Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

CutFEM-based MEG forward modeling improves source separability and sensitivity to quasi-radial sources: A somatosensory group study.

Source analysis of magnetoencephalography (MEG) data requires the computation of the magnetic fields induced by current sources in the brain. This so-called MEG forward problem includes an accurate estimation of the volume conduction effects in the human head. Here, we introduce the Cut finite element method (CutFEM) for the MEG forward problem. CutFEM's meshing process imposes fewer restrictions on tissue anatomy than tetrahedral meshes while being able to mesh curved geometries contrary to hexahedral meshing. To evaluate the new approach, we compare CutFEM with a boundary element method (BEM) that distinguishes three tissue compartments and a 6-compartment hexahedral FEM in an n = 19 group study of somatosensory evoked fields (SEF). The neural generators of the 20 ms post-stimulus SEF components (M20) are reconstructed using both an unregularized and a regularized inversion approach. Changing the forward model resulted in reconstruction differences of about 1 centimeter in location and considerable differences in orientation. The tested 6-compartment FEM approaches significantly increase the goodness of fit to the measured data compared with the 3-compartment BEM. They also demonstrate higher quasi-radial contributions for sources below the gyral crowns. Furthermore, CutFEM improves source separability compared with both other approaches. We conclude that head models with 6 compartments rather than 3 and the new CutFEM approach are valuable additions to MEG source reconstruction, in particular for sources that are predominantly radial.

Algorithmic fairness in precision psychiatry: analysis of prediction models in individuals at clinical high risk for psychosis.

BACKGROUND: Computational models offer promising potential for personalised treatment of psychiatric diseases. For their clinical deployment, fairness must be evaluated alongside accuracy. Fairness requires predictive models to not unfairly disadvantage specific demographic groups. Failure to assess model fairness prior to use risks perpetuating healthcare inequalities. Despite its importance, empirical investigation of fairness in predictive models for psychiatry remains scarce. AIMS: To evaluate fairness in prediction models for development of psychosis and functional outcome. METHOD: Using data from the PRONIA study, we examined fairness in 13 published models for prediction of transition to psychosis (n = 11) and functional outcome (n = 2) in people at clinical high risk for psychosis or with recent-onset depression. Using accuracy equality, predictive parity, false-positive error rate balance and false-negative error rate balance, we evaluated relevant fairness aspects for the demographic attributes 'gender' and 'educational attainment' and compared them with the fairness of clinicians' judgements. RESULTS: Our findings indicate systematic bias towards assigning less favourable outcomes to individuals with lower educational attainment in both prediction models and clinicians' judgements, resulting in higher false-positive rates in 7 of 11 models for transition to psychosis. Interestingly, the bias patterns observed in algorithmic predictions were not significantly more pronounced than those in clinicians' predictions. CONCLUSIONS: Educational bias was present in algorithmic and clinicians' predictions, assuming more favourable outcomes for individuals with higher educational level (years of education). This bias might lead to increased stigma and psychosocial burden in patients with lower educational attainment and suboptimal psychosis prevention in those with higher educational attainment.

Gray matter matters: Cognitive stability and flexibility in schizophrenia spectrum disorder.

Cognitive dysfunction constitutes a core characteristic of schizophrenia spectrum disorders (SZ). Specifically, deficits in updating generative models (i.e., cognitive flexibility) and shielding against distractions (i.e., cognitive stability) are considered critical contributors to cognitive impairment in these patients. Here, we examined the structural integrity of frontostriatal networks and their associations with reduced cognitive stability and flexibility in SZ patients. In a sample of 21 patients diagnosed with SZ and 22 healthy controls, we measured gray matter volume (GMV) using structural MRI. Further, cognitive stability and flexibility were assessed using a switch-drift paradigm, quantifying the successful ignoring of distracters and detection of rule switches. Compared to controls, patients showed significantly smaller GMV in the whole brain and three predefined regions of interest: the medial prefrontal cortex (mPFC), inferior frontal gyrus (IFG), and caudate nucleus (CN). Notably, GMV in these areas positively correlated with correct rule-switch detection but not with ignoring rule-compatible drifts. Further, the volumetric differences between SZ patients and controls were statistically explainable by considering the behavioral performance in the switch-drift task. Our results indicate that morphological abnormalities in frontostriatal networks are associated with deficient flexibility in SZ patients and highlight the necessity of minimizing neurodevelopmental and progressive brain atrophy in this population.

