of task rules and pairs relationships and used elaborated cognitive strategies more often. CONCLUSIONS: Our results support previous findings that some individuals with schizophrenia show RM impairment even with extensive TP training. We shed light on neuropsychological and metacognitive factors associated with TP performance. This knowledge could enhance interventions targeted to improve relational memory in schizophrenia when extensive training fails.

Minds@Work: A New Manualized Intervention to Improve Job Tenure in Psychosis Based on Scoping Review and Logic Model.

Introduction A significant proportion of people experiencing psychosis are unemployed, despite a strong desire to work. Current supported employment programs appear effective in helping them obtain employment, yet job tenure remains an arduous challenge. The objective of this study was to review the literature and model the results to inform the development of a new manualized group psychosocial intervention-'Minds@Work'-aimed specifically at improving job tenure in psychosis. Methods The study was registered on the Open Science Framework platform ( https://osf.io/he68z ). The literature was searched in Medline, Embase, PsycInfo and Cochrane Library databases for studies examining predictors of job tenure in psychosis and existing occupational psychosocial interventions. Data were extracted using a pre-established form and synthesized using logic models. Results A total of 94 studies were included and their findings were modeled using different categories: intervention typologies, mechanisms of action, predictors of job tenure, outcomes and contextual factors. The 'Minds@Work' program was built based on these modeled findings and aimed to target specific predictors of job tenure while addressing some of the limitations of existing interventions. The program uses evidence-based techniques and is divided into 9 modules covering 4 themes: positive psychology (motivation, character strengths, self-compassion), neurocognitive remediation (attention, memory, problem-solving), cognitive biases training (jumping to conclusions, defeatists beliefs, theory of mind, attributional styles) and socioemotional coping skills (emotion regulation, communication). Conclusions Once validated, this new program is meant to be used either as a stand-alone intervention or integrated in supported employment initiatives, by employment specialists or healthcare workers.

Robust arterial input function surrogate measurement from the superior sagittal sinus complex signal for fast dynamic contrast-enhanced MRI in the brain.

PURPOSE: Accurately estimating the arterial input function for dynamic contrast-enhanced MRI is challenging. An arterial input function is typically determined from signal magnitude changes related to a contrast agent, often leading to underestimation of peak concentrations. Alternatively, signal phase recovers the accurate peak concentration for straight vessels but suffers from high noise. A recent method proposed to fit the signal in the complex plane by combining the advantages of the previous 2 methods. The purpose of this work is to refine this complex-based method to determine the venous output function (VOF), an arterial input function surrogate, from the superior sagittal sinus. METHODS: We propose a state-of-the-art complex-based method that includes direct compensation for blood inflow and signal phase correction accounting for the curvature of the superior sagittal sinus, generally assumed collinear with B0 . We compared the magnitude-, phase-, and complex-based VOF determination methods against various simulated biases as well as for 29 brain metastases patients. RESULTS: Angulation of the superior sagittal sinus relative to B0 varied widely within patients, and its effect on the signal phase caused an underestimation of peak concentrations of up to 65%. Correction significantly increased the VOF peak concentration for the phase- and complex-based VOFs in the cohort. The phase-based method recovered accurate peak concentrations but lacked precision in the tail of the VOF. Our complex-based VOF completely recovered the effect of inflow and resulted in a high-peak concentration with limited noise. CONCLUSION: The new complex-based method resulted in high-quality VOF robust against superior sagittal sinus curvature and variations in patient positioning.

Contribution of perfusion to the 11 C-acetate signal in brown adipose tissue assessed by DCE-MRI and 68 Ga-DOTA PET in a rat model.

PURPOSE: Determine if dynamic contrast enhanced (DCE) -MRI and/or 68 gallium 1,4,7,10-tetraazacyclododecane N, N', N″, N‴-tretraacetic acid (68 Ga-DOTA) positron emission tomography (PET) can assess perfusion in rat brown adipose tissue (BAT). Evaluate changes in perfusion between cold-stimulated and heat-inhibited BAT. Determine if the 11 C-acetate pharmacokinetic model can be constrained with perfusion information to improve assessment of BAT oxidative metabolism. METHODS: Rats were split into three groups. In group 1 (N = 6), DCE-MRI with gadobutrol was compared directly to 68 Ga-DOTA PET following exposure to 10 °C for 48 h. 11 C-Acetate PET was also performed to assess oxidation. In group 2 (N = 4), only 68 Ga-DOTA PET was acquired following exposure to 10 °C for 48 h. Finally, in group 3 (N = 10), perfusion was assessed with DCE-MRI in rats exposed to 10 °C or 30 °C for 48 h, and oxidation was measured with 11 C-acetate. Perfusion was quantified with a two-compartment pharmacokinetic model, while oxidation was assessed by a four-compartment model. RESULTS: DCE-MRI and 68 Ga-DOTA PET provided similar perfusion measures, but a decrease in the perfusion signal was noted with longer imaging sessions. Exposure to 10 °C or 30 °C did not affect the perfusion measures, but the 11 C-acetate signal increased in BAT at 10 °C. Without prior information about blood volume, the 11 C-acetate compartment model overestimated blood volume and underestimated oxidation in 10 °C BAT. CONCLUSION: Precise assessment of oxidation via 11 C-acetate PET requires prior information about blood volume which can be obtained by DCE-MRI or 68 Ga-DOTA PET. Since perfusion can change rapidly, simultaneous PET-MRI would be preferred.

