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Background and Hypothesis The integration of information that typifies working memory (WM) operation requires a flexible, dynamic functional relationship among brain regions. In schizophrenia, though WM capacity is prominently impaired at higher loads, the mechanistic underpinnings are unclear. As a result, we lack convincing cognitive remediation of load-dependent deficits. We hypothesize that reduced WM capacity arises from a disruption in dynamic functional connectivity when patients face cognitive demands. Study Design We calculate the dynamic voxel-wise degree centrality (dDC) across the functional connectome in 142 patients with schizophrenia and 88 healthy controls (HCs) facing different WM loads during an n-back task. We tested associations of the altered variability in dDC and clinical symptoms and identified intermediate connectivity configurations (clustered states) across time during WM operation. These analyses were repeated in another independent dataset of 169 subjects (102 with schizophrenia). Study Results Compared with HCs, patients showed an increased dDC variability of supplementary motor area (SMA) for the "2back vs. 0back" contrast. This instability at the SMA seen in patients correlated with increased positive symptoms and followed a limited "U-shape" pattern at rest-condition and 2 loads. In the clustering analysis, patients showed reduced centrality in the SMA, superior temporal gyrus, and putamen. These results were replicated in a constrained search in the second independent dataset. Conclusions Schizophrenia is characterized by a load-dependent reduction of stable centrality in SMA; this relates to the severity of positive symptoms, especially disorganized behaviour. Restoring SMA stability in the presence of cognitive demands may have a therapeutic effect in schizophrenia. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Active inference has become an influential concept in psychopathology. We apply active inference to investigate conceptual disorganization in first-episode schizophrenia. We conceptualize speech production as a decision-making process affected by the latent "conceptual organization"—as a special case of uncertainty about the causes of sensory information. Uncertainty is both minimized via speech production—in which function words index conceptual organization in terms of analytic thinking—and tracked by a domain-general salience network. We hypothesize that analytic thinking depends on conceptual organization. Therefore, conceptual disorganization in schizophrenia would be both indexed by low conceptual organization and reflected in the effective connectivity within the salience network. Study Design With 1-minute speech samples from a picture description task and resting state fMRI from 30 patients and 30 healthy subjects, we employed dynamic causal and probabilistic graphical models to investigate if the effective connectivity of the salience network underwrites conceptual organization. Study Results Low analytic thinking scores index low conceptual organization which affects diagnostic status. The influence of the anterior insula on the anterior cingulate cortex and the self-inhibition within the anterior cingulate cortex are elevated given low conceptual organization (ie, conceptual disorganization). Conclusions Conceptual organization, a construct that explains formal thought disorder, can be modeled in an active inference framework and studied in relation to putative neural substrates of disrupted language in schizophrenia. This provides a critical advance to move away from rating-scale scores to deeper constructs in the pursuit of the pathophysiology of formal thought disorder. [ABSTRACT FROM AUTHOR]

Background Pathophysiological inquiries into schizophrenia require a consideration of one of its most defining features: disorganization and impoverishment in verbal behavior. This feature, often captured using the term Formal Thought Disorder (FTD), still remains to be one of the most poorly understood and understudied dimensions of schizophrenia. In particular, the large-scale network level dysfunction that contributes to FTD remains obscure to date. Study Design In this narrative review, we consider the various challenges that need to be addressed for us to move towards mapping FTD (construct) to a brain network level account (circuit). Study Results The construct-to-circuit mapping goal is now becoming more plausible than it ever was, given the parallel advent of brain stimulation and the tools providing objective readouts of human speech. Notwithstanding this, several challenges remain to be overcome before we can decisively map the neural basis of FTD. We highlight the need for phenotype refinement, robust experimental designs, informed analytical choices, and present plausible targets in and beyond the Language Network for brain stimulation studies in FTD. Conclusions Developing a therapeutically beneficial pathophysiological model of FTD is a challenging endeavor, but holds the promise of improving interpersonal communication and reducing social disability in schizophrenia. Addressing the issues raised in this review will be a decisive step in this direction. [ABSTRACT FROM AUTHOR]

Background and hypothesis Following the first episode of psychosis, some patients develop poor social and occupational outcomes, while others display a pattern of preserved functioning. Evidence from preclinical, genetic, and biochemical studies suggest a role for high oxidative stress in poor functional outcomes among patients. The measurement of intracortical glutathione (GSH) using magnetic resonance spectroscopy (MRS) enables investigating the relationship between central antioxidant tone and functional outcomes at the time of first-episode psychosis (FEP). We hypothesized that patients with higher central antioxidant tone at first presentation will have better functional outcomes in early stages of illness. Study design We scanned 57 patients with FEP and 30 matched healthy controls and estimated GSH resonance using 7-Tesla MRS. We minimized the confounding effects of illness chronicity, long-term treatment exposure, and metabolic complications by recruiting patients with <2 weeks of lifetime antipsychotic exposure on average and followed up this cohort for the next 1 year to determine functional outcomes. Study results Patients who achieved employment/education or training status (EET) in the first year, had higher GSH at the baseline than healthy controls. Social and occupational functioning assessment scale (SOFAS) scores were also significantly higher in patients with higher GSH levels at the outset, after adjusting for various confounds including baseline SOFAS. Patients who were not in EET did not differ from healthy subjects in their GSH levels. Conclusion Our observations support a key role for the central antioxidant tone in the functional outcomes of early psychosis. [ABSTRACT FROM AUTHOR]

This special issue of DISCOURSE in Psychosis focuses on the role of language in psychosis, including the relationships between formal thought disorder and conceptual disorganization, with speech and language markers and the neural mechanisms underlying these features in psychosis. It also covers the application of computational techniques in the study of language in psychosis, as well as the potential for using speech and language data for digital phenotyping in psychiatry. [ABSTRACT FROM AUTHOR]

Common and distinct neural bases of Schizophrenia (SZ) and bipolar disorder (BP) have been explored using resting-state fMRI (rs-fMRI) functional connectivity (FC). However, fMRI is an indirect measure of neural activity, which is a convolution of the hemodynamic response function (HRF) and latent neural activity. The HRF, which models neurovascular coupling, varies across the brain within and across individuals, and is altered in many psychiatric disorders. Given this background, this study had three aims: quantifying HRF aberrations in SZ and BP, measuring the impact of such HRF aberrations on FC group differences, and exploring the genetic basis of HRF aberrations. We estimated voxel-level HRFs by deconvolving rs-fMRI data obtained from SZ (N = 38), BP (N = 19), and matched healthy controls (N = 35). We identified HRF group differences (P <.05, FDR corrected) in many regions previously implicated in SZ/BP, with mediodorsal, habenular, and central lateral nuclei of the thalamus exhibiting HRF differences in all pairwise group comparisons. Thalamus seed-based FC analysis revealed that ignoring HRF variability results in false-positive and false-negative FC group differences, especially in insula, superior frontal, and lingual gyri. HRF was associated with DRD2 gene expression (P <.05, 1.62 < |Z| < 2.0), as well as with medication dose (P <.05, 1.75 < |Z| < 3.25). In this first study to report HRF aberrations in SZ and BP, we report the possible modulatory effect of dopaminergic signalling on HRF, and the impact that HRF variability can have on FC studies in clinical samples. To mitigate the impact of HRF variability on FC group differences, we suggest deconvolution during data preprocessing. [ABSTRACT FROM AUTHOR]

