Mapping default mode connectivity alterations following a single season of subconcussive impact exposure in youth football

Repetitive head impact (RHI) exposure in collision sports may contribute to adverse neurological outcomes in former players. In contrast to a concussion, or mild traumatic brain injury, “subconcussive” RHIs represent a more frequent and asymptomatic form of exposure. The neural network‐level signatures characterizing subconcussive RHIs in youth collision‐sport cohorts such as American Football are not known. Here, we used resting‐state functional MRI to examine default mode network (DMN) functional connectivity (FC) following a single football season in youth players (n = 50, ages 8–14) without concussion. Football players demonstrated reduced FC across widespread DMN regions compared with non‐collision sport controls at postseason but not preseason. In a subsample from the original cohort (n = 17), players revealed a negative change in FC between preseason and postseason and a positive and compensatory change in FC during the offseason across the majority of DMN regions. Lastly, significant FC changes, including between preseason and postseason and between in‐ and off‐season, were specific to players at the upper end of the head impact frequency distribution. These findings represent initial evidence of network‐level FC abnormalities following repetitive, non‐concussive RHIs in youth football. Furthermore, the number of subconcussive RHIs proved to be a key factor influencing DMN FC.     

Static and Dynamic Characteristics of Cerebral Blood Flow During the Resting State in Schizophrenia

Background:

The cerebral network that is active during rest and is deactivated during goal-oriented activity is called the default mode network (DMN). It appears to be involved in self-referential mental activity. Atypical functional connectivity in the DMN has been observed in schizophrenia. One hypothesis suggests that pathologically increased DMN connectivity in schizophrenia is linked with a main symptom of psychosis, namely, misattribution of thoughts.

Methods:

A resting-state pseudocontinuous arterial spin labeling (ASL) study was conducted to measure absolute cerebral blood flow (CBF) in 34 schizophrenia patients and 27 healthy controls. Using independent component analysis (ICA), the DMN was extracted from ASL data. Mean CBF and DMN connectivity were compared between groups using a 2-sample t test.

Results:

Schizophrenia patients showed decreased mean CBF in the frontal and temporal regions (P < .001). ICA demonstrated significantly increased DMN connectivity in the precuneus (x/y/z = −16/−64/38) in patients than in controls (P < .001). CBF was not elevated in the respective regions. DMN connectivity in the precuneus was significantly correlated with the Positive and Negative Syndrome Scale scores (P < .01).

Conclusions:

In schizophrenia patients, the posterior hub—which is considered the strongest part of the DMN—showed increased DMN connectivity. We hypothesize that this increase hinders the deactivation of the DMN and, thus, the translation of cognitive processes from an internal to an external focus. This might explain symptoms related to defective self-monitoring, such as auditory verbal hallucinations or ego disturbances.Key words: psychosis, default mode network, arterial spin labeling, functional connectivity, precuneus     

The default mode network and cognition in Parkinson's disease: A multimodal resting‐state network approach

Involvement of the default mode network (DMN) in cognitive symptoms of Parkinson''s disease (PD) has been reported by resting‐state functional MRI (rsfMRI) studies. However, the relation to metabolic measures obtained by [18F]‐fluorodeoxyglucose positron emission tomography (FDG‐PET) is largely unknown. We applied multimodal resting‐state network analysis to clarify the association between intrinsic metabolic and functional connectivity abnormalities within the DMN and their significance for cognitive symptoms in PD. PD patients were classified into normal cognition (n = 36) and mild cognitive impairment (MCI; n = 12). The DMN was identified by applying an independent component analysis to FDG‐PET and rsfMRI data of a matched subset (16 controls and 16 PD patients) of the total cohort. Besides metabolic activity, metabolic and functional connectivity within the DMN were compared between the patients'' groups and healthy controls (n = 16). Glucose metabolism was significantly reduced in all DMN nodes in both patient groups compared to controls, with the lowest uptake in PD‐MCI (p < .05). Increased metabolic and functional connectivity along fronto‐parietal connections was identified in PD‐MCI patients compared to controls and unimpaired patients. Functional connectivity negatively correlated with cognitive composite z‐scores in patients (r = −.43, p = .005). The current study clarifies the commonalities of metabolic and hemodynamic measures of brain network activity and their individual significance for cognitive symptoms in PD, highlighting the added value of multimodal resting‐state network approaches for identifying prospective biomarkers.     