Delusional content at initial presentation to a catchment-based early intervention service for psychosis.

BACKGROUND: During a psychotic episode, patients frequently suffer from severe maladaptive beliefs known as delusions. Despite the abundant literature investigating the simple presence or absence of these beliefs, there exists little detailed knowledge regarding their actual content and severity at the onset of illness. AIMS: This study reports on delusions during the initiation of indicated treatment for first-episode psychosis (FEP). METHOD: Data were systematically collected from a sample of 636 patients entering a catchment-based early intervention service for FEP. The average severity and frequency of each delusional theme at baseline was reported with the Scale for the Assessment of Positive Symptoms. Delusional severity (globally and per theme) was examined across a number of sociodemographic and clinical variables. RESULTS: Delusions were present in the vast majority of individuals experiencing onset of FEP (94%), with persecutory (77.7%) being the most common theme. Persecutory delusions remained consistent in severity across diagnoses, but were more severe with older age at onset of FEP. No meaningful differences in delusional severity were observed across gender, affective versus non-affective psychosis, or presence/absence of substance use disorder. Globally, delusion severity was associated with anxiety, but not depression. Delusions commonly referred to as passivity experiences were related to hallucinatory experiences. CONCLUSIONS: This community sample offers a rare clinical lens into the severity and content of delusions in FEP. Although delusional severity was consistent across certain sociodemographic and clinical variables, this was not always the case. Future research should now consider the course of delusion themes over time.

Brain cortical and subcortical morphology in adolescents with depression and a history of suicide attempt.

Background: Suicidal behaviours are a major source of mortality and morbidity among adolescents. Given the maturational changes that occur in cortical and subcortical structures during adolescence, we tested whether atypical brain structural measurements were associated with a history of suicide attempt. Methods: We assessed 3 groups of adolescents (n = 92; 79% female, mean age 15.9 years, range 11.6-18.1 years): patients with a depressive disorder and a history of suicide attempt (n = 28); patient controls, who had a depressive disorder but no history of suicide attempt (n = 34); and healthy controls (n = 30). We derived regional cortical thickness and surface area, and subcortical volumes, from T1-weighted anatomic MRI scans acquired at 3 T. Results: We found significant group differences in surface area in the prefrontal, temporal and parietal regions, as well as in the volume of several subcortical nuclei (pFDR ≤ 0.05), but not in cortical thickness. Post hoc analyses indicated that morphological alterations primarily differentiated patients with a history of suicide attempt from healthy controls, but not from patient controls. However, patients with a history of suicide attempt exhibited positive correlations between age and cortical thickness in the temporal cortices and right insula, and between age and right putamen volume (i.e., thicker regional cortex and larger subcortical volumes with age). These correlations were negative in both patient controls and healthy controls (i.e., thinner regional cortex and smaller subcortical volumes). Limitations: Sample sizes, cross-sectional findings and psychiatric heterogeneity were limitations of this study. Conclusion: Macroscopic structural differences in several brain regions differentiated adolescents with a history of suicide attempt from healthy controls, but not from patient controls. However, adolescents with a history of suicide attempt may present with atypical maturation of specific cortical and subcortical regions that might contribute to the risk of suicidal behaviour.

Understanding Components of Duration of Untreated Psychosis and Relevance for Early Intervention Services in the Canadian Context: Comprendre les Composantes de la Durée de la Psychose Non Traitée et la Pertinence de Services D'intervention Précoce Dans le Contexte Canadien.