Background Thalamocortical circuit imbalance characterized by prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity has been consistently documented at rest in schizophrenia (SCZ). However, this thalamocortical imbalance has not been studied during task engagement to date, limiting our understanding of its role in cognitive dysfunction in schizophrenia. Methods Both n-back working memory (WM) task-fMRI and resting-state fMRI data were collected from 172 patients with SCZ and 103 healthy control subjects (HC). A replication sample with 49 SCZ and 48 HC was independently obtained. Sixteen thalamic subdivisions were employed as seeds for the analysis. Results During both task-performance and rest, SCZ showed thalamic hyperconnectivity with sensorimotor cortices, but hypoconnectivity with prefrontal-cerebellar regions relative to controls. Higher sensorimotor-thalamic connectivity and lower prefronto-thalamic connectivity both relate to poorer WM performance (lower task accuracy and longer response time) and difficulties in discriminating target from nontarget (lower d′ score) in n-back task. The prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity were anti-correlated both in SCZ and HCs; this anti-correlation was more pronounced with less cognitive demand (rest>0-back>2-back). These findings replicated well in the second sample. Finally, the hypo- and hyper-connectivity patterns during resting-state positively correlated with the hypo- and hyper-connectivity during 2-back task-state in SCZ respectively. Conclusions The thalamocortical imbalance reflected by prefronto-thalamic hypoconnectivity and sensorimotor-thalamic hyperconnectivity is present both at rest and during task engagement in SCZ and relates to working memory performance. The frontal reduction, sensorimotor enhancement pattern of thalamocortical imbalance is a state-invariant feature of SCZ that affects a core cognitive function. [ABSTRACT FROM AUTHOR]

Treatment resistance (TR) in patients with first-episode psychosis (FEP) is a major cause of disability and functional impairment, yet mechanisms underlying this severe disorder are poorly understood. As one view is that TR has neurodevelopmental roots, we investigated whether its emergence relates to disruptions in synchronized cortical maturation quantified using gyrification-based connectomes. Seventy patients with FEP evaluated at their first presentation to psychiatric services were followed up using clinical records for 4 years; of these, 17 (24.3%) met the definition of TR and 53 (75.7%) remained non-TR at 4 years. Structural MRI images were obtained within 5 weeks from first exposure to antipsychotics. Local gyrification indices were computed for 148 contiguous cortical regions using FreeSurfer; each subject's contribution to group-based structural covariance was quantified using a jack-knife procedure, providing a single deviation matrix for each subject. The latter was used to derive topological properties that were compared between TR and non-TR patients using a Functional Data Analysis approach. Compared to the non-TR patients, TR patients showed a significant reduction in small-worldness (Hedges's g = 2.09, P <.001) and a reduced clustering coefficient (Hedges's g = 1.07, P <.001) with increased length (Hedges's g = −2.17, P <.001), indicating a disruption in the organizing principles of cortical folding. The positive symptom burden was higher in patients with more pronounced small-worldness (r =.41, P =.001) across the entire sample. The trajectory of synchronized cortical development inferred from baseline MRI-based structural covariance highlights the possibility of identifying patients at high-risk of TR prospectively, based on individualized gyrification-based connectomes. [ABSTRACT FROM AUTHOR]

This study aimed to shed light on the linguistic style affecting the communication discourse in first-episode schizophrenia (FES) by investigating the analytic thinking index in relation to clinical scores of conceptual and thought disorganization (Positive and Negative Syndrome Scale, PANSS-P2 and Thought and Language Index, TLI). Using robust Bayesian modeling, we report three major findings: (1) FES subjects showed reduced analytic thinking, exhibiting a less categorical linguistic style than healthy control (HC) subjects (Bayes factor, BF10 > 1000), despite using the same proportion of function and content words as HCs; (2) the lower the analytic thinking score, the higher the symptoms scores of conceptual disorganization (PANSS-P2, BF = 22.66) and global disorganization of thinking (TLI, BF10 = 112.73); (3) the linguistic style is a better predictor of conceptual disorganization than the cognitive measure of processing speed in schizophrenia (SZ). These findings provide an objectively detectable linguistic style with a focus on Natural Language Processing Analytics of transcribed speech samples of patients with SZ that require no clinical judgment. These findings also offer a crucial insight into the primacy of linguistic structural disruption in clinically ascertained disorganized thinking in SZ. Our work contributes to an emerging body of literature on the psychopathology of SZ using a first-order lexeme-level analysis and a hypothesis-driven approach. At a utilitarian level, this has implications for improving educational and social outcomes in patients with SZ. [ABSTRACT FROM AUTHOR]

Progressive reduction in glutamatergic transmission has been proposed as an important component of the illness trajectory of schizophrenia. Despite its popularity, to date, this notion has not been convincingly tested in patients in early stages of schizophrenia. In a longitudinal 7T magnetic resonance spectroscopy (1H-MRS), we quantified glutamate at the dorsal anterior cingulate cortex in 21 participants with a median lifetime antipsychotic exposure of less than 3 days and followed them up after 6 months of treatment. Ten healthy controls were also scanned at 2 time points. While patients had significantly lower overall glutamate levels than healthy controls (F(1,27) = 5.23, P = .03), we did not observe a progressive change of glutamate concentration in patients (F(1,18) = 0.47, P = .50), and the group by time interaction was not significant (F(1,27) = 0.86, P = .36). On average, patients with early psychosis receiving treatment showed a 0.02 mM/y increase, while healthy controls showed a 0.06 mM/y reduction of MRS glutamate levels. Bayesian analysis of our observations does not support early, post-onset gluta-mate loss in schizophrenia. Interestingly, it provides evidence in favor of a lack of progressive glutamate change in our schizophrenia sample--indicating that the glutamate level at the onset of illness was the best predictor of the levels 6 months after treatment. A more nuanced view of glutamatergic physiology, linked to early cortical maturation, may be required to understand glutamate-mediated dynamics in schizophrenia. [ABSTRACT FROM AUTHOR]

Background Working memory (WM) deficit is a key feature of schizophrenia that relates to a generalized neural inefficiency of extensive brain areas. To date, it remains unknown how these distributed regions are systemically organized at the connectome level and how the disruption of such organization brings about the WM impairment seen in schizophrenia. Methods We used graph theory to examine the neural efficiency of the functional connectome in different granularity in 155 patients with schizophrenia and 96 healthy controls during a WM task. These analyses were repeated in another independent dataset (81 patients and 54 controls). Linear regression analysis was used to test associations of altered graph properties, clinical symptoms, and WM accuracy in patients. A machine-learning approach was adopted to study the ability of multivariate connectome features from one dataset to discriminate patients from controls in the second dataset. Results Small-worldness of the whole-brain connectome was significantly increased in schizophrenia during the WM task; this increase is related to better (though subpar) WM accuracy in patients with more severe negative symptom burden. There was a shift in the degree distribution to a more homogeneous form in patients. The machine-learning approach classified a new set of patients from controls with 84.3% true-positivity rate for schizophrenia and 71.6% overall accuracy. Conclusions We demonstrate a putative mechanistic link between connectome topology, hub redistribution, and impaired n -back performance in schizophrenia. The task-dependent modulation of the connectome relates to, but remains inefficient in, improving the performance above par in the presence of severe negative symptoms. [ABSTRACT FROM AUTHOR]