The Epidemiology and Associated Phenomenology of Formal Thought Disorder: A Systematic Review

Background: Authors of the Diagnostic and Statistical Manual, Fifth Edition (DSM-V) have recommended to “integrate dimensions into clinical practice.” The epidemiology and associated phenomenology of formal thought disorder (FTD) have been described but not reviewed. We aimed to carry out a systematic review of FTD to this end. Methods: A systematic review of FTD literature, from 1978 to 2013, using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: A total of 881 abstracts were reviewed and 120 articles met inclusion criteria; articles describing FTD factor structure (n = 15), prevalence and longitudinal course (n = 41), role in diagnosis (n = 22), associated clinical variables (n = 56), and influence on outcome (n = 35) were included. Prevalence estimates for FTD in psychosis range from 5% to 91%. Dividing FTD into domains, by factor analysis, can accurately identify 91% of psychotic diagnoses. FTD is associated with increased clinical severity. Poorer outcomes are predicted by negative thought disorder, more so than the typical construct of “disorganized speech.” Conclusion: FTD is a common symptom of psychosis and may be considered a marker of illness severity. Detailed dimensional assessment of FTD can clarify diagnosis and may help predict prognosis.Key words: formal thought disorder, thought disorder, phenomenology, epidemiology, prognosis, psychosis, schizophrenia, language, communication     

DRD2 Genotype-Based Variation of Default Mode Network Activity and of Its Relationship With Striatal DAT Binding

The default mode network (DMN) comprises a set of brain regions with “increased” activity during rest relative to cognitive processing. Activity in the DMN is associated with functional connections with the striatum and dopamine (DA) levels in this brain region. A functional single-nucleotide polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560 G > T) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. However, the effects of this polymorphism on DMN have not been explored. The aim of this study was to evaluate the effects of rs1076560 on DMN and striatal connectivity and on their relationship with striatal DA signaling. Twenty-eight subjects genotyped for rs1076560 underwent functional magnetic resonance imaging during a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([₁₂₃I]-FP-CIT SPECT) imaging (a measure of dopamine transporter [DAT] binding). Spatial group-independent component (IC) analysis was used to identify DMN and striatal ICs. Within the anterior DMN IC, GG subjects had relatively greater connectivity in medial prefrontal cortex (MPFC), which was directly correlated with striatal DAT binding. Within the posterior DMN IC, GG subjects had reduced connectivity in posterior cingulate relative to T carriers. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity and that these changes are correlated with striatal function and presynaptic DA signaling.     

Biomarker Profiles in Psychosis Risk Groups Within Unaffected Relatives Based on Familiality and Age

Investigating biomarkers in unaffected relatives (UR) of individuals with psychotic disorders has already proven productive in research on psychosis neurobiology. However, there is considerable heterogeneity among UR based on features linked to psychosis vulnerability. Here, using the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) dataset, we examined cognitive and neurophysiologic biomarkers in first-degree UR of psychosis probands, stratified by 2 widely used risk factors: familiality status of the respective proband (the presence or absence of a first- or second-degree relative with a history of psychotic disorder) and age (within or older than the common age range for developing psychosis). We investigated biomarkers that best differentiate the above specific risk subgroups. Additionally, we examined the relationship of biomarkers with Polygenic Risk Scores for Schizophrenia (PRS_SCZ) in a subsample of Caucasian probands and healthy controls (HC). Our results demonstrate that the Brief Assessment of Cognition in Schizophrenia (BACS) score, antisaccade error (ASE) factor, and stop-signal task (SST) factor best differentiate UR (n = 169) from HC (n = 137) (P = .013). Biomarker profiles of UR of familial (n = 82) and non-familial (n = 83) probands were not significantly different. Furthermore, ASE and SST factors best differentiated younger UR (age ≤ 30) (n = 59) from older UR (n = 110) and HC from both age groups (age ≤ 30 years, n=49; age > 30 years, n = 88) (P < .001). In addition, BACS (r = −0.175, P = .006) and ASE factor (r = 0.188, P = .006) showed associations with PRS_SCZ. Taken together, our findings indicate that cognitive biomarkers—“top-down inhibition” impairments in particular—may be of critical importance as indicators of psychosis vulnerability.     