[Recovery-oriented treatment and peer support in psychiatry]. / Recovery-orientierte Behandlung und Genesungsbegleitung in der Psychiatrie.

The concept of recovery in the care of mentally ill individuals is now firmly established both nationally and internationally. While clinical recovery focuses on a measurable ultimate goal based on the expression of symptoms with the intention of returning individuals to a premorbid state, personal recovery implies a process of personal development. The three key pillars are salutogenesis, resilience and empowerment. Collaborating with peer support workers is essential for the authentic expansion of therapy offers in line with the principles of recovery. These individuals have their own experiences with psychiatric care, which they utilize to support individuals in their unique recovery journey. The implementation process of recovery-oriented services presents a range of challenges and requires openness and a reorientation on the part of professional treatment teams.

Neurocognitive skills and vulnerability for psychosis in depression and across the psychotic spectrum: findings from the PRONIA Consortium.

BACKGROUND: Neurocognitive deficits are a core feature of psychosis and depression. Despite commonalities in cognitive alterations, it remains unclear if and how the cognitive deficits in patients at clinical high risk for psychosis (CHR) and those with recent-onset psychosis (ROP) are distinct from those seen in recent-onset depression (ROD). AIMS: This study was carried out within the European project 'Personalized Prognostic Tools for Early Psychosis Management', and aimed to characterise the cognitive profiles of patients with psychosis or depression. METHOD: We examined cognitive profiles for patients with ROP (n = 105), patients with ROD (n = 123), patients at CHR (n = 116) and healthy controls (n = 372) across seven sites in five European countries. Confirmatory factor analysis identified four cognitive factors independent of gender, education and site: speed of processing, attention and working memory, verbal learning and spatial learning. RESULTS: Patients with ROP performed worse than healthy controls in all four domains (P < 0.001), whereas performance of patients with ROD was not affected (P > 0.05). Patients at CHR performed worse than healthy controls in speed of processing (P = 0.001) and spatial learning (P = 0.003), but better than patients with ROP across all cognitive domains (all P ≤ 0.01). CHR and ROD groups did not significantly differ in any cognitive domain. These findings were independent of comorbid depressive symptoms, substance consumption and illness duration. CONCLUSIONS: These results show that neurocognitive abilities are affected in CHR and ROP, whereas ROD seems spared. Although our findings may support the notion that those at CHR have a specific vulnerability to psychosis, future studies investigating broader transdiagnostic risk cohorts in longitudinal designs are needed.

Prevalence of cognitive impairments and strengths in the early course of psychosis and depression.

BACKGROUND: Studies investigating cognitive impairments in psychosis and depression have typically compared the average performance of the clinical group against healthy controls (HC), and do not report on the actual prevalence of cognitive impairments or strengths within these clinical groups. This information is essential so that clinical services can provide adequate resources to supporting cognitive functioning. Thus, we investigated this prevalence in individuals in the early course of psychosis or depression. METHODS: A comprehensive cognitive test battery comprising 12 tests was completed by 1286 individuals aged 15-41 (mean age 25.07, s.d. 5.88) from the PRONIA study at baseline: HC (N = 454), clinical high risk for psychosis (CHR; N = 270), recent-onset depression (ROD; N = 267), and recent-onset psychosis (ROP; N = 295). Z-scores were calculated to estimate the prevalence of moderate or severe deficits or strengths (>2 s.d. or 1-2 s.d. below or above HC, respectively) for each cognitive test. RESULTS: Impairment in at least two cognitive tests was as follows: ROP (88.3% moderately, 45.1% severely impaired), CHR (71.2% moderately, 22.4% severely impaired), ROD (61.6% moderately, 16.2% severely impaired). Across clinical groups, impairments were most prevalent in tests of working memory, processing speed, and verbal learning. Above average performance (>1 s.d.) in at least two tests was present for 40.5% ROD, 36.1% CHR, 16.1% ROP, and was >2 SDs in 1.8% ROD, 1.4% CHR, and 0% ROP. CONCLUSIONS: These findings suggest that interventions should be tailored to the individual, with working memory, processing speed, and verbal learning likely to be important transdiagnostic targets.