The diagnosis of schizophrenia is thought to embrace several distinct subgroups. The manifold entities in a single clinical patient group increase the variance of biological measures, deflate the group-level estimates of causal factors, and mask the presence of treatment effects. However, reliable neurobiological boundaries to differentiate these subgroups remain elusive. Since cortical thinning is a well-established feature in schizophrenia, we investigated if individuals (patients and healthy controls) with similar patterns of regional cortical thickness form naturally occurring morphological subtypes. K-means algorithm clustering was applied to regional cortical thickness values obtained from 256 structural MRI scans (179 patients with schizophrenia and 77 healthy controls [HCs]). GAP statistics revealed three clusters with distinct regional thickness patterns. The specific patterns of cortical thinning, clinical characteristics, and cognitive function of each clustered subgroup were assessed. The three clusters based on thickness patterns comprised of a morphologically impoverished subgroup (25% patients, 1% HCs), an intermediate subgroup (47% patients, 46% HCs), and an intact subgroup (28% patients, 53% HCs). The differences of clinical features among three clusters pertained to age-of-onset, N-back performance, duration exposure to treatment, total burden of positive symptoms, and severity of delusions. Particularly, the morphologically impoverished group had deficits in N-back performance and less severe positive symptom burden. The data-driven neuroimaging approach illustrates the occurrence of morphologically separable subgroups in schizophrenia, with distinct clinical characteristics. We infer that the anatomical heterogeneity of schizophrenia arises from both pathological deviance and physiological variance. We advocate using MRI-guided stratification for clinical trials as well as case–control investigations in schizophrenia. [ABSTRACT FROM AUTHOR]

In the classical descriptions of schizophrenia, Kraepelin and Bleuler recognized disorganization and impoverishment of mental activity as fundamental symptoms. Their classical descriptions also included a tendency to persisting disability. The psychopathological processes underlying persisting disability in schizophrenia remain poorly understood. The delineation of a core deficit underlying persisting disability would be of value in predicting outcome and enhancing treatment. We tested the hypothesis that mental disorganization and impoverishment are associated with persisting impairments of cognition and role function, and together reflect a latent core deficit that is discernible in cases diagnosed by modern criteria. We used Confirmatory Factor Analysis to determine whether measures of disorganization, mental impoverishment, impaired cognition, and role functioning in 40 patients with schizophrenia represent a single latent variable. Disorganization scores were computed from the variance shared between disorganization measures from 3 commonly used symptom scales. Mental impoverishment scores were computed similarly. A single factor model exhibited a good fit, supporting the hypothesis that these measures reflect a core deficit. Persisting brain disorders are associated with a reduction in post-movement beta rebound (PMBR), the characteristic increase in electrophysiological beta amplitude that follows a motor response. Patients had significantly reduced PMBR compared with healthy controls. PMBR was negatively correlated with core deficit score. While the symptoms constituting impoverished and disorganized mental activity are dissociable in schizophrenia, nonetheless, the variance that these 2 symptom domains share with impaired cognition and role function, appears to reflect a pathophysiological process that might be described as the core deficit of classical schizophrenia. [ABSTRACT FROM AUTHOR]

Schizophrenia is genetic in origin and associated with a fecundity disadvantage. The deficits in schizophrenia have been attributed to variation related to the human capacity for language or brain laterality. How sex influences the relative connectivity of the 2 hemispheres is a route to understanding these 2 functions. Using resting-state functional magnetic resonance imaging (fMRI) we searched for sex- and hemisphere-specific changes in whole-brain functional-connectivity in multi-site datasets (altogether 672 subjects including 286 patients, all right-handed) in the first-episode schizophrenia (illness duration ≤ 1 year, mostly drug naive) and in chronic stages of schizophrenia (illness duration > 1 year), respectively. We used meta-analyses to integrate data from different sources concerning individuals at the same illness stage. We found first-episode male patients are predominantly left-lateralized in aberrant connectivity with a focus on Broca's area. Female patients show a lesser degree of lateralization than males, but to the right particularly in orbital frontal cortex. In the chronic stage, the focus of aberrant connectivity shifted from anterior to posterior structures with prominent involvement of the thalamus and pre- and post-central gyri bilaterally and in both sexes. While the "deviant connectivity" is right-sided in both the first-episode and the chronic stages in females, in males there is a shift between stages from the left to the right hemisphere. We hypothesized that the pathophysiology of schizophrenia may lie in the interaction between sex and lateralization, ie, in genetic mechanisms located on the X and Y chromosomes, intrinsic to the evolution of language. [ABSTRACT FROM AUTHOR]

Background: Although oxytocin is one of the most widely studied neuropeptides in recent times, the mechanistic process by which it modulates social-affective behavior in the brain is not yet clearly understood. Thus, to understand the neurophysiological basis of oxytocin effects, we used resting-state functional MRI to examine the effects of intranasal oxytocin on brain connectivity in healthy males. Methods: Using a randomized, double-blinded, placebo-controlled, crossover design, 15 healthy male volunteers received 24 IU intranasal oxytocin or placebo prior to resting-state functional MRI acquisition at 3T. Results: We found that oxytocin significantly reduced the degree centrality of the right precuneus (P < .05). Oxytocin also reduced connectivity between the bilateral amygdalae and between the right precuneus and the right and left amygdala (P < .05). Although there were no significant changes in regional homogeneity at the whole brain level, posthoc results showed a reduction involving the right precuneus (P < .05). Conclusions: These results show that oxytocin affects one of the key centers in the brain for social cognition and introspective processing, the precuneus, and enhances our understanding of how oxytocin can modulate brain networks at rest. An improved understanding of the neurophysiological effects of oxytocin can be important in terms of evaluating the mechanisms that are likely to underlie the clinical responses observed upon long-term oxytocin administration. [ABSTRACT FROM AUTHOR]

The point of rarity in brain structure and function that separates the 2 major psychotic disorders—schizophrenia and bipolar disorder—is presently unknown. The aim of this study is to combine surface anatomical and functional imaging modalities to quantify the integrity of cortical connectivity in pursuit of the neural basis of the Kraepelinian “line of divide.” We tested the hypothesis that multimodal brain regions show overlapping abnormalities in both disorders, while schizophrenia-specific defects are likely to be localized to sensory processing regions. Cortical folding patterns (gyrification) and functional connectivity hub architecture (degree centrality) were studied in a sample of 39 subjects with established schizophrenia, 20 subjects with psychotic bipolar disorder, and 34 healthy controls. We observed a significant difference between the 2 groups in both gyrification and functional connectivity of the visual processing regions. Further, the aberrant functional connectivity of the visual processing regions predicted persistent symptom burden better than the diagnostic information. Using a spatial similarity analysis, we observed that the degree of overlap between the 2 disorders was small (25%) for changes in cortical gyrification and modest (51%) for changes in functional connectivity measured during a cognitive task (n-back). In conclusion, our results suggest that prominent unimodal sensory processing deficits are more likely to be present in schizophrenia than in bipolar disorder. Further, connectivity-based neuroimaging measures appear to be better indicators of diagnostic discontinuity than the symptom-based clinical information. [ABSTRACT FROM PUBLISHER]