BACKGROUND: Clinical, functional, and cost-effectiveness outcomes from early intervention services (EIS) for psychosis are significantly associated with the duration of untreated psychosis (DUP) for the patients they serve. However, most EIS patients continue to report long DUP, while a reduction of DUP may improve outcomes. An understanding of different components of DUP and the factors associated with them may assist in targeting interventions toward specific sources of DUP. OBJECTIVES: To examine the components of DUP and their respective determinants in order to inform strategies for reducing delay in treatment in the context of an EIS. METHODS: Help-seeking (DUP-H), Referral (DUP-R), and Administrative (DUP-A) components of DUP, pathways to care, and patient characteristics were assessed in first episode psychosis (N = 532) patients entering an EIS that focuses on systemic interventions to promote rapid access. Determinants of each component were identified in the present sample using multivariate analyses. RESULTS: DUP-H (mean 25.64 ± 59.00) was longer than DUP-R (mean = 14.95 ± 45.67) and DUP-A (mean 1.48 ± 2.55). Multivariate analyses showed that DUP-H is modestly influenced by patient characteristics (diagnosis and premorbid adjustment; R2 = 0.12) and DUP-R by a combination of personal characteristics (age of onset and education) and systemic factors (first health services contact and final source of referral; R2 = 0.21). Comorbid substance abuse and referral from hospital emergency services have a modest influence on DUP-A (R2 = 0.08). Patients with health care contact prior to onset of psychosis had a shorter DUP-H and DUP-R than those whose first contact was after psychosis onset (F(1, 498) = 4.85, P < 0.03 and F(1, 492) = 3.34, P < 0.07). CONCLUSIONS: Although much of the variance in DUP is unexplained, especially for help-seeking component, the systemic portion of DUP may be partially determined by relatively malleable factors. Interventions directed at altering pathways to care and promote rapid access may be important targets for reducing DUP. Simplifying administrative procedures may further assist in reducing DUP.

Suicidality Over the First 5 Years of Psychosis: Does Extending Early Intervention Have Benefits?

OBJECTIVE: We aimed to investigate whether individuals with first-episode psychosis (FEP) receiving extended early intervention (EI) were less likely to experience suicidal ideation and behaviors than those transferred to regular care after 2 years of EI. Another objective was to examine the 5-year course of suicidality in FEP. METHODS: We conducted a secondary analysis of a randomized controlled trial where 220 patients were randomized after 2 years of EI to receive extended EI or regular care for the subsequent 3 years. Suicidality was rated using the Brief Psychiatric Rating Scale. Linear mixed model analysis was used to study time and group effects on suicidality. RESULTS: Extended EI and regular care groups did not differ on suicidality. There was a small decrease in suicidality over time, F(7, 1038) = 1.84, P = 0.077, with an immediate sharp decline within a month of treatment, followed by stability over the remaining 5 years. Patients who endorsed suicidality at entry (46.6%) had higher baseline positive, negative, and depressive symptoms. The 5-year course fell in 3 groups: never endorsed suicidality (33.9%), endorsed suicidality at low-risk levels (43.1%), and endorsed high-risk levels (23.0%). The high-risk group had a higher proportion of affective versus nonaffective psychosis diagnosis; higher baseline positive and depressive symptoms; higher 5-year mean depression scores, and fewer weeks of positive symptom remission over the 5-year course. CONCLUSIONS: The first month of treatment is a critical period for suicide risk in FEP. Although early reductions in suicidality are often maintained, our findings make the case for sustained monitoring for suicide risk management.

The Relational Trip Task, a novel ecological measure of relational memory: data from a schizophrenia sample.

INTRODUCTION: Relational memory (RM) is severely impaired in schizophrenia. Unitisation can circumvent RM impairments in clinical populations as measured by the transverse-patterning (TP) task, a well-established measure of RM capacity. We compared memory performance on a new ecological RM measure, the Relational Trip Task (RTT), to that of TP at baseline and examined the effects of a unitisation intervention in RTT performance. RTT involves learning relational information of real-life stimuli, such as the relationship between people and places or objects. METHODS: TP and RTT performances were examined in 45 individuals with schizophrenia. TP-impaired participants (n = 22) were randomised to either the intervention or an active control group. TP and RTT were administered again after unitisation training. Task validity and reliability were assessed. Intervention group's pre- and post-RTT accuracies were compared and contrasted to that in the control group. RESULTS: RTT and TP were moderately correlated. TP non-learners had inferior performance in RTT at baseline. Improvement in RTT performance after unitisation training was observed in the intervention group; no pre-post improvement was observed in the control group. CONCLUSION: RTT has an acceptable criterion validity and excellent alternate-form reliability. Unitisation seemed to be successfully generalized to support associations of real-life stimuli.