Obesity and brain structure in schizophrenia - ENIGMA study in 3021 individuals.

Schizophrenia is frequently associated with obesity, which is linked with neurostructural alterations. Yet, we do not understand how the brain correlates of obesity map onto the brain changes in schizophrenia. We obtained MRI-derived brain cortical and subcortical measures and body mass index (BMI) from 1260 individuals with schizophrenia and 1761 controls from 12 independent research sites within the ENIGMA-Schizophrenia Working Group. We jointly modeled the statistical effects of schizophrenia and BMI using mixed effects. BMI was additively associated with structure of many of the same brain regions as schizophrenia, but the cortical and subcortical alterations in schizophrenia were more widespread and pronounced. Both BMI and schizophrenia were primarily associated with changes in cortical thickness, with fewer correlates in surface area. While, BMI was negatively associated with cortical thickness, the significant associations between BMI and surface area or subcortical volumes were positive. Lastly, the brain correlates of obesity were replicated among large studies and closely resembled neurostructural changes in major depressive disorders. We confirmed widespread associations between BMI and brain structure in individuals with schizophrenia. People with both obesity and schizophrenia showed more pronounced brain alterations than people with only one of these conditions. Obesity appears to be a relevant factor which could account for heterogeneity of brain imaging findings and for differences in brain imaging outcomes among people with schizophrenia.

Effects of DRD2/ANKK1 and COMT Val158Met polymorphisms on stabilization against and adaptation to unexpected events.

Genetic variations affecting dopaminergic neuromodulation such as the DRD2/ANKK1 and the COMT Val158Met polymorphisms contribute to goal-directed behavior that requires a balance between stabilization and updating of current states and behaviors. Dopamine is also thought to be relevant for encoding of surprise signals to sensory input and adaptive learning. A link between goal-directed behavior and learning from surprise is therefore plausible. In the present fMRI study, we investigated whether DRD2 and COMT polymorphisms are related to behavioral responses and neural signals in the caudate nucleus and dlPFC during updating or stabilizing internal models of predictable digit sequences. To-be-detected switches between sequences and to-be-ignored digit omissions within a sequence varied by information-theoretic quantities of surprise and entropy. We found that A1 noncarriers and Val-carriers showed a lower response threshold along with increased caudate and dlPFC activation to surprising switches compared with A1-carriers and Met-homozygotes, whose dlPFC activity increased with decreasing switch surprise. In contrast, there were overall smaller differences in behavioral and neural modulation by drift surprise. Our results suggest that the impact of dopamine-relevant polymorphisms in the flexibility-stability trade-off may result in part from the role of dopamine in encoding the weight afforded to events requiring updating or stabilization.

Novel Gyrification Networks Reveal Links with Psychiatric Risk Factors in Early Illness.

Adult gyrification provides a window into coordinated early neurodevelopment when disruptions predispose individuals to psychiatric illness. We hypothesized that the echoes of such disruptions should be observed within structural gyrification networks in early psychiatric illness that would demonstrate associations with developmentally relevant variables rather than specific psychiatric symptoms. We employed a new data-driven method (Orthogonal Projective Non-Negative Matrix Factorization) to delineate novel gyrification-based networks of structural covariance in 308 healthy controls. Gyrification within the networks was then compared to 713 patients with recent onset psychosis or depression, and at clinical high-risk. Associations with diagnosis, symptoms, cognition, and functioning were investigated using linear models. Results demonstrated 18 novel gyrification networks in controls as verified by internal and external validation. Gyrification was reduced in patients in temporal-insular, lateral occipital, and lateral fronto-parietal networks (pFDR < 0.01) and was not moderated by illness group. Higher gyrification was associated with better cognitive performance and lifetime role functioning, but not with symptoms. The findings demonstrated that gyrification can be parsed into novel brain networks that highlight generalized illness effects linked to developmental vulnerability. When combined, our study widens the window into the etiology of psychiatric risk and its expression in adulthood.