Background: The efficiency of human brain depends on the integrity of both long- and short-range connections, but the long-range connections need to be “penalized” to reduce overall wiring costs. This principle, termed as the anatomical distance function (ADF), refers to the presence of an inverse relationship between anatomical distance and connectivity. A crucial developmental feature that occurs in normal adolescence is the weakening of ADF, which is characterized by a selective strengthening of long-distance connections. Schizophrenia is associated with widespread dysconnectivity that is linked to aberrant cortical development. Methods: We studied the ADF in adults with schizophrenia (n = 28), their age-matched siblings (n = 28), and healthy controls (n = 60). We investigated the proportional abnormalities in the long-range connections involving interhemispheric, subcortical, frontal, and salience network regions and localized the connections showing most significant changes in schizophrenia. The groups were discriminated on the basis of short- and long-range connectivity using a machine-learning algorithm. Results: Both patients and their siblings showed abnormally pronounced ADF. This was associated with a disproportionate reduction in the number of long-range connections, affecting the subcortical, interhemispheric, and the salience network connections. The abnormalities in long-range connections had superior ability to accurately identify group membership. Conclusions: A crucial organizing principle of the brain architecture that becomes apparent during normal adolescence is disturbed in schizophrenia. While siblings show some evidence of compensating for this deficit, patients lack putative compensatory changes. Age-related shift in ADF provides an explanatory framework for the developmental emergence of widespread dysconnectivity that is influenced by genetic risk in schizophrenia. [ABSTRACT FROM PUBLISHER]

Background: For more than 100 years, disorganization and impoverishment of mental activity have been recognised as fundamental symptoms of schizophrenia. These symptoms may reflect a core brain process underlying persisting disability. Predisposition to persisting disability is a clinically important aspect of schizophrenia, yet the psychopathological processes predisposing to persisting disability are poorly understood. The delineation of a putative core deficit associated with persisting disability would be of potentially great value in delineating the underlying pathological processes and eventually in enhancing treatment. Aims: To derive scores for mental disorganization and impoverishment from commonly used rating scales, and test the hypothesis that disorganization and impoverishment, along with impaired cognition and role-function reflect a latent variable that is a plausible candidate for the putative core deficit. Methods: In a group of 40 patients with schizophrenia, we tested the hypothesis that mental disorganization and impoverishment, along with impaired cognition and role-function reflect a latent variable that is a plausible candidate for the core deficit. We derived disorganization and impoverishment factors from three symptom scales: PANSS, SSPI and CASH. For each of the three scales, we demonstrated significant correlation between these factors and impaired role function assessed using the Social and Occupational Functioning Scale (SOFAS) and cognitive impairment measured using the Digit Symbol Substitution Test (DSST). We then assessed the relationship between this latent “core deficit” variable and Post Movement Beta Rebound (PMBR), measured using magnetoencephalography and associated with persisting brain disorders. Results: A single factor model provided excellent fit for the four features of core deficit, requiring no further modifications. Results were consistently similar for measures from all three scales. χ2 value was non-significant (range: 0.30 to 2.13, df = 2, p > 0.35), GFI met the threshold of greater than 0.9 (range = .976 to .996) and RMSEA was lesser than 0.06 (range = 0.000 to 0.040). PMBR was found to be significantly reduced in the schizophrenia group compared to healthy controls (t (28) =44.2 ± 12.1, p = 0.001). PMBR was strongly correlated with disorganization (r (40) = .600, p=0.001). In the hierarchical regression, neither age nor medication dose were significant predictors, but PMBR did predict the severity of the core deficit (F (1, 23) = 12.6, P=0.002, R² = -.592). Discussion: Scores for the two latent variables representing impoverishment and disorganization of mental activity in schizophrenia can be derived from each of three symptom rating scales. A composite measure of impoverishment, disorganization, impaired cognition and impaired role function reflects an underlying psychopathological process that might be described as the core deficit of classical schizophrenia. [ABSTRACT FROM AUTHOR]

The ability to visualize alive human brain's function, structure and chemical composition in ultra-high field 7-Tesla MRI has opened the doors for several neuroscientific advances in recent times. This symposium will focus on the data gathered from this high-resolution access to a patient's brain tissue to question some of the existing views on the mechanisms linked to psychosis. The symposium has the following objectives each discussed by the presenters: (a) Dr. Frangou will demonstrate how the increased spatial resolution of 7T structural imaging enabled the development and validation of a new method for deriving lamina-specific measures of intracortical myelin. Using this measure, it is possible to identify brain regions of disrupted intracortical organization in schizophrenia that map to symptomatic severity and cognitive disruption. (b) Dr. Palaniyappan shows that the highly resolved, dynamic course of glutamate and glutathione changes using 7T functional spectroscopy is a promising marker of early prognostic course that advances our approach to identifying an oxidative stress-prone subgroup of patients with schizophrenia. (c) Dr. Lahti used magnetoencephalography (MEG), 7T Spectroscopy, and 7T fMRI during task performance to show that illness-related changes in MRI and MEG signals were correlated, while changes in the highly resolved glutamate and NAA represented an independent underlying pathological mechanism. (d) Dr. Hulshoff Pol will leverage the power of cortical layer-specific investigations using 7T as well as spectroscopy to demonstrate illness-related abnormalities in the GABAergic system. She will present data showing that patients with SCZ have significantly lower prefrontal GABA/Cr ratios that were inversely correlated with cognitive functioning. Dr. Laura Rowland will lead the discussion, proffering further means to probe mechanistic aspects of psychosis as well as highlighting the future of a discovery-led approach in 7T neuroimaging in psychotic disorders. [ABSTRACT FROM AUTHOR]

Background The hippocampus and associated circuitry are integral to the manifestation of psychosis and associated symptoms. There is evidence for the hippocampus as a key hub in healthy brain networks, which situates the hippocampus as an important target in the emerging view of psychosis as a disorder of altered connectome development. Here, we test the hypothesis that longitudinal changes in the hippocampus and surrounding white matter in relation to coordinated changes within intracortical (IC) and superficial white matter (SWM) microstructure in first episode psychosis (FEP) patients is altered compared to controls. We also examine whether such alterations are associated with changes in negative symptoms and verbal memory, two significant predictors of functional outcome. Methods Longitudinal MRI scans (3T; 2–4 visits over 3–21 months) were acquired for 23 FEP and 26 HC. MP2RAGE quantitative T1 (qT1) maps, sensitive to myelin content, were used to sample microstructure of the hippocampus, IC and SWM regions. Mean qT1 for hippocampal subfields and output circuitry (fimbria, alveus, fornix, mammillary bodies) were calculated based on labels extracted from high-resolution T2-weighted scans (0.64 mm3) with MAGeT-Brain. IC qT1 was defined as the average qT1 at 35/45/55/65% cortical depths, and SWM qT1 was sampled 1mm below the grey-white matter boundary, across 81924 points of the brain surface, in relation to grey and white matter surfaces generated by CIVET. Cortical regions were then parcellated based on the Desikan-Killiany-Tourville atlas. Relationships between pair-wise regional trajectories were calculated for each subject, defined as the theta angle of separation between the qT1 rates of change of any two brain regions between timepoints. Parcellations of brain regions were defined a priori, where hippocampal subfields and surrounding white matter formed one parcel, and cortical regions were assigned to 7 parcels based on known functional networks. Graph theory was used to calculate participation coefficient (PC), to measure the distribution of connections between the hippocampal parcel to IC and SWM of the 7 cortical parcels. Mean PC of the hippocampal module was compared between FEP and controls, then correlated to changes in negative symptoms and Logical Memory from the Weschler Memory Scale in FEP. Results The PC of the hippocampal parcel in relation to IC networks was significantly reduced in FEP compared to HC (F1,45=9.85, p=0.003), and nominally reduced in relation to SWM (F1,45=4.67, p=0.036). Post-hoc analyses of individual subregions were restricted to hippocampal-IC networks, where CA1 and alveus bilaterally, left molecular layer, fornix, mammillary body and right fimbria significantly contributed to reduced hippocampal PC (p<0.05). Lower PC of the hippocampal parcel was significantly associated with worsening negative symptoms (r=-0.58, p=0.0043) and nominally associated with worsening verbal memory (r=0.46, p=0.031). These associations were driven by left CA1, alveus, mammillary body, and right fimbria (p<0.05). Discussion This study provides evidence for reduced hippocampal centrality in FEP in relation to coordinated anatomical changes within intracortical microstructure, suggesting the hippocampus may be related to changes in cortico-cortical connectivity. Particularly, centrality of output structures of the hippocampus, situated as putative connector hubs, are significantly related to changes in factors that contribute to patient functional outcomes. The myelin-rich output regions of the hippocampus may serve as an important therapeutic target in early psychosis, with cascading effects on broader cortical networks and resultant clinical profiles. [ABSTRACT FROM AUTHOR]

