Adjustment of Regional Cortical Thickness Measures for Global Cortical Thickness Obscures Deficits Across the Schizophrenia Spectrum: A Cautionary Note About Normative Modeling of Brain Imaging Data.

Recent neuroimaging studies and publicly disseminated analytic tools suggest that regional morphometric analyses covary for global thickness. We empirically demonstrated that this statistical approach severely underestimates regional thickness dysmorphology in psychiatric disorders. Study 1 included 90 healthy control participants, 51 participants at clinical high risk for psychosis, and 78 participants with early-illness schizophrenia. Study 2 included 56 healthy control participants, 83 participants with nonaffective psychosis, and 30 participants with affective psychosis. We examined global and regional thickness correlations, global thickness group differences, and regional thickness group differences with and without global thickness covariation. Global and regional thickness were strongly correlated across groups. Global thickness was lower in the schizophrenia spectrum groups than the other groups. Regional thickness deficits in schizophrenia spectrum groups were attenuated or eliminated with global thickness covariation. Eliminating the variation that regional thickness shares with global thickness eliminated disease-related effects. This statistical approach results in erroneous conclusions that regional thickness is normal in disorders like schizophrenia or clinical high risk syndrome.

Brain Age Gap in Early Illness Schizophrenia and the Clinical High-Risk Syndrome: Associations With Experiential Negative Symptoms and Conversion to Psychosis.

BACKGROUND AND HYPOTHESIS: Brain development/aging is not uniform across individuals, spawning efforts to characterize brain age from a biological perspective to model the effects of disease and maladaptive life processes on the brain. The brain age gap represents the discrepancy between estimated brain biological age and chronological age (in this case, based on structural magnetic resonance imaging, MRI). Structural MRI studies report an increased brain age gap (biological age > chronological age) in schizophrenia, with a greater brain age gap related to greater negative symptom severity. Less is known regarding the nature of this gap early in schizophrenia (ESZ), if this gap represents a psychosis conversion biomarker in clinical high-risk (CHR-P) individuals, and how altered brain development and/or aging map onto specific symptom facets. STUDY DESIGN: Using structural MRI, we compared the brain age gap among CHR-P (n = 51), ESZ (n = 78), and unaffected comparison participants (UCP; n = 90), and examined associations with CHR-P psychosis conversion (CHR-P converters n = 10; CHR-P non-converters; n = 23) and positive and negative symptoms. STUDY RESULTS: ESZ showed a greater brain age gap relative to UCP and CHR-P (Ps < .010). CHR-P individuals who converted to psychosis showed a greater brain age gap (P = .043) relative to CHR-P non-converters. A larger brain age gap in ESZ was associated with increased experiential (P = .008), but not expressive negative symptom severity. CONCLUSIONS: Consistent with schizophrenia pathophysiological models positing abnormal brain maturation, results suggest abnormal brain development is present early in psychosis. An increased brain age gap may be especially relevant to motivational and functional deficits in schizophrenia.

Alpha Event-Related Desynchronization During Reward Processing in Schizophrenia.

BACKGROUND: Alterations in the brain's reward system may underlie motivation and pleasure deficits in schizophrenia (SZ). Neuro-oscillatory desynchronization in the alpha band is thought to direct resource allocation away from the internal state, to prioritize processing salient environmental events, including reward feedback. We hypothesized reduced reward-related alpha event-related desynchronization (ERD) in SZ, consistent with less externally focused processing during reward feedback. METHODS: Electroencephalography was recorded while participants with SZ (n = 54) and healthy control participants (n = 54) played a simple slot machine task. Total alpha band power (8-14 Hz), a measure of neural oscillation magnitude, was extracted via principal component analysis and compared between groups and reward outcomes. The clinical relevance of hypothesized alpha power alterations was examined by testing associations with negative symptoms within the SZ group and with trait rumination, dimensionally, across groups. RESULTS: A group × reward outcome interaction (p = .018) was explained by healthy control participants showing significant posterior-occipital alpha power suppression to wins versus losses (p < .001), in contrast to participants with SZ (p > .1). Among participants with SZ, this alpha ERD was unrelated to negative symptoms (p > .1). Across all participants, less alpha ERD to reward outcomes covaried with greater trait rumination for both win (p = .005) and loss (p = .002) outcomes, with no group differences in slope. CONCLUSIONS: These findings demonstrate alpha ERD alterations in SZ during reward outcome processing. Additionally, higher trait rumination was associated with less alpha ERD during reward feedback, suggesting that individual differences in rumination covary with external attention to reward processing, regardless of reward outcome valence or group membership.