Default Mode Network quantitative diffusion and resting‐state functional magnetic resonance imaging correlates in sporadic Creutzfeldt‐Jakob disease

Grey matter involvement is a well‐known feature in sporadic Creutzfeldt–Jakob disease (sCJD), yet precise anatomy‐based quantification of reduced diffusivity is still not fully understood. Default Mode Network (DMN) areas have been recently demonstrated as selectively involved in sCJD, and functional connectivity has never been investigated in prion diseases. We analyzed the grey matter involvement using a quantitatively multi‐parametric MRI approach. Specifically, grey matter mean diffusivity of 37 subjects with sCJD was compared with that of 30 age‐matched healthy controls with a group‐wise approach. Differences in mean diffusivity were also examined between the cortical (MM(V)1, MM(V)2C, and VV1) and subcortical (VV2 and MV2K) subgroups of sCJD for those with autopsy data available (n = 27, 73%). We also assessed resting‐state functional connectivity of both ventral and dorsal components of DMN in a subset of subject with a rs‐fMRI dataset available (n = 17). Decreased diffusivity was predominantly present in posterior cortical regions of the DMN, but also outside of the DMN in temporal areas and in a few limbic and frontal areas, in addition to extensive deep nuclei involvement. Both subcortical and cortical sCJD subgroups showed decreased diffusivity subcortically, whereas only the cortical type expressed significantly decreased diffusivity cortically, mainly in parietal, occipital, and medial‐inferior temporal cortices bilaterally. Interestingly, we found abnormally increased connectivity in both dorsal and ventral components of the DMN in sCJD subjects compared with healthy controls. The significance and possible utility of functional imaging as a biomarker for tracking disease progression in prion disease needs to be explored further.     

Functional Outcome in People at High Risk for Psychosis Predicted by Thalamic Glutamate Levels and Prefronto-Striatal Activation

Little is known about the neurobiological factors that determine functional outcome in people at high risk for psychosis. We use multimodal neuroimaging to investigate whether cortical responses during a cognitive task and thalamic glutamate levels were associated with subsequent functional outcome. Sixty subjects participated: 27 healthy controls (CTRL) and 33 at ultrahigh risk (UHR) for psychosis. At baseline, cortical responses during a verbal fluency task were measured using functional Magnetic Resonance Imaging (fMRI) and proton Magnetic Resonance Spectroscopy (1H-MRS) was used to measure thalamic glutamate levels. The UHR subjects were then followed clinically for a mean duration of 18 months, and subdivided into “good” and “poor” functional outcome subgroups according to their Global Assessment of Function score at follow-up. UHR subjects with a poor functional outcome showed greater cortical and subcortical activation than UHR subjects with a good functional outcome. They also had lower levels of thalamic glutamate and showed a negative relationship between thalamic glutamate levels and prefrontal-striatal activation that was not present in the good functional outcome or control groups. In people at high risk for psychosis, their subsequent level of functioning may depend on the extent to which neurophysiological and neurochemical function is perturbed when they first present to clinical services.Key words: psychosis, ultra-high risk, functional outcomes, functional MRI, spectroscopy, glutamate     

Very preterm brain at rest: longitudinal social–cognitive network connectivity during childhood

Very preterm (VPT: ≤32 weeks of gestational age) birth poses an increased risk for social and cognitive morbidities that persist throughout life. Resting-state functional network connectivity studies provide information about the intrinsic capacity for cognitive processing. We studied the following four social–cognitive resting-state networks: the default mode, salience, frontal-parietal and language networks. We examined functional connectivity using magnetoencephalography with individual head localization using each participant’s MRI at 6 (n = 40) and 8 (n = 40) years of age compared to age- and sex-matched full-term (FT) born children (n = 38 at 6 years and n = 43 at 8 years). VPT children showed increased connectivity compared to FT children in the gamma band (30–80 Hz) at 6 years within the default mode network (DMN), and between the DMN and the salience, frontal-parietal and language networks, pointing to more diffuse, less segregated processing across networks at this age. At 8 years, VPT children had more social and academic difficulties. Increased DMN connectivity at 6 years was associated with social and working memory difficulties at 8 years. Therefore, we suggest that increased DMN connectivity contributes to the observed emerging social and cognitive morbidities in school age.     