Using combined environmental-clinical classification models to predict role functioning outcome in clinical high-risk states for psychosis and recent-onset depression.

BACKGROUND: Clinical high-risk states for psychosis (CHR) are associated with functional impairments and depressive disorders. A previous PRONIA study predicted social functioning in CHR and recent-onset depression (ROD) based on structural magnetic resonance imaging (sMRI) and clinical data. However, the combination of these domains did not lead to accurate role functioning prediction, calling for the investigation of additional risk dimensions. Role functioning may be more strongly associated with environmental adverse events than social functioning. AIMS: We aimed to predict role functioning in CHR, ROD and transdiagnostically, by adding environmental adverse events-related variables to clinical and sMRI data domains within the PRONIA sample. METHOD: Baseline clinical, environmental and sMRI data collected in 92 CHR and 95 ROD samples were trained to predict lower versus higher follow-up role functioning, using support vector classification and mixed k-fold/leave-site-out cross-validation. We built separate predictions for each domain, created multimodal predictions and validated them in independent cohorts (74 CHR, 66 ROD). RESULTS: Models combining clinical and environmental data predicted role outcome in discovery and replication samples of CHR (balanced accuracies: 65.4% and 67.7%, respectively), ROD (balanced accuracies: 58.9% and 62.5%, respectively), and transdiagnostically (balanced accuracies: 62.4% and 68.2%, respectively). The most reliable environmental features for role outcome prediction were adult environmental adjustment, childhood trauma in CHR and childhood environmental adjustment in ROD. CONCLUSIONS: Findings support the hypothesis that environmental variables inform role outcome prediction, highlight the existence of both transdiagnostic and syndrome-specific predictive environmental adverse events, and emphasise the importance of implementing real-world models by measuring multiple risk dimensions.

Altered functional synchrony between gray and white matter as a novel indicator of brain system dysconnectivity in schizophrenia.

BACKGROUND: There is increasing evidence that blood oxygenation level-dependent signaling in white matter (WM) reflects WM functional activity. Whether this activity is altered in schizophrenia remains uncertain, as does whether it is related to established alterations of gray matter (GM) or the microstructure of WM tracts. METHODS: A total of 153 antipsychotic-naïve schizophrenia patients and 153 healthy comparison subjects were assessed by resting-state functional magnetic resonance imaging, diffusion tensor imaging, and high-resolution T1-weighted imaging. We tested for case-control differences in the functional activity of WM, and examined their relation to the functional activity of GM and WM microstructure. The relations between fractional anisotropy (FA) in WM and GM-WM functional synchrony were investigated as well. Then, we examined the associations of identified abnormalities to age, duration of untreated psychosis (DUP), and symptom severity. RESULTS: Schizophrenia patients displayed reductions of the amplitude of low-frequency fluctuations (ALFF), GM-WM functional synchrony, and FA in widespread regions. Specifically, the genu of corpus callosum not only had weakening in the synchrony of functional activity but also had reduced ALFF and FA. Positive associations were found between FA and functional synchrony in the genu of corpus callosum as well. No significant association was found between identified abnormalities and DUP, and symptom severity. CONCLUSIONS: The widespread weakening in the synchrony of functional activity of GM and WM provided novel evidence for functional alterations in schizophrenia. Regarding the WM function as a component of brain systems and investigating its alternation represent a promising direction for future research.