Background The hippocampus and its subfields are considered putative markers in schizophrenia. In particular, earliest volume deficits in select subfields have been demonstrated in multiple studies and extending to the rest later in the disease. Recently, there is increasing interest in studying the white matter projections from the hippocampus including the alveus, fimbria, and fornix that envelop the hippocampal formation--while there is mixed evidence towards their involvement in psychosis. Here, we leveraged a novel neuroanatomical atlas and automated segmentation to study the hippocampal subfields (GM) and white matter (WM) regions in first-episode psychosis (FEP). Methods Participants were recruited as part of a longitudinal neuroimaging project that follows changes in early psychosis during the course of treatment. 28 healthy control (HC) and 43 antipsychotic-naive FEP subjects were included. Subjects were assessed using DSM-5 criteria and the 8 item Positive and Negative Syndrome Scale (PANSS-8). All underwent magnetic resonance imaging at 7T using the MP2RAGE sequence to assess both grey matter and myelin content (qT1). High-resolution T1-weighted images (0.75mm3) were used to delineate the hippocampal subregions using the MAGeT Brain algorithm as previously validated. Volumes and qT1 in 9 structures (CA1, CA2/3, CA4/DG, SR/SL/SM, subiculum, and alveus, fimbria, fornix, mammillary bodies) were measured. Statistical analyses included the following: 1) Multiple linear regression with total hippocampal GM and WM volumes as dependent variables, examining the main effect of diagnosis accounting for age, gender as covariates, 2) Similarly, MANCOVA with subregion measures (volume and qT1) as dependent variables seeking the effect of diagnosis with age/gender covariates, 3) Partial least-squares (PLS) regression to determine the relationship between subregion measures and PANSS. Results Initial analyses included the entire cohort (28 HC, 43 FEP). We found significantly lower hippocampal GM (left: t= -2.33, p= 0.023, right: t=-2.64, p=0.010) and WM (left: t= -1.71, p=0.092, right: -2.351, p=0.022) volumes in FEP compared to HC. PLS regression (in the entire FEP cohort; N=43) identified two components that explained ~25% of the variance in total PANSS scores, with the first component significantly correlated with negative symptom scores (R=0.39, p=0.01), and second with positive symptom scores (R=0.31, p=0.04). We subsequently included only FEP subjects with a later diagnosis of schizophrenia, with more pronounced differences in GM (left: t=-2.24, p=0.030, right: t=-2.83, p=6.88E-03) and WM (left: t=-1.86, p=0.069, right: t=-3.319, p=1.77E-03). Subsequent analyses include only FEP-schizophrenia (25 FES). MANCOVA for subregion volumes and qT1 was not significant (p > 0.1), while post-hoc univariate testing showed significant contraction of the right CA4DG (t=-3.08, p=3.53E-03), stratum (t=-2.84, p=6.73E-03) and fimbria (t=-2.79, p=7.65E-03). In addition, we found qT1 increases mostly in the right stratum (t= 3.02, p=4.17E-03), CA2/CA3 (t=2.75, p=8.61E-03). For both volumes and qT1, less pronounced effects of diagnosis were seen in other subfields (p < 0.05). Discussion We replicated previous findings of selective reduction of hippocampal subfields, with an asymmetric preference towards the right. We additionally show contraction in white matter subregions with concurrent qT1 increases suggesting the possibility of myelin loss in early psychosis. Lastly, we demonstrate that these measures predict psychosis severity at baseline across diagnostic groups. Taken together, these findings indicate subfield specific abnormalities in the hippocampus as an anatomical feature of psychosis. [ABSTRACT FROM AUTHOR]

Background Predictive coding and active inference framework states that subjects with psychotic disorders overly ascribe confidence (precision) to both sensory information and prior beliefs, leading to delusions and hallucinations. When considered in terms of brain connectivity, we predict that this computational aberrance should map onto strong forward and backward connections between sensory and higher cortical areas, in particular the anterior insula —deemed to be a critical node in the salience network. We tested this prediction in untreated, acute first-episode-psychosis (FEP) using both cognitive and neurophysiological data. Methods Twenty FEP and 20 healthy control (HC) subjects (matched on age and gender) performed the Stroop task and were subsequently scanned during task-free state with ultra-high-field (7 Tesla) functional magnetic resonance imaging. From a theory-driven modeling perspective, we fit hierarchical (Bayesian) drift-diffusion models (HDDM) to the distributions of reaction time and accuracy data and spectral dynamic causal models (DCM) to the fMRI data. Three competing HDDM tested the hypotheses that group differences in behavioral data would be accounted for aberrant prior precision (H1, mapped onto the starting point parameter), aberrant sensory precision (H2, mapped onto the drift-rate parameter), or both aberrant prior precision and aberrant prior beliefs (H3, mapped onto the starting point and drift-rate parameters). With DCM, we evaluated the differences in parameter estimates (β) of effective connections (i.e. causal influence) between the right inferior occipital gyrus (rIOG) and the right anterior insula (rAI). Specifically, we performed Bayesian parameter averaging at a group level and a matched analysis (Bayesian estimations of differences in means) at a subject level to evaluate whether FEP subjects would show stronger forward rIOG → rAI (indexing aberrant sensory precision) and stronger backward rAI → rIOG connections (indexing aberrant prior beliefs) than HC subjects. Results In the Stroop task, FEP performed less accurately (posterior proportion, PP, of the most credible values of difference in means, PP =.97 and more slowly, PP = 1.0) than HC. The HDDM representing prior and sensory precision (H3) accounted for this difference, FEP showed larger prior precision (PP = 0.93) and lower sensory precision (PP = 1.0) than HC. The spectral DCM showed that the influence from the sensory area to the insula (rIOG → rAI) was negative (implying an attenuation) in both groups during resting state (βHC = -0.29, βFEP = -0.13; PP =1). However, FEP showed less sensory attenuation than HC (PP = 0.95). Furthermore, in both groups the insular cortex positively influenced the sensory area, indicating a facilitatory effect (rAI → rIOG, βHC = 0.3, βFEP = 0.12; PP =1). However, this effect was weaker in FEP than in HC (PP = 0.98). Discussion We have demonstrated that low sensory attenuation in subjects with psychosis is associated with strong forward connections from sensory to higher cortical areas. Contrary to our expectation, we observed a reduction, rather than a compensatory increase in backward connectivity. However, aberrant prior precision during the Stroop task suggests the hypothesis that strong backward connections could be context-dependent, elicited in highly uncertain situations (e.g. during the resolution of incongruent stimuli in task fMRI) –which is congruent with our previous findings. Mapping a neurocomputational construct (aberrant sensory precision) onto visual-insular effective connectivity provides empirical support to disrupted hierarchical information processing in early stages of psychosis. [ABSTRACT FROM AUTHOR]