Cortical and subcortical brain morphometry abnormalities in youth at clinical high-risk for psychosis and individuals with early illness schizophrenia.

Neuroimaging studies have documented morphometric brain abnormalities in schizophrenia, but less is known about them in individuals at clinical high-risk for psychosis (CHR-P), including how they compare with those observed in early schizophrenia (ESZ). Accordingly, we implemented multivariate profile analysis of regional morphometric profiles in CHR-P (n = 89), ESZ (n = 93) and healthy controls (HC; n = 122). ESZ profiles differed from HC and CHR-P profiles, including 1) cortical thickness: significant level reduction and regional non-parallelism reflecting widespread thinning, except for entorhinal and pericalcarine cortex, 2) basal ganglia volume: significant level increase and regional non-parallelism reflecting larger caudate and pallidum, and 3) ventricular volume: significant level increase with parallel regional profiles. CHR-P and ESZ cerebellar profiles showed significant non-parallelism with HC profiles. Regional profiles did not significantly differ between groups for cortical surface area or subcortical volume. Compared to CHR-P followed for ≥18 months without psychosis conversion (n = 31), CHR-P converters (n = 17) showed significant non-parallel ventricular volume expansion reflecting specific enlargement of lateral and inferolateral regions. Antipsychotic dosage in ESZ was significantly correlated with frontal cortical thinning. Results suggest that morphometric abnormalities in ESZ are not present in CHR-P, except for ventricular enlargement, which was evident in CHR-P who developed psychosis.

Rich-club connectivity and structural connectome organization in youth at clinical high-risk for psychosis and individuals with early illness schizophrenia.

Brain dysconnectivity has been posited as a biological marker of schizophrenia. Emerging schizophrenia connectome research has focused on rich-club organization, a tendency for brain hubs to be highly-interconnected but disproportionately vulnerable to dysconnectivity. However, less is known about rich-club organization in individuals at clinical high-risk for psychosis (CHR-P) and how it compares with abnormalities early in schizophrenia (ESZ). Combining diffusion tensor imaging (DTI) and magnetic resonance imaging (MRI), we examined rich-club and global network organization in CHR-P (n = 41) and ESZ (n = 70) relative to healthy controls (HC; n = 74) after accounting for normal aging. To characterize rich-club regions, we examined rich-club MRI morphometry (thickness, surface area). We also examined connectome metric associations with symptom severity, antipsychotic dosage, and in CHR-P specifically, transition to a full-blown psychotic disorder. ESZ had fewer connections among rich-club regions (ps < .024) relative to HC and CHR-P, with this reduction specific to the rich-club even after accounting for other connections in ESZ relative to HC (ps < .048). There was also cortical thinning of rich-club regions in ESZ (ps < .013). In contrast, there was no strong evidence of global network organization differences among the three groups. Although connectome abnormalities were not present in CHR-P overall, CHR-P converters to psychosis (n = 9) had fewer connections among rich-club regions (ps < .037) and greater modularity (ps < .037) compared to CHR-P non-converters (n = 19). Lastly, symptom severity and antipsychotic dosage were not significantly associated with connectome metrics (ps < .012). Findings suggest that rich-club and connectome organization abnormalities are present early in schizophrenia and in CHR-P individuals who subsequently transition to psychosis.

Dysfunctional Cortical Gradient Topography in Treatment-Resistant Major Depressive Disorder.