Dysconnectivity Within the Default Mode in First-Episode Schizophrenia: A Stochastic Dynamic Causal Modeling Study With Functional Magnetic Resonance Imaging

We report the first stochastic dynamic causal modeling (sDCM) study of effective connectivity within the default mode network (DMN) in schizophrenia. Thirty-three patients (9 women, mean age = 25.0 years, SD = 5) with a first episode of psychosis and diagnosis of schizophrenia—according to the Diagnostic and Statistic Manual of Mental Disorders, 4th edition, revised criteria—were studied. Fifteen healthy control subjects (4 women, mean age = 24.6 years, SD = 4) were included for comparison. All subjects underwent resting state functional magnetic resonance imaging (fMRI) interspersed with 2 periods of continuous picture viewing. The anterior frontal (AF), posterior cingulate (PC), and the left and right parietal nodes of the DMN were localized in an unbiased fashion using data from 16 independent healthy volunteers (using an identical fMRI protocol). We used sDCM to estimate directed connections between and within nodes of the DMN, which were subsequently compared with t tests at the between subject level. The excitatory effect of the PC node on the AF node and the inhibitory self-connection of the AF node were significantly weaker in patients (mean values = 0.013 and −0.048 Hz, SD = 0.09 and 0.05, respectively) relative to healthy subjects (mean values = 0.084 and −0.088 Hz, SD = 0.15 and 0.77, respectively; P < .05). In summary, sDCM revealed reduced effective connectivity to the AF node of the DMN—reflecting a reduced postsynaptic efficacy of prefrontal afferents—in patients with first-episode schizophrenia.Key words: brain connectivity, default mode network, dysconnectivity, first-episode schizophrenia, functional magnetic resonance imaging (fMRI), resting state, stochastic dynamic causal modeling (DCM)     

Tormenting thoughts: The posterior cingulate sulcus of the default mode network regulates valence of thoughts and activity in the brain's pain network during music listening

Many individuals spend a significant amount of their time “mind‐wandering”. Mind‐wandering often includes spontaneous, nonintentional thought, and a neural correlate of this kind of thought is the default mode network (DMN). Thoughts during mind‐wandering can have positive or negative valence, but only little is known about the neural correlates of positive or negative thoughts. We used resting‐state functional magnetic resonance imaging (fMRI) and music to evoke mind‐wandering in n = 33 participants, with positive‐sounding music eliciting thoughts with more positive valence and negative‐sounding music eliciting thoughts with more negative valence. Applying purely data‐driven analysis methods, we show that medial orbitofrontal cortex (mOFC, part of the ventromedial prefrontal cortex) and the posterior cingulate sulcus (likely area 23c of the posterior cingulate cortex), two sub‐regions of the DMN, modulate the valence of thought‐contents during mind‐wandering. In addition, across two independent experiments, we observed that the posterior cingulate sulcus, a region involved in pain, shows valence‐specific functional connectivity with core regions of the brain''s putative pain network. Our results suggest that two DMN regions (mOFC and posterior cingulate sulcus) support the formation of negative spontaneous, nonintentional thoughts, and that the interplay between these structures with regions of the putative pain network forms a neural mechanism by which thoughts can become painful.     

Cognitive Subtyping in Schizophrenia: A Latent Profile Analysis

Cognitive dysfunction is a core feature of schizophrenia. The subtyping of cognitive performance in schizophrenia may aid the refinement of disease heterogeneity. The literature on cognitive subtyping in schizophrenia, however, is limited by variable methodologies and neuropsychological tasks, lack of validation, and paucity of studies examining longitudinal stability of profiles. It is also unclear if cognitive profiles represent a single linear severity continuum or unique cognitive subtypes. Cognitive performance measured with the Brief Assessment of Cognition in Schizophrenia was analyzed in schizophrenia patients (n = 767). Healthy controls (n = 1012) were included as reference group. Latent profile analysis was performed in a schizophrenia discovery cohort (n = 659) and replicated in an independent cohort (n = 108). Longitudinal stability of cognitive profiles was evaluated with latent transition analysis in a 10-week follow-up cohort. Confirmatory factor analysis (CFA) was carried out to investigate if cognitive profiles represent a unidimensional structure. A 4-profile solution was obtained from the discovery cohort and replicated in an independent cohort. It comprised of a “less-impaired” cognitive subtype, 2 subtypes with “intermediate cognitive impairment” differentiated by executive function performance, and a “globally impaired” cognitive subtype. This solution showed relative stability across time. CFA revealed that cognitive profiles are better explained by distinct meaningful profiles than a severity linear continuum. Associations between profiles and negative symptoms were observed. The subtyping of schizophrenia patients based on cognitive performance and its associations with symptomatology may aid phenotype refinement, mapping of specific biological mechanisms, and tailored clinical treatments.     