Background The structural integrity of the anterior cingulum has been repeatedly observed to be abnormal in psychosis. Cingulum tract carries fibers that connect medial prefrontal structures with precuneus, thus serving as the major pathway within the default mode network (DMN), critical for self-related processing. Persistent disorganization (or formal thought disorder) is largely considered to be a language-related dysfunction, though the neural basis of acute disorganization is yet unknown. We studied bilateral cingulum tract to identify if fractional anisotropy (indicating reduced white matter integrity) differed between patients with high vs. low levels of conceptual disorganization at first presentation, before initiating treatment. Methods We used ultra-high resolution (7 Tesla) diffusion weighted imaging in 40 patients with first-episode psychosis and 25 controls, to investigate bilateral cingulum, defined according to JHU white matter atlas. Based on the conceptual disorganization scores of PANSS, we divided patients in to 2 groups, low (P2=1,2,3) and high (P2=4,5,6) groups. These two groups were not different in their severity of other positive and negative symptoms. TBSS was applied to compare fractional anisotropy (FA) values using FSL software and permutation (5000) correction was used within the selected tract. F tests were used for group comparisons. We undertook post-hoc comparisons of radial diffusivity (reflecting myelin content), axial diffusivity (reflecting axonal integrity) and mode of anisotropy (reflecting fiber organization) for the regions showing significant FA abnormalities. Results There was a significant reduction in FA (p=0.036) in a cluster in left cingulum, with high P2 groups showing lower values than low P2 and controls. Post hoc showed that high P2 group had lower AD values compared to low P2 group (P=0.021). Interestingly, we also noted that patients with low P2 group had significantly higher AD values than healthy controls, indicating resilience from disorganization conferred by increased cingulum integrity. We did not find any significant difference in RD and MO value among the 3 groups. These FA differences were not explained by the distribution of other symptom scores. Discussion Our findings suggest that acute conceptual disorganization may relate to white matter damage of cingulum, the microstructural organization of which is critical for functional synchronization within the default mode network. We propose that the neural correlates of acute conceptual disorganization may differ from those of chronic, persistent formal thought disorder, in that language areas are less likely to be involved in acute disorganization. [ABSTRACT FROM AUTHOR]

Background In addition to positive and negative symptoms, patients with schizophrenia have notable disturbances in their ability to produce integrated, complex thoughts. Clinical quantification of thought disorder is a challenging process, contributing to the paucity of mechanistic understanding of disorganization seen in early stages of psychosis. We studied the linguistic aspects of clinically quantified dimensions of thought disorder – especially the dimension of disorganized thinking, in a sample of patients with untreated, first episode psychosis and healthy controls. Methods Data were collected from a sample of antipsychotic-naïve FEPs (n=37) and group matched HCs(n=24) as part of a longitudinal clinical study. Participants were recruited from the Prevention and Early Intervention Program for Psychoses in London, Ontario, Canada (PEPP-London). After completing a comprehensive assessment of clinical symptoms, participants were administered the Thought Language Index (TLI) in which one minute of speech was induced using pictures from Thematic Apperception Test. Analyses of linguistic characteristics were conducted using Coh-Metrix, a software system that analyzes written and transcribed speech samples for various linguistic characteristics. Patients and controls were compared on levels of (1) Syntactic Complexity (2) Syntactic categories [word information] (3) Connectives and (4) Lexical Diversity after controlling for total words spoken, parental socioeconomic status, and gender. A single metric for each of these four measures were derived using principal component analyses applied to individual items of CohMetrix from each of these 4 aspects of speech. All 4 measures were used to predict the scores of TLI Disorganization. Results Compared to HCs, FEPs showed higher overall syntactic complexity (F=6.7, p=0.012), indicating an increase in the overall linguistic complexity of FEP speech samples. FEPs also showed abnormalities in the incidence of syntactic categories (F=5.1, p =0.028), especially a higher use of the first-person singular pronoun. Patients and controls did not differ significantly on the use of connectives and lexical diversity. Within the patient sample, TLI disorganization was predicted by excessive use of connectives (F=9.8, p=0.005), indicating a strong role for inappropriate cohesive links forged between ideas as a cardinal feature of disorganized thinking. Discussion To our knowledge, the higher syntactic complexity and abnormal employment of syntactic categories among patients is a novel finding in untreated psychosis. The construct of disorganization, measured using clinical judgment, likely relates to the excessive use of connectives, likely contributing to the clinical intuition of incoherence. In early stages of active psychosis, formal thought disorder could be quantified more reliably using automated syntax analysis. [ABSTRACT FROM AUTHOR]

Background Ultra-high field 7T imaging greatly enhances the estimation of altered structure-function correspondence in disease states and provides unprecedented access to estimate neurometabolites with high specificity. Glutathione and glutamate have emerged as promising therapeutic targets for patients showing inadequate response. Nevertheless, the role of these non-dopaminergic treatment targets in the neurobiology of treatment response is poorly understood. Methods Using a longitudinal design and ultra-high field 7-Tesla magnetic resonance spectroscopy (MRS), we investigated the association of glutamate and glutathione with time to response in the dorsal anterior cingulate cortex (dACC) in patients with drug-naïve or minimally medicated first episode psychosis (n=26) and healthy controls (n= 27). Time to response was defined as the number of weeks it took to reach a 50% improvement on the PANSS-8 from baseline. We also studied the time-course of glutamate and glutathione changes using 7T functional spectroscopy and related metabolite dynamics at the onset to the early clinical course of psychosis. Results Higher dACC glutathione at baseline was associated with decreased time to response, while higher dACC glutamate was associated with functional impairment at baseline. There were no significant differences between patients and controls on measures of glutamate, or glutathione. Glutamate and glutathione levels are highly correlated in healthy controls, but this association is weakened among patients. Conclusions In a sample of acutely psychotic drug-naïve first-episode subjects, the highly resolved dynamic spectroscopic measures emerge as promising markers of early prognostic course. We believe these results add credibility to the claim that an aberrant redox subtype of schizophrenia can be identified early on at the time of first episode psychosis. [ABSTRACT FROM AUTHOR]