BACKGROUND: Treatment-resistant depression (TRD) refers to patients with major depressive disorder who do not remit after 2 or more antidepressant trials. TRD is common and highly debilitating, but its neurobiological basis remains poorly understood. Recent neuroimaging studies have revealed cortical connectivity gradients that dissociate primary sensorimotor areas from higher-order associative cortices. This fundamental topography determines cortical information flow and is affected by psychiatric disorders. We examined how TRD impacts gradient-based hierarchical cortical organization. METHODS: In this secondary study, we analyzed resting-state functional magnetic resonance imaging data from a mindfulness-based intervention enrolling 56 patients with TRD and 28 healthy control subjects. Using gradient extraction tools, baseline measures of cortical gradient dispersion within and between functional brain networks were derived, compared across groups, and associated with graph theoretical measures of network topology. In patients, correlation analyses were used to associate measures of cortical gradient dispersion with clinical measures of anxiety, depression, and mindfulness at baseline and following the intervention. RESULTS: Cortical gradient dispersion was reduced within major intrinsic brain networks in patients with TRD. Reduced cortical gradient dispersion correlated with increased network degree assessed through graph theory-based measures of network topology. Lower dispersion among default mode, control, and limbic network nodes related to baseline levels of trait anxiety, depression, and mindfulness. Patients' baseline limbic network dispersion predicted trait anxiety scores 24 weeks after the intervention. CONCLUSIONS: Our findings provide preliminary support for widespread alterations in cortical gradient architecture in TRD, implicating a significant role for transmodal and limbic networks in mediating depression, anxiety, and lower mindfulness in patients with TRD.

Advanced brain age correlates with greater rumination and less mindfulness in schizophrenia.

BACKGROUND: Individual variation in brain aging trajectories is linked with several physical and mental health outcomes. Greater stress levels, worry, and rumination correspond with advanced brain age, while other individual characteristics, like mindfulness, may be protective of brain health. Multiple lines of evidence point to advanced brain aging in schizophrenia (i.e., neural age estimate > chronological age). Whether psychological dimensions such as mindfulness, rumination, and perceived stress contribute to brain aging in schizophrenia is unknown. METHODS: We estimated brain age from high-resolution anatomical scans in 54 healthy controls (HC) and 52 individuals with schizophrenia (SZ) and computed the brain predicted age difference (BrainAGE-diff), i.e., the delta between estimated brain age and chronological age. Emotional well-being summary scores were empirically derived to reflect individual differences in trait mindfulness, rumination, and perceived stress. Core analyses evaluated relationships between BrainAGE-diff and emotional well-being, testing for slopes differences across groups. RESULTS: HC showed higher emotional well-being (greater mindfulness and less rumination/stress), relative to SZ. We observed a significant group difference in the relationship between BrainAge-diff and emotional well-being, explained by BrainAGE-diff negatively correlating with emotional well-being scores in SZ, and not in HC. That is, SZ with younger appearing brains (predicted age < chronological age) had emotional summary scores that were more like HC, a relationship that endured after accounting for several demographic and clinical variables. CONCLUSIONS: These data reveal clinically relevant aspects of brain age heterogeneity among SZ and point to case-control differences in the relationship between advanced brain aging and emotional well-being.

Psychological Dimensions Relevant to Motivation and Pleasure in Schizophrenia.

Motivation and pleasure deficits are common in schizophrenia, strongly linked with poorer functioning, and may reflect underlying alterations in brain functions governing reward processing and goal pursuit. While there is extensive research examining cognitive and reward mechanisms related to these deficits in schizophrenia, less attention has been paid to psychological characteristics that contribute to resilience against, or risk for, motivation and pleasure impairment. For example, psychological tendencies involving positive future expectancies (e.g., optimism) and effective affect management (e.g., reappraisal, mindfulness) are associated with aspects of reward anticipation and evaluation that optimally guide goal-directed behavior. Conversely, maladaptive thinking patterns (e.g., defeatist performance beliefs, asocial beliefs) and tendencies that amplify negative cognitions (e.g., rumination), may divert cognitive resources away from goal pursuit or reduce willingness to exert effort. Additionally, aspects of sociality, including the propensity to experience social connection as positive reinforcement may be particularly relevant for pursuing social goals. In the current review, we discuss the roles of several psychological characteristics with respect to motivation and pleasure in schizophrenia. We argue that individual variation in these psychological dimensions is relevant to the study of motivation and reward processing in schizophrenia, including interactions between these psychological dimensions and more well-characterized cognitive and reward processing contributors to motivation. We close by emphasizing the value of considering a broad set of modulating factors when studying motivation and pleasure functions in schizophrenia.

Validation of ketamine as a pharmacological model of thalamic dysconnectivity across the illness course of schizophrenia.