Towards a Psychosis Risk Blood Diagnostic for Persons Experiencing High-Risk Symptoms: Preliminary Results From the NAPLS Project

Introduction: A barrier to preventative treatments for psychosis is the absence of accurate identification of persons at highest risk. A blood test that could substantially increase diagnostic accuracy would enhance development of psychosis prevention interventions. Methods: The North American Prodrome Longitudinal Study project is a multisite endeavor that aims to better understand predictors and mechanisms for the development of psychosis. In this study, we measured expression of plasma analytes reflecting inflammation, oxidative stress, hormones, and metabolism. A “greedy algorithm” selected analytes that best distinguished persons with clinical high-risk symptoms who developed psychosis (CHR-P; n = 32) from unaffected comparison (UC) subjects (n = 35) and from those who did not develop psychosis during a 2-year follow-up (CHR-NP; n = 40). Results: The classifier included 15 analytes (selected from 117), with an area under the receiver operating curve for CHR-P vs UC of 0.91 and CHR-P vs CHR-NP of 0.88. Randomly scrambled group membership followed by reconstructions of the entire classifier method yielded consistently weak classifiers, indicating that the true classifier is highly unlikely to be a chance occurrence. Such randomization methods robustly imply the assays contain consistent information distinguishing the groups which was not obscured by the data normalization method and was revealed by classifier construction. These results support the hypothesis that inflammation, oxidative stress, and dysregulation of hypothalamic-pituitary axes may be prominent in the earliest stages of psychosis. Conclusion: If confirmed in other groups of persons at elevated risk of psychosis, a multiplex blood assay has the potential for high clinical utility.Key words: clinical high risk, psychosis, prodrome, multiplex, risk prediction, malondialdehyde-modified low-density lipoprotein (MDA-LDL), immune, inflammation, oxidative stress     

Prevalence and Clinical Significance of DSM-5–Attenuated Psychosis Syndrome in Adolescents and Young Adults in the General Population: The Bern Epidemiological At-Risk (BEAR) Study

Objective: Section III of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) lists attenuated psychosis syndrome as a condition for further study. One important question is its prevalence and clinical significance in the general population. Method: Analyses involved 1229 participants (age 16–40 years) from the general population of Canton Bern, Switzerland, enrolled from June 2011 to July 2012. “Symptom,” “onset/worsening,” “frequency,” and “distress/disability” criteria of attenuated psychosis syndrome were assessed using the structured interview for psychosis-risk syndromes. Furthermore, help-seeking, psychosocial functioning, and current nonpsychotic axis I disorders were surveyed. Well-trained psychologists performed assessments using the computer-assisted telephone interviewing technique. Results: The symptom criterion was met by 12.9% of participants, onset/worsening by 1.1%, frequency by 3.8%, and distress/disability by 7.0%. Symptom, frequency, and distress/disability were met by 3.2%. Excluding trait-like attenuated psychotic symptoms (APS) decreased the prevalence to 2.6%, while adding onset/worsening reduced it to 0.3%. APS were associated with functional impairments, current mental disorders, and help-seeking although they were not a reason for help-seeking. These associations were weaker for attenuated psychosis syndrome. Conclusions: At the population level, only 0.3% met current attenuated psychosis syndrome criteria. Particularly, the onset/worsening criterion, originally included to increase the likelihood of progression to psychosis, lowered its prevalence. Because progression is not required for a self-contained syndrome, a revision of the restrictive onset criterion is proposed to avoid the exclusion of 2.3% of persons who experience and are distressed by APS from mental health care. Secondary analyses suggest that a revised syndrome would also possess higher clinical significance than the current syndrome.Key words: attenuated psychosis syndrome, general population, prevalence, distress, disability, functional impairment     