Background Since the time of Ernst von Feuchtersleben who coined the term psychosis (1845), psychotic disorders have been suspected to be associated with disturbances in cerebral blood supply. The use of modern neuroimaging approaches has uncovered abnormalities in the resting-state regional cerebral blood flow (rCBF) across various brain regions in schizophrenia. In a healthy brain, rCBF is tightly coupled to resting cerebral glucose metabolism (rCMRglu), which increases with synaptic activity. The coupling of rCBF (measured using arterial spin labelling, ASL) and rCMRglu (measured using 18flurodeoxyglucose positron emission tomography, FDG-PET) depends on the integrity of the neurovascular unit. In schizophrenia, several lines of evidence point towards aberrant neurovascular coupling especially in the prefrontal regions, though no simultaneous ASL-PET studies identifying regions with concordance or discordance between metabolism and perfusion have been reported to our knowledge. To address this gap, we undertook a voxel-based bimodal meta-analysis to examine the relationship between rCBF and rCMRglu in schizophrenia. We hypothesized that several brain regions would show combined abnormalities of perfusion and metabolism, while uncoupling of these 2 parameters will be observed in prefrontal regions. Methods We undertook a systematic literature search to include all available studies reporting voxelwise ASL or FDG-PET changes in schizophrenia using coordinates based multimodal meta-analysis implemented using Signed Differential Mapping (SDM) software. 31 studies met the inclusion criteria, comprised of data from 599 patients and 590 controls, available for meta-analysis. We used conjunction and moderator analyses to evaluate areas with concordant and discordant abnormalities in rCBF and rCMRglu respectively. We also undertook meta-regression analyses to study the effect of age, gender, duration of illness, anti-psychotic dosage, and illness severity on the illness-related changes in rCBF and rCMRglu. Results Among patients with schizophrenia, we observed a conjoint reduction in rCBF and rCMRglu in the left frontoinsular cortex and bilateral dorsal anterior cingulate cortex (z>2, cluster inclusion p<0.0001). A conjoint increase in rCBF and rCMRglu was noted in bilateral striatum and temporal pole. Regional neurovascular uncoupling was notable in the superior frontal gyrus (reduced rCMRglu, normal rCBF) and cerebellum (increased rCMRglu, normal rCBF). Meta-regression analyses were unstable due to the low number of eligible studies. Discussion Our results suggest that several key regions implicated in the pathophysiology of schizophrenia such as the frontoinsular cortex, dorsal ACC, putamen and temporal pole (constituting the regions of the Salience Network) show conjoint metabolic and perfusion abnormalities in patients. In contrast, discordance between metabolism and perfusion was seen in the superior frontal gyrus and the cerebellum, indicating that factors contributing to neurovascular uncoupling (e.g. inflammation, mitochondrial dysfunction or oxidative stress) are likely to operate at these loci. Hybrid ASL-PET studies focusing on these regions could confirm our proposition. [ABSTRACT FROM AUTHOR]

Background The family physician has been identified as a key player on the pathway to care in first-episode psychosis, as the majority of young people with early psychosis make help-seeking contacts in primary care. This involvement of family physicians has been shown to reduce the likelihood of negative pathways to care. As such, increasing the involvement of family physicians in the identification of early psychosis would be beneficial for improving service-related outcomes. Our objectives were to estimate the proportion of youth with early psychosis who are diagnosed in primary care, and to identify patient- and physician-level factors associated with a first diagnosis of psychosis in primary care. Methods Using population-based health administrative data, we constructed a retrospective cohort of people aged 14 to 35 years with a first diagnosis of psychosis in Ontario between 2005 and 2015. We extracted data on all mental health help-seeking attempts in primary care in the six-month period preceding the first diagnosis of psychotic disorder. Restricting the sample to people with help seeking attempts in primary care, we used multilevel logistic regression models, with physician as the clustering unit, to model the patient and physician characteristics associated with first diagnosis in primary care. Results Nearly two thirds (63%) of young people with early psychosis (n = 39,449) had mental health help-seeking contacts in primary care in the six-month period prior to first diagnosis. Of those, 47% were diagnosed in primary care (30% of total cohort), whereas 53% received their diagnosis in secondary or tertiary care services (33% of total cohort). Initial results suggest that people who are older at psychosis onset are more likely to receive their first diagnosis in primary care, and people who have a history of other psychosocial comorbidities are less likely to be diagnosed in primary care. Full results for patient- and physician-level factors associated with a first diagnosis in primary care will be presented. Discussion Approximately one in three young people with early psychosis in Ontario receive their first diagnosis of psychotic disorder from a family physician, and an additional third of people with early psychosis made help-seeking attempts in primary care for mental health reasons but received their first diagnosis in secondary or tertiary care services. The findings from these analyses will allow us to identify subgroups of primary care providers to target with continuing medical education efforts to better support family physicians in their central role in pathways to care for first-episode psychosis. [ABSTRACT FROM AUTHOR]

Background The clinical diagnosis of schizophrenia is suspected to include several distinct subgroups of patients, but reliable neurobiological boundaries to differentiate the subgroups remain elusive. These unknown subgroups increase the variance of biological measures within the clinically identified patient group, deflating the group-level estimates of causal factors and treatment effects. Prior studies seeking homogeneous subgroups of schizophrenia based on brain-based measures have not found consistent solutions. A major limitation in prior studies is the assumption that healthy controls form a relatively homogeneous group, that deviates biologically from the patient subgroups. As a result, cluster solutions have been generally sought only within patient samples, without pooling the patient and control data. In the current study, we assessed whether the regional values of cortical thickness estimated from structural MRI are sufficiently sensitive to identify subgroups of patients and healthy controls. Methods We used high resolution (3 Tesla) imaging in 179 patients with schizophrenia and 77 healthy controls, to investigate possible subtypes of schizophrenia. K-means algorithm was applied to perform clustering analysis on cortical thickness data from 68 regions in Desikan-Kiliany Atlas using Freesurfer software, and gap statistics was used to find best cluster solution. General linear models were used to compare cortical thickness, cognitive performance and symptom severity among the identified clusters. Results A 3-cluster solution provided the most optimal clustering, with the first cluster (C1) comprised almost entirely of patients, while the other 2 clusters (C2 and C3) including a substantial number of patients as well as control subjects. There was no significant difference in cognitive performance among the 3 schizophrenia subtypes. C1 was the most morphologically impoverished group with significantly thin cortex in multiple brain regions but had no more symptom/cognitive burden than the other subtypes. C2 was an intermediate group with significant thinning in selected brain regions, with higher burden of negative symptoms. C3 was the morphologically most intact subgroup with a cortical thickness profile like healthy controls, despite having more severe delusions. In addition, C1 also had higher duration of exposure to medication among the 3 patient groups, with longer illness duration. Discussion We report 3 major findings: 1) 3 distinct morphological profiles are observed in schizophrenia 2) A large number of patients with schizophrenia have the cortical morphological profiles of apparently normal healthy controls 3) cortical thickness profiles do not map well to cognitive and symptomatic profiles in schizophrenia. Interestingly, we observed a pattern of morphological preservation among patients with higher levels of delusion. We provide evidence for the presence of morphological subgroups of schizophrenia, the delineation of which may help stratifying patients for future prognostic studies. [ABSTRACT FROM AUTHOR]