Altered hippocampal centrality and dynamic anatomical covariance of intracortical microstructure in first episode psychosis.

Hippocampal circuitry has been posited to be fundamental to positive symptoms in psychosis, but its contributions to other factors important for outcome remains unclear. We hypothesized that longitudinal changes in the hippocampal circuit and concomitant changes of intracortical microstructure are altered in first episode psychosis (FEP) patients and that such changes are associated with negative symptoms and verbal memory. Longitudinal brain scans (2-4 visits over 3-15 months) were acquired for 27 FEP and 29 age- and sex-matched healthy controls. Quantitative T1 maps, sensitive to myelin content, were used to sample the microstructure of the hippocampal subfields and output circuitry (fimbria, alveus, fornix, mammillary bodies), and intracortical regions. Dynamic anatomical covariance in pair-wise regional trajectories were assessed for each subject, and graph theory was used to calculate a participation coefficient metric that quantifies the similarity/divergence between hippocampal and intracortical microstructure. The mean participation coefficient of the hippocampus was significantly reduced in FEP patients compared with controls, reflecting differences in output hippocampal regions. Importantly, lower participation coefficient of the hippocampal circuit was associated with worse negative symptoms, a relationship that was mediated by changes in verbal memory. This study provides evidence for reduced hippocampal centrality in FEP and concomitant changes in intracortical anatomy. Myelin-rich output regions of the hippocampus may be an important biological trigger in early psychosis, with cascading effects on broader cortical networks and resultant clinical profiles.

Cerebrovascular inflammation promotes the formation of brain metastases.

Brain metastases are the most prevalent intracranial malignancy. Patient outcome is poor and treatment options are limited. Hence, new avenues must be explored to identify potential therapeutic targets. Inflammation is a known critical component of cancer progression. Intratumoral inflammation drives progression and leads to the release of circulating tumor cells (CTCs). Inflammation at distant sites promotes adhesion of CTCs to the activated endothelium and then initiates the formation of metastases. These interactions mostly involve cell adhesion molecules expressed by activated endothelial cells. For example, the vascular cell adhesion molecule-1 (VCAM-1) is known to promote transendothelial migration of cancer cells in different organs. However, it is unclear whether a similar mechanism occurs within the specialized environment of the brain. Our objective was therefore to use molecular imaging to assess the potential role of VCAM-1 in promoting the entry of CTCs into the brain. First, magnetic resonance imaging (MRI) and histological analyses revealed that cerebrovascular inflammation induced by intracranial injection of lipopolysaccharide significantly increased the expression of VCAM-1 in the Balb/c mouse brain. Next, intracardiac injection of 4T1 mammary carcinoma cancer cells in animals with cerebrovascular inflammation yielded a higher brain metastasis burden than in the control animals. Finally, blocking VCAM-1 prior to 4T1 cells injection prevented this increased metastatic burden. Here, we demonstrated that by contributing to CTCs adhesion to the activated cerebrovascular endothelium, VCAM-1 improves the capacity of CTCs to form metastatic foci in the brain.

Cerebrovascular MRI in the mouse without an exogenous contrast agent.

PURPOSE: To assess the effect of a variety of anesthetic regimes on T2∗ -weighted MRI of the mouse brain and to determine the optimal regimes to perform T2∗ -weighted MRI of the mouse cerebrovasculature without a contrast agent. METHODS: Twenty mice were imaged with a 3D T2∗ -weighted sequence under isoflurane, dexmedetomidine, or ketamine-xylazine anesthesia with a fraction of inspired oxygen varied between 10% and 95% + 5% CO2 . Some mice were also imaged after an injection of an iron oxide contrast agent as a positive control. For every regime, whole brain vessel conspicuity was visually assessed and the apparent vessel density in the cortex was quantified and compared. RESULTS: The commonly used isoflurane anesthetic leads to poor vessel conspicuity for fraction of inspired oxygen higher or equal to 21%. Dexmedetomidine and ketamine-xylazine enable the visualization of a significantly larger portion of the vasculature for the same breathing gas. Under isoflurane anesthesia, the fraction of inspired oxygen must be lowered to between 10% and 14% to obtain similar vessel conspicuity. Initial results on automatic segmentation of veins and arteries using the iron oxide positive control are also reported. CONCLUSION: T2∗ -weighted MRI in combination with an appropriate anesthetic regime can be used to visualize the mouse cerebrovasculature without a contrast agent. The differences observed between regimes are most likely caused by blood-oxygen level dependent effects, highlighting the important impact of the anesthetic regimes on cerebral blood oxygenation of the mouse brain at rest.