[The Well-informed Patient: a Survey on Patients' Initiative in Seeking Disease-related Information]. / Der gut informierte Patient: Wie stationär behandelte psychiatrische Patienten die Suche nach Informationen über ihre Erkrankung erleben.

Internet and print media are frequently used by laypersons to learn about health issues. The objective of this study was to find out whether people with mental disorders showed a special pattern of usage. Where and why do they seek for information about their disorder? How do they experience their search? In semi-standardized interviews, we surveyed 200 psychiatric inpatients. Only patients of the following diagnostic groups were included: 1. Schizophrenia, schizotypal and delusional disorders (F20-F29), 2. Affective disorders (F30-F39) and 3. Disorders of adult personality and behavior (F60-F69). We focused on the sources the patients had used and the experiences they had in the course of their internet search. The vast majority had already searched for information about psychiatry, psychology or medication via internet or in print media. Most participants described positive emotions while reading. More than two-thirds rated the information as useful. Only 10 participants discontinued or rejected therapeutic measures due to information they had gained. Patients with personality disorders were significantly more likely than other patients to attribute their symptoms to a wrong diagnosis after seeking for information. Overall, psychiatric patients mostly experience helpful effects of reading medical information. In rare cases there are negative effects, e. g. negative emotions, discontinuation of therapy or an incorrect assessment of one's own illness. Further research is required in order to find out how the use of internet by people with mental disorders, which is already successful in many cases, can be improved even further.

Detailed clinical phenotyping and generalisability in prognostic models of functioning in at-risk populations.

Personalised prediction of functional outcomes is a promising approach for targeted early intervention in psychiatry. However, generalisability and resource efficiency of such prognostic models represent challenges. In the PRONIA study (German Clinical Trials Register: DRKS00005042), we demonstrate excellent generalisability of prognostic models in individuals at clinical high-risk for psychosis or with recent-onset depression, and substantial contributions of detailed clinical phenotyping, particularly to the prediction of role functioning. These results indicate that it is possible that functioning prediction models based only on clinical data could be effectively applied in diverse healthcare settings, so that neuroimaging data may not be needed at early assessment stages.

Characteristics of the corpus callosum in chronic schizophrenia treated with clozapine or risperidone and those never-treated.

BACKGROUND: The corpus callosum (CC) deficits have been well documented in chronic schizophrenia. However, the long-term impacts of antipsychotic monotherapies on callosal anatomy remain unclear. This cross-sectional study sought to explore micro- and macro-structural characteristics of the CC in never-treated patients and those with long-term mono-antipsychotic treatment. METHODS: The study included 23 clozapine-treated schizophrenia patients (CT-SCZ), 19 risperidone-treated schizophrenia patients (RT-SCZ), 23 never-treated schizophrenia patients (NT-SCZ), and 35 healthy controls (HCs). High resolution structural images and diffusion tensor imaging (DTI) data for each participant were obtained via a 3.0 T MR scanner. FreeSurfer was used to examine the volumes and fractional anisotropy (FA) values of the CC for each participant. RESULTS: There were significant deficits in the total and sub-regional CC volume and white matter integrity in NT-SCZ in comparison with healthy subjects. Compared with NT-SCZ, both CT-SCZ and RT-SCZ showed significantly increased FA values in the anterior CC region, while only RT-SCZ showed significantly increased volume in the mid-anterior CC region. Moreover, the volume of the mid-anterior CC region was significantly smaller in CT-SCZ compared to HCs. No correlations of clinical symptoms with callosal metrics were observed in schizophrenia patients. CONCLUSIONS: Our findings provide insight into micro- and macro-structural characteristics of the CC in chronic schizophrenia patients with or without antipsychotics. These results suggest that the pathology itself is responsible for cerebral abnormalities in schizophrenia and that chronic exposure to antipsychotics may have an impact on white matter structure of schizophrenia patients, especially in those with risperidone treatment.

Impact on carer burden when stable patients with schizophrenia transitioned from 1-monthly to 3-monthly paliperidone palmitate.