N-methyl-D-aspartate receptor (NMDAR) hypofunction is a leading pathophysiological model of schizophrenia. Resting-state functional magnetic resonance imaging (rsfMRI) studies demonstrate a thalamic dysconnectivity pattern in schizophrenia involving excessive connectivity with sensory regions and deficient connectivity with frontal, cerebellar, and thalamic regions. The NMDAR antagonist ketamine, when administered at sub-anesthetic doses to healthy volunteers, induces transient schizophrenia-like symptoms and alters rsfMRI thalamic connectivity. However, the extent to which ketamine-induced thalamic dysconnectivity resembles schizophrenia thalamic dysconnectivity has not been directly tested. The current double-blind, placebo-controlled study derived an NMDAR hypofunction model of thalamic dysconnectivity from healthy volunteers undergoing ketamine infusions during rsfMRI. To assess whether ketamine-induced thalamic dysconnectivity was mediated by excess glutamate release, we tested whether pre-treatment with lamotrigine, a glutamate release inhibitor, attenuated ketamine's effects. Ketamine produced robust thalamo-cortical hyper-connectivity with sensory and motor regions that was not reduced by lamotrigine pre-treatment. To test whether the ketamine thalamic dysconnectivity pattern resembled the schizophrenia pattern, a whole-brain template representing ketamine's thalamic dysconnectivity effect was correlated with individual participant rsfMRI thalamic dysconnectivity maps, generating "ketamine similarity coefficients" for people with chronic (SZ) and early illness (ESZ) schizophrenia, individuals at clinical high-risk for psychosis (CHR-P), and healthy controls (HC). Similarity coefficients were higher in SZ and ESZ than in HC, with CHR-P showing an intermediate trend. Higher ketamine similarity coefficients correlated with greater hallucination severity in SZ. Thus, NMDAR hypofunction, modeled with ketamine, reproduces the thalamic hyper-connectivity observed in schizophrenia across its illness course, including the CHR-P period preceding psychosis onset, and may contribute to hallucination severity.

Thalamic dysconnectivity in the psychosis risk syndrome and early illness schizophrenia.

BACKGROUND: Schizophrenia (SZ) is associated with thalamic dysconnectivity. Compared to healthy controls (HCs), individuals with SZ have hyperconnectivity with sensory regions, and hypoconnectivity with cerebellar, thalamic, and prefrontal regions. Despite replication of this pattern in chronically ill individuals, less is known about when these abnormalities emerge in the illness course and if they are present prior to illness onset. METHODS: Resting-state functional magnetic resonance imaging data were collected from psychosis risk syndrome (PRS) youth (n = 45), early illness SZ (ESZ) (n = 74) patients, and HCs (n = 85). Age-adjusted functional connectivity, seeded from the thalamus, was compared among the groups. RESULTS: Significant effects of group were observed in left and right middle temporal regions, left and right superior temporal regions, left cerebellum, and bilateral thalamus. Compared to HCs, ESZ demonstrated hyperconnectivity to all temporal lobe regions and reduced connectivity with cerebellar, anterior cingulate, and thalamic regions. Compared to HCs, PRS demonstrated hyperconnectivity with the left and right middle temporal regions, and hypoconnectivity with the cerebellar and other thalamic regions. Compared to PRS participants, ESZ participants were hyperconnected to temporal regions, but did not differ from PRS in hypoconnectivity with cerebellar and thalamic regions. Thalamic dysconnectivity was unrelated to positive symptom severity in ESZ or PRS groups. CONCLUSIONS: PRS individuals demonstrated an intermediate level of thalamic dysconnectivity, whereas ESZ showed a pattern consistent with prior observations in chronic samples. These cross-sectional findings suggest that thalamic dysconnectivity may occur prior to illness onset and become more pronounced in early illness stages.

Age affects temporal response, but not durability, to serial ketamine infusions for treatment refractory depression.