Background Cannabis appears to have a distinct effect on cortical and subcortical white matter, possibly mediated by altered oligodendrocyte function. This may have cognitive implications especially in patients with psychosis. We investigated whether this myelin-altering effect of cannabis is more likely to be concentrated in specific white matter tracts of the brain, especially those that have a high likelihood of being altered by the presence of schizophrenia. We undertook a coordinates-based effect size meta-analysis to locate tracts that are maximally affected by cannabis as well as the diagnosis of schizophrenia and studied the overlapping effects if these two factors. Methods Using the key words ((diffusion AND (weighted or tensor)) AND ((substance OR drug OR alcohol OR cannabis) AND (use OR users OR abuse OR dependence))) in Medline we included the studies that met the following criteria: (1) used DW-MRI, and reported differences in fractional anisotropy (FA) (2) used a voxelwise or tract-based spatial statistic (TBSS) approach, (3) reported between-group comparisons of a defined group of cannabis users vs. non-users, irrespective of dose (4) published in English in a peer-reviewed journal, (5) published after 1990. The authors were then contacted to collect any relevant information. Effect-Size Signed Differential Mapping (ES-SDM) was used as the meta-analytical method of choice, as it combines peak co-ordinates and statistical parametric maps. A jackknife analysis was employed to determine the reproducibility of the results by iterating the mean analysis several times, each time excluding a specific study from the analysis. A heterogeneity analysis generated the Q statistic to assess the between-study variability in the results. Meta-regressions were conducted to study the sources of between-studies variability with age, gender, handedness, alcohol comorbidity, and MRI strength as predictors of interest. Results Of the 118 studies identified through PubMed, 75 were excluded in the initial stage as they did not involve cannabis. 43 abstracts were then assessed, and any studies using an ROI based framework were excluded. 10 studies, (5 VBA and 5 TBSS), comprising of data from 223 cannabis-users and 182 non-using controls were pooled. All except one study reported significant between-group differences. Seven regions show significant reduction in the FA in the cannabis user group and only one region showing a significant increase in FA compared to the non-users. The corpus callosum, right pons, left inferior network (inferior longitudinal fasciculus), left cortico-spinal projections, right superior longitudinal fasciculus III, left anterior thalamic projections, and the left frontal orbito-polar tract all showed FA reduction in cannabis users. The right inferior fronto-occipital fasciculus showed higher FA in cannabis users. Jackknife sensitivity analyses indicated that the deficit in the corpus callosum (MNI coordinates 14,-42,16, z=1.899, p=0.00001) was especially robust, withstanding the removal of any of the 10 studies. Discussion We have demonstrated that the corpus callosum is the most vulnerable brain region to the effects of recreational cannabis use. While we noted a significant between-studies heterogeneity, this was not explained by age, gender distribution or comorbid alcohol use in the samples. In long term cannabis users, longitudinal tracking of the integrity of corpus callosum can provide valuable insights to the relationship with emergence of psychosis as well as cognitive impairment related to the use of cannabis. [ABSTRACT FROM AUTHOR]

Background Family physicians are a key player in facilitating access to psychiatric treatment for people with first-episode psychosis, and this involvement can reduce aversive events in pathways to care. However, approximately a third of people do not seek help for mental health reasons from primary care in the period leading up to the first diagnosis, and it is unclear whether this help-seeking gap is related to lack of access to a regular family physician. Our objective was to estimate the proportion of people with first-episode psychosis who do not have access to a family physician at psychosis onset, and to examine and factors associated with lack of access. Methods Using population-based health administrative data, we constructed a retrospective cohort of people aged 14 to 35 years with a first diagnosis of psychosis in Ontario between 2005 and 2015. We randomly selected four general population controls matched on age, sex, and neighborhood. We compared factors associated with access to a primary care physician at the time of psychosis onset between the two groups using prevalence ratios (PR) estimated from modified Poisson regression models with robust variance estimators. Results Over one quarter (28%) of young people with early psychosis (n = 39,449) did not have access to a family physician at illness onset. People with psychotic disorders were more likely to have a regular family physician relative to matched controls (PR = 1.28; 95%CI = 1.27, 1.29). However, after adjustment for physical and psychosocial comorbidities, people with psychotic disorders were less likely to have access to a regular family physician (PR = 0.96; 95%CI = 0.96, 0.97). Among young people with psychotic disorders, factors associated with lack of access to a family physician included older age, male gender, low neighborhood-level income quintile, residential instability, and migrant status. People living in rural areas and those with chronic physical or psychosocial comorbidities were more likely to have access to a regular family physician. Discussion Approximately one in four young people with early psychosis in Ontario lack access to a regular family physician at psychosis onset, suggesting that the help-seeking gap in primary care prior to the onset of psychotic disorder may be partially attributed to this lack of access. Interventions aimed at improving access to family physicians among vulnerable groups, and at supporting family physicians in referral to early psychosis intervention services, may improve pathways to care for youth with first-episode psychosis. [ABSTRACT FROM AUTHOR]

Background Of the various symptom complexes of established psychosis, network level dysconnectivity has been widely studied in association with positive and negative symptoms. Very few studies have focused on studying the dysconnectivity patterns associated with disorganization, specifically conceptual disorganization (CD), which explains the impairments in both the goal-directed sequencing of thought processes and real-world functioning. Systematic reviews have revealed aberrant connectivity patterns in formal thought disorder (a construct related to CD) at all stages of the illness, suggesting the underlying persistence of CD. However, these studies investigate connectivity patterns between specific regions of interest or resting state networks. No studies have investigated the whole-brain functional correlates of CD in psychosis. We thus sought to investigate the brain regions explaining the severity of CD in patients with first-episode psychosis (FEPs) in comparison with healthy controls (HCs). Methods Participants were recruited as part of a longitudinal neuroimaging project that follows changes in early psychosis during the course of treatment. 31 HC and 38 antipsychotic-naive FEP subjects were included in the study sample. Subjects were assessed using DSM-5 criteria and the 8 item Positive and Negative Syndrome Scale (PANSS-8) and underwent 2 magnetic resonance imaging (MRI) scans at 7T (one T2*-weighted resting-state functional MRI (rs-fMRI) scan, one T1-weighted structural MRI). After preprocessing, whole-brain binarized degree centrality (bDC) maps were computed to characterize the patterns of network connectivity in the two study samples. Statistical analyses included the following: 1) A two-sample t-test comparing connectivity patterns in the HC and FEP groups with bDC maps as the dependent variable, examining the effect of diagnosis accounting for gender as the covariate, 2) Similarly, a two-sample t-test comparing connectivity patterns in the two patient groups (low CD or Low P2, high CD or High P2) with bDC maps as the dependent variable, examining the effect of the severity of symptoms accounting for gender as the covariate. Results Compared to HCs, the FEPs showed a reduction in hubness of a cluster located in the superior temporal gyrus (rSTG) (right: t = 5.00, p < 0.001). This cluster was functionally connected with clusters in the middle frontal gyrus (left: t = 8.41, p < 0.001; right: t = 7.59, p < 0.001), cerebellum (left: t = 8.02, p < 0.001) and thalamus (left: t = 9.72, p < 0.001). In patients exhibiting high CD severity, increased hubness of a medial superior parietal (mSPL) cluster (left: t = 4.93, p = 0.001) was observed, compared to patients exhibiting low CD severity. This cluster was functionally connected with clusters in the superior temporal (right: t = 8.39, p < 0.001) and middle temporal (right: t = 7.07, p < 0.001) gyri. The summary measure (first eigenvariate) of the mSPL cluster's centrality showed strong correlation with the severity of CD but no other symptoms. Discussion Our observations extend the previous findings of reduced hubness in the superior temporal and insular regions in established schizophrenia to early-stage untreated, active phase of illness. Nevertheless, the increase in peripheral hubness in this first-episode sample was limited to conceptually disorganized patients, indicating the possible role of functional cortical reorganization and re-routing of information transfer in early stages of thought disorder. [ABSTRACT FROM AUTHOR]