RATIONALE: Reducing the frequency of long-acting injectable antipsychotic medication may reduce carer burden. OBJECTIVES: To evaluate the impact of reduced frequency of long-acting injectable antipsychotic medication on carer burden in stable patients with schizophrenia. METHODS: Carer burden was assessed using the Involvement Evaluation Questionnaire (IEQ) within a 52-week, prospective, single-arm, non-randomised, open-label, international, multicentre study evaluating the impact of transitioning stable patients with schizophrenia to paliperidone palmitate 3-monthly (PP3M) from paliperidone palmitate 1-monthly (PP1M). RESULTS: 159 carers completed the IEQ (mean [standard deviation, SD] age: 54.8 [12.8] years); 52.2% were the patients' parent and > 50% had >32 h/week of patient contact. At baseline, mean [SD] IEQ total score was in the lower range (23.8 [12.6]), reflecting patient stabilisation. At last observation carried forward (LOCF) endpoint, the IEQ total score decreased by a mean (95% CI) of -4.0 (-5.9, -2.1), indicating a significant overall reduction in carer burden (P < 0.0001). The six IEQ items with the highest carer burden at baseline were within the urging and worrying domains, in which burden was significantly improved at LOCF endpoint (P < 0.0001). Exploratory analyses found that higher carer burden was associated with lower functional remission (Personal and Social Performance score >70) at baseline and LOCF endpoint, and with the patient being part of the carer's household. Shorter disease duration correlated with better general health of carers at LOCF endpoint. CONCLUSION: Reducing the frequency of antipsychotic medication administration in stable patients with schizophrenia by switching from PP1M to PP3M may reduce carer burden.

Following Forrest Gump: Smooth pursuit related brain activation during free movie viewing.

Most fMRI studies investigating smooth pursuit (SP) related brain activity have used simple synthetic stimuli such as a sinusoidally moving dot. However, real-life situations are much more complex and SP does not occur in isolation but within sequences of saccades and fixations. This raises the question whether the same brain networks for SP that have been identified under laboratory conditions are activated when following moving objects in a movie. Here, we used the publicly available studyforrest data set that provides eye movement recordings along with 3 â€‹T fMRI recordings from 15 subjects while watching the Hollywood movie "Forrest Gump". All three major eye movement events, namely fixations, saccades, and smooth pursuit, were detected with a state-of-the-art algorithm. In our analysis, smooth pursuit (SP) was the eye movement of interest, while saccades were acting as the steady state of viewing behaviour due to their lower variability. For the fMRI analysis we used an event-related design modelling saccades and SP as regressors initially. Because of the interdependency of SP and content motion, we then added a new low-level content motion regressor to separate brain activations from these two sources. We identified higher BOLD-responses during SP than saccades bilaterally in MT+/V5, in middle cingulate extending to precuneus, and in the right temporoparietal junction. When the motion regressor was added, SP showed higher BOLD-response relative to saccades bilaterally in the cortex lining the superior temporal sulcus, precuneus, and supplementary eye field, presumably due to a confounding effect of background motion. Only parts of V2 showed higher activation during saccades in comparison to SP. Taken together, our approach should be regarded as proof of principle for deciphering brain activity related to SP, which is one of the most prominent eye movements besides saccades, in complex dynamic naturalistic situations.

Characteristics of White Matter Structural Networks in Chronic Schizophrenia Treated With Clozapine or Risperidone and Those Never Treated.