RATIONALE: Ketamine is a novel, rapid-acting antidepressant for treatment refractory depression (TRD); however, clinical durability is poor and treatment response trajectories vary. Little is known about which patient characteristics predict faster or more durable ketamine responses. Ketamine's antidepressant mechanism may involve modulation of glutamatergic signaling and long-term potentiation (LTP); these neuroplasticity pathways are also attenuated with older age. OBJECTIVE: A retrospective analysis examining the impact of patient age on the speed and durability of ketamine's antidepressant effects in 49 veterans receiving serial intravenous ketamine infusions for TRD. METHOD: The relationship between age and percent change in Beck Depression Inventory (BDI-II) scores was compared across six serial ketamine infusions (twice-weekly for 3 weeks) using a linear-mixed model. RESULTS: A significant Age-X-Infusion number interaction (F = 3.01, p = .0274) indicated that the relationship between age and treatment response depended on infusion number. Follow-up tests showed that younger age significantly predicted greater clinical improvement at infusion #4 (t = 3.02, p = .004); this relationship was attenuated at infusion #5 (t = 1.95, p = .057) and was absent at infusion #6. Age was not a significant predictor of treatment durability, defined as percent change in BDI-II 3 weeks following infusion #6. CONCLUSIONS: These data preliminarily suggest that younger age is associated with a faster response over six serial ketamine infusions; by infusion #6 and subsequent weeks of clinical follow-up, age no longer predicts ketamine's antidepressant activity. Age may mediate the speed but not the durability or total efficacy of ketamine treatment, suggesting that dissociable mechanisms may underlie differing aspects of ketamine's antidepressant activity.

Deficits in auditory predictive coding in individuals with the psychosis risk syndrome: Prediction of conversion to psychosis.

The mismatch negativity (MMN) event-related potential (ERP) component is increasingly viewed as a prediction error signal elicited when a deviant sound violates the prediction that a frequent "standard" sound will repeat. Support for this predictive coding framework emerged with the identification of the repetition positivity (RP), a standard stimulus ERP component that increases with standard repetition and is thought to reflect strengthening of the standard's memory trace and associated predictive code. Using electroencephalographic recordings, we examined the RP elicited by repeating standard tones presented during a traditional "constant standard" MMN paradigm in individuals with the psychosis risk syndrome (PRS; n = 579) and healthy controls (HC; n = 241). Clinical follow-up assessments identified PRS participants who converted to a psychotic disorder (n = 77) and PRS nonconverters who were followed for the entire 24-month clinical follow-up period and either remained symptomatic (n = 144) or remitted from the PRS (n = 94). In HC, RP linearly increased from early- to late-appearing standards within local trains of repeating standards (p < .0001), consistent with auditory predictive code/memory trace strengthening. Relative to HC, PRS participants showed a reduced RP across standards (p = .0056). PRS converters showed a relatively small RP deficit for early appearing standards relative to HC (p = .0.0107) and a more prominent deficit for late-appearing standards (p = .0006) relative to both HC and PRS-remitted groups. Moreover, greater RP deficits predicted shorter time to conversion in a subsample of unmedicated PRS individuals (p = .02). Thus, auditory predictive coding/memory trace deficits precede psychosis onset and predict future psychosis risk in PRS individuals. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Reward processing electrophysiology in schizophrenia: Effects of age and illness phase.

BACKGROUND: Reward processing abnormalities may underlie characteristic pleasure and motivational impairments in schizophrenia. Some neural measures of reward processing show age-related modulation, highlighting the importance of considering age effects on reward sensitivity. We compared event-related potentials (ERPs) reflecting reward anticipation (stimulus-preceding negativity, SPN) and evaluation (reward positivity, RewP; late positive potential, LPP) across individuals with schizophrenia (SZ) and healthy controls (HC), with an emphasis on examining the effects of chronological age, brain age (i.e., predicted age based on neurobiological measures), and illness phase. METHODS: Subjects underwent EEG while completing a slot-machine task for which rewards were not dependent on performance accuracy, speed, or response preparation. Slot-machine task EEG responses were compared between 54 SZ and 54 HC individuals, ages 19 to 65. Reward-related ERPs were analyzed with respect to chronological age, categorically-defined illness phase (early; ESZ versus chronic schizophrenia; CSZ), and were used to model brain age relative to chronological age. RESULTS: Illness phase-focused analyses indicated there were no group differences in average SPN or RewP amplitudes. However, a group × reward outcome interaction revealed that ESZ differed from HC in later outcome processing, reflected by greater LPP responses following loss versus reward (a reversal of the HC pattern). While brain age estimates did not differ among groups, depressive symptoms in SZ were associated with older brain age estimates while controlling for negative symptoms. CONCLUSIONS: ESZ and CSZ did not differ from HC in reward anticipation or early outcome processing during a cognitively undemanding reward task, highlighting areas of preserved functioning. However, ESZ showed altered later reward outcome evaluation, pointing to selective reward deficits during the early illness phase of schizophrenia. Further, an association between ERP-derived brain age and depressive symptoms in SZ extends prior findings linking depression with reward-related ERP blunting. Taken together, both illness phase and age may impact reward processing among SZ, and brain aging may offer a promising, novel marker of reward dysfunction that warrants further study.