Neuropsychological and functional outcomes in recent-onset major depression,bipolar disorder and schizophrenia-spectrum disorders: a longitudinal cohort study

Functional disability is the lead contributor to burden of mental illness. Cognitive deficits frequently limit functional recovery, although whether changes in cognition and disability are longitudinally associated in recent-onset individuals remains unclear. Using a prospective, cohort design, 311 patients were recruited and assessed at baseline. One hundred and sixty-seven patients met eligibility criteria (M=21.5 years old, s.d.=4.8) and returned for follow-up (M=20.6 months later, s.d.=7.8). Two-hundred and thirty participants were included in the final analysis, comprising clinically stable patients with major depression (n=71), bipolar disorder (BD; n=61), schizophrenia-spectrum disorders (n=35) and 63 healthy controls. Neuropsychological functioning and self-rated functional disability were examined using mixed-design, repeated-measures analysis, across diagnoses and cognitive clusters, covarying for relevant confounds. Clinical, neuropsychological and functional changes did not differ between diagnoses (all P>0.05). Three reliable neuropsychological subgroups emerged through cluster analysis, characterized by psychomotor slowing, improved sustained attention, and improved verbal memory. Controlling for diagnosis and changes in residual symptoms, clusters with improved neuropsychological functioning observed greater reductions in functional disability than the psychomotor slowing cluster, which instead demonstrated a worsening in disability (P<0.01). Improved sustained attention was independently associated with greater likelihood of follow-up employment (P<0.01). Diagnosis of BD uniquely predicted both follow-up employment and independent living. Neuropsychological course appears to be independently predictive of subjective and objective functional outcomes. Importantly, cognitive phenotypes may reflect distinct pathophysiologies shared across major psychiatric conditions, and be ideal targets for personalized early intervention.     

Validity of the Prodromal Risk Syndrome for First Psychosis: Findings From the North American Prodrome Longitudinal Study

Treatment and prevention studies over the past decade have enrolled patients believed to be at risk for future psychosis. These patients were considered at risk for psychosis by virtue of meeting research criteria derived from retrospective accounts of the psychosis prodrome. This study evaluated the diagnostic validity of the prospective “prodromal risk syndrome” construct. Patients assessed by the Structured Interview for Prodromal Syndromes as meeting criteria of prodromal syndromes (n = 377) from the North American Prodrome Longitudinal Study were compared with normal comparison (NC, n = 196), help-seeking comparison (HSC, n = 198), familial high-risk (FHR, n = 40), and schizotypal personality disorder (SPD, n = 49) groups. Comparisons were made on variables from cross-sectional demographic, symptom, functional, comorbid diagnostic, and family history domains of assessment as well as on follow-up outcome. Prodromal risk syndrome patients as a group were robustly distinguished from NC subjects across all domains and distinguished from HSC subjects and from FHR subjects on most measures in many of these domains. Adolescent and young adult SPD patients, while distinct from prodromal patients on definitional grounds, were similar to prodromals on multiple measures, consistent with SPD in young patients possibly being an independent risk syndrome for psychosis. The strong evidence of diagnostic validity for the prodromal risk syndrome for first psychosis raises the question of its evaluation for inclusion in Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition).     

Geolocation as a Digital Phenotyping Measure of Negative Symptoms and Functional Outcome

ObjectiveNegative symptoms and functional outcome have traditionally been assessed using clinical rating scales, which rely on retrospective self-reports and have several inherent limitations that impact validity. These issues may be addressed with more objective digital phenotyping measures. In the current study, we evaluated the psychometric properties of a novel “passive” digital phenotyping method: geolocation. MethodParticipants included outpatients with schizophrenia or schizoaffective disorder (SZ: n = 44), outpatients with bipolar disorder (BD: n =19), and demographically matched healthy controls (CN: n = 42) who completed 6 days of “active” digital phenotyping assessments (eg, surveys) while geolocation was recorded. ResultsResults indicated that SZ patients show less activity than CN and BD, particularly, in their travel from home. Geolocation variables demonstrated convergent validity by small to medium correlations with negative symptoms and functional outcome measured via clinical rating scales, as well as active digital phenotyping behavioral indices of avolition, asociality, and anhedonia. Discriminant validity was supported by low correlations with positive symptoms, depression, and anxiety. Reliability was supported by good internal consistency and moderate stability across days. ConclusionsThese findings provide preliminary support for the reliability and validity of geolocation as an objective measure of negative symptoms and functional outcome. Geolocation offers enhanced precision and the ability to take a “big data” approach that facilitates sophisticated computational models. Near-continuous recordings and large numbers of samples may make geolocation a novel outcome measure for clinical trials due to enhanced power to detect treatment effects.     