BACKGROUND: Despite its benefits, a major concern regarding antipsychotic treatment is its possible impact on the brain's structure and function. This study sought to explore the characteristics of white matter structural networks in chronic never-treated schizophrenia and those treated with clozapine or risperidone, and its potential association with cognitive function. METHODS: Diffusion tensor imaging was performed on a unique sample of 34 schizophrenia patients treated with antipsychotic monotherapy for over 5 years (17 treated with clozapine and 17 treated with risperidone), 17 never-treated schizophrenia patients with illness duration over 5 years, and 27 healthy control participants. Graph theory and network-based statistic approaches were employed. RESULTS: We observed a disrupted organization of white matter structural networks as well as decreased nodal and connectivity characteristics across the schizophrenia groups, mainly involving thalamus, prefrontal, and occipital regions. Alterations in nodal and connectivity characteristics were relatively milder in risperidone-treated patients than clozapine-treated patients and never-treated patients. Altered global network measures were significantly associated with cognitive performance levels. Structural connectivity as reflected by network-based statistic mediated the difference in cognitive performance levels between clozapine-treated and risperidone-treated patients. LIMITATIONS: These results are constrained by the lack of random assignment to different types of antipsychotic treatment. CONCLUSION: These findings provide insight into the white matter structural network deficits in patients with chronic schizophrenia, either being treated or untreated, and suggest white matter structural networks supporting cognitive function may benefit from antipsychotic treatment, especially in those treated with risperidone.

Smooth pursuit eye movement deficits as a biomarker for psychotic features in bipolar disorder-Findings from the PARDIP study.

OBJECTIVES: Smooth pursuit eye movement deficits are an established psychosis biomarker across schizophrenia, schizoaffective and psychotic bipolar disorder (BPwP). Whether smooth pursuit deficits are also seen in bipolar disorder without psychosis (BPwoP) is unclear. Here we present data from the Psychosis and Affective Research Domains and Intermediate Phenotypes (PARDIP) study comparing bipolar patients with and without psychotic features. METHODS: Probands with BPwP (N = 49) and BPwoP (N = 36), and healthy controls (HC, N = 71) performed eye tracking tasks designed to evaluate specific sensorimotor components relevant for pursuit initiation and pursuit maintenance. RESULTS: While BPwoP did not differ from either BPwP or HC on initial eye acceleration, they performed significantly better than BPwP on early (P < .01) and predictive (P = .02) pursuit maintenance measures, both without differing from HC. BPwP were impaired compared to HC on initial eye acceleration, and on early and predictive pursuit maintenance (all P < .01). In contrast to the three pursuit measures, BPwP and BPwoP were both impaired on general neurocognitive assessments in relation to HC (both P < .001), without a significant difference between the two bipolar patient groups. CONCLUSIONS: Our findings support the model that impairments of sensorimotor and cognitive processing as required for early and later predictive smooth pursuit maintenance are relatively specific to those bipolar patients with a history of psychosis. This suggests that the neural circuitry for developing feed-forward predictive models for accurate pursuit maintenance is associated with the occurrence of psychotic features in bipolar patients. In contrast, generalized neuropsychological impairments did not differentiate the two bipolar patient groups.

Alterations in intrinsic fronto-thalamo-parietal connectivity are associated with cognitive control deficits in psychotic disorders.

Despite a growing number of reports about alterations in intrinsic/resting brain activity observed in patients with psychotic disorders, their relevance to well-established cognitive control deficits in this patient group is not well understood. Totally 88 clinically stabilized patients with a psychotic disorder and 50 healthy controls participated in a resting-state magnetic resonance imaging study (rs-MRI) and performed an antisaccade task in the laboratory to assess voluntary inhibitory control ability. Deficits on this task are a well-established biomarker across psychotic disorders as we found in the present patient sample. First, regional cerebral function was evaluated by measuring the amplitude of low frequency fluctuations (ALFF) in rs-MRI BOLD signals. We found reduced ALFF in patients in regions known to be relevant to antisaccade task performance including bilateral frontal eye fields (FEF), supplementary eye fields (SEF) and thalamus. Second, areas with ALFF alterations were used as seed areas in whole-brain functional connectivity (FC) analysis. Altered FC was observed in a fronto-thalamo-parietal network that was associated with inhibition error rate in patients but not in controls. In contrast, faster time to generate a correct antisaccade was associated with FC in FEF and SEF in controls but this effect was not seen in patients. These findings establish a behavioral relevance of resting-state fMRI findings in psychotic disorders, and extend previous reports of alterations in fronto-thalamo-parietal network activation during antisaccade performance seen in task-based fMRI studies.