Should I Stay or Should I Go? FMRI Study of Response Inhibition in Early Illness Schizophrenia and Risk for Psychosis.

Response inhibition (RI) is a component of the cognitive control systems that support optimal cognition. Cognitive control deficits are well-described in schizophrenia, but are not well characterized in individuals at clinical high risk (CHR) for developing psychosis. Functional magnetic resonance imaging during Go/NoGo task performance was collected from 30 CHR youth, 23 early illness schizophrenia patients (ESZ), and 72 healthy adolescents and young adults (HC). Voxelwise main effects of group were examined (P < .005 height threshold, family-wise error-corrected cluster threshold, P < .05) for correct NoGo-Go contrast values and task-based functional connectivity. CHR and ESZ groups had slower and more variable reaction times (RT) on Go trials compared to HCs. Significant main effects of group in bilateral dorsal anterior cingulate (dACC) and right inferior frontal cortex stemmed from CHR and ESZ groups showing significantly less NoGo-Go activation, relative to HCs. Faster responding HCs had less functional coupling between dACC and medial prefrontal cortex, a default mode network (DMN) region during NoGo vs Go trials. This functional connectivity-performance relationship was not present in ESZ or CHR groups. The pattern of findings suggests CHR and ESZ groups were deficient in developing strong and consistent prepotent responding, based on their slow and variable motor responses and decreased engagement of dACC and right inferior frontal regions implicated in inhibitory control. Furthermore, only the control group showed a functional connectivity relationship consistent with greater response prepotency requiring more decoupling of inhibitory control regions from DMN regions during RI.

Transient Patterns of Functional Dysconnectivity in Clinical High Risk and Early Illness Schizophrenia Individuals Compared with Healthy Controls.

Schizophrenia shows abnormal dynamic functional network connectivity (dFNC), but it is unclear whether these abnormalities are present early in the illness course or precede illness onset in individuals at clinical high risk (CHR) for psychosis. We examined dFNC from resting-state functional magnetic resonance imaging data in CHR (n = 53), early illness schizophrenia (ESZ; n = 58), and healthy control (HC; n = 70) individuals. We applied a sliding temporal window approach capturing five distinct dFNC states. In ESZ patients, the likelihood of transitioning from state 4, a state that exhibited greater cortical-subcortical hyperconnectivity and also lacked typically observed anticorrelation between the default mode network and other functional networks, to a hypoconnected state was increased compared with HC and CHR groups. Furthermore, we investigated the interaction of group and state on dFNC. Overall, HC individuals showed significant changes of connectivity between states that were absent or altered in ESZ patients and CHR individuals. Connectivity differences between groups were identified primarily in two out of the five states, in particular, between HC and ESZ groups. In summary, it appears that the interaction effect was mostly driven by (1) dynamic connectivity changes in HC that were abnormal in CHR and ESZ individuals and (2) the fact that dysconnectivity between groups was only present in some states. These findings underscore the likelihood that abnormalities are present not only in static FNC but also in dFNC, in individuals at CHR for schizophrenia.

Reduced higher-dimensional resting state fMRI dynamism in clinical high-risk individuals for schizophrenia identified by meta-state analysis.

New techniques to investigate functional network connectivity in resting state functional magnetic resonance imaging data have recently emerged. One novel approach, called meta-state analysis, goes beyond the mere cross-correlation of time courses of distinct brain areas and explores temporal dynamism in more detail, allowing for connectivity states to overlap in time and capturing global dynamic behavior. Previous studies have shown that patients with chronic schizophrenia exhibit reduced neural dynamism compared to healthy controls, but it is not known whether these alterations extend to earlier phases of the illness. In this study, we analyzed individuals at clinical high-risk (CHR, n = 53) for developing psychosis, patients in an early stage of schizophrenia (ESZ, n = 58), and healthy controls (HC, n = 70). ESZ individuals exhibit reduced neural dynamism across all domains compared to HC. CHR individuals also show reduced neural dynamism but only in 2 out of 4 domains investigated. Overall, meta-state analysis adds information about dynamic fluidity of functional connectivity.

Dynamic functional connectivity impairments in early schizophrenia and clinical high-risk for psychosis.

Individuals at clinical high-risk (CHR) for psychosis are characterized by attenuated psychotic symptoms. Only a minority of CHR individuals convert to full-blown psychosis. Therefore, there is a strong interest in identifying neurobiological abnormalities underlying the psychosis risk syndrome. Dynamic functional connectivity (DFC) captures time-varying connectivity over short time scales, and has the potential to reveal complex brain functional organization. Based on resting-state functional magnetic resonance imaging (fMRI) data from 70 healthy controls (HCs), 53 CHR individuals, and 58 early illness schizophrenia (ESZ) patients, we applied a novel group information guided ICA (GIG-ICA) to estimate inherent connectivity states from DFC, and then investigated group differences. We found that ESZ patients showed more aberrant connectivities and greater alterations than CHR individuals. Results also suggested that disease-related connectivity states occurred in CHR and ESZ groups. Regarding the dominant state with the highest contribution to dynamic connectivity, ESZ patients exhibited greater impairments than CHR individuals primarily in the cerebellum, frontal cortex, thalamus and temporal cortex, while CHR and ESZ populations shared common aberrances mainly in the supplementary motor area, parahippocampal gyrus and postcentral cortex. CHR-specific changes were also found in the connections between the superior frontal gyrus and calcarine cortex in the dominant state. Our findings suggest that CHR individuals generally show an intermediate functional connectivity pattern between HCs and SZ patients but also have unique connectivity alterations.

Identifying functional network changing patterns in individuals at clinical high-risk for psychosis and patients with early illness schizophrenia: A group ICA study.

Although individuals at clinical high risk (CHR) for psychosis exhibit a psychosis-risk syndrome involving attenuated forms of the positive symptoms typical of schizophrenia (SZ), it remains unclear whether their resting-state brain intrinsic functional networks (INs) show attenuated or qualitatively distinct patterns of functional dysconnectivity relative to SZ patients. Based on resting-state functional magnetic imaging data from 70 healthy controls (HCs), 53 CHR individuals (among which 41 subjects were antipsychotic medication-naive), and 58 early illness SZ (ESZ) patients (among which 53 patients took antipsychotic medication) within five years of illness onset, we estimated subject-specific INs using a novel group information guided independent component analysis (GIG-ICA) and investigated group differences in INs. We found that when compared to HCs, both CHR and ESZ groups showed significant differences, primarily in default mode, salience, auditory-related, visuospatial, sensory-motor, and parietal INs. Our findings suggest that widespread INs were diversely impacted. More than 25% of voxels in the identified significant discriminative regions (obtained using all 19 possible changing patterns excepting the no-difference pattern) from six of the 15 interrogated INs exhibited monotonically decreasing Z-scores (in INs) from the HC to CHR to ESZ, and the related regions included the left lingual gyrus of two vision-related networks, the right postcentral cortex of the visuospatial network, the left thalamus region of the salience network, the left calcarine region of the fronto-occipital network and fronto-parieto-occipital network. Compared to HCs and CHR individuals, ESZ patients showed both increasing and decreasing connectivity, mainly hypo-connectivity involving 15% of the altered voxels from four INs. The left supplementary motor area from the sensory-motor network and the right inferior occipital gyrus in the vision-related network showed a common abnormality in CHR and ESZ groups. Some brain regions also showed a CHR-unique alteration (primarily the CHR-increasing connectivity). In summary, CHR individuals generally showed intermediate connectivity between HCs and ESZ patients across multiple INs, suggesting that some dysconnectivity patterns evident in ESZ predate psychosis in attenuated form during the psychosis risk stage. Hence, these connectivity measures may serve as possible biomarkers to predict schizophrenia progression.

Blunted amygdala activity is associated with depression severity in treatment-resistant depression.

Up to 50% of individuals with major depressive disorder (MDD) do not recover after two antidepressant medication