Aberrant Dependence of Default Mode/Central Executive Network Interactions on Anterior Insular Salience Network Activity in Schizophrenia

In schizophrenia, consistent structural and functional changes have been demonstrated for the insula including aberrant salience processing, which is critical for psychosis. Interactions within and across default mode and central executive network (DMN, CEN) are impaired in schizophrenia. The question arises whether these 2 types of changes are related. Recently, the anterior insula has been demonstrated to control DMN/CEN interactions. We hypothesized that aberrant insula and DMN/CEN activity in schizophrenia is associated with an impaired dependence of DMN/CEN interactions on anterior insular salience network (SN) activity. Eighteen patients with schizophrenia during psychosis and 20 healthy controls were studied by resting-state-fMRI and psychometric examination. High-model-order independent component analysis of fMRI data revealed spatiotemporal patterns of synchronized ongoing blood-oxygenation-level-dependent (BOLD) activity including SN, DMN, and CEN. Scores of functional and time-lagged connectivity across networks’ time courses were calculated. Connectivity scores and spatial network maps were compared between groups and related with patients’ hallucination and delusion severity. Spatial BOLD-synchronicity was altered in patients’ SN, DMN, and CEN, including decreased activity in the right anterior insula (rAI). Patients’ functional connectivity between DMN and CEN was increased and related with hallucinations severity. Importantly, patients’ time-lagged connectivity between SN and DMN/CEN was reduced, and decreased rAI activity of the SN was associated with both hallucinations and increased functional connectivity between DMN and CEN. Data provide evidence for an aberrant dependence of DMN/CEN interactions on anterior insular SN activity, linking impaired insula, DMN, CEN activity, and psychosis in schizophrenia.Key words: schizophrenia, psychosis, anterior insula, salience network, default mode network, central executive network     

Schizophrenia Candidate Gene ERBB4: Covert Routes of Vulnerability to Psychosis Detected at the Population Level

Prior genetic and functional evidence established ERBB4 as a probable schizophrenia susceptibility gene that may confer risk via modulating brain information processing dependent on the integrity of frontotemporal brain circuitry. Utilizing retrospective data drawn from the cross-sectional population-based Athens Study of Psychosis Proneness and Incidence of Schizophrenia (ASPIS) (n = 1127), we attempted to independently replicate and further extend previous findings by examining the effects of ERBB4 gene variants on 3 broad population–based psychosis-related phenotypes: verbal working memory (VWM), trait schizotypy, and stress-induced subclinical psychotic experiences (PE). Three common ERBB4 single nucleotide polymorphisms that were previously associated with schizophrenia and impaired frontotemporal-related information processing (rs7598440, rs839523, and rs707284), their haplotypes, and corresponding diplotypes were tested. VWM performance was significantly associated with rs839523 and rs707284 markers even after correction for multiple testing, thus validating reported findings that have implicated ERBB4 gene variation on working memory. No associations were detected between these ERBB4 variants and trait schizotypy. However, we were able to detect a significant effect of rs7598440 marker on PE expressed under stressful environmental conditions. Combined haplotype analysis of the above 3 markers, identified a “yin-yang” pattern of association, confirmed at the diplotype level. While GGG haplotype homozygotes were associated with “protective” effects on VWM performance and PE, AAA “risk” haplotype carriers were associated with worse VWM performance and simultaneously exhibited significantly elevated PE. This dual, possibly pleiotropic, impact on frontotemporal circuitry and increased sensitivity to psychosocial stress may represent subtle manifestations of ERBB4-related vulnerability to psychosis, expressed at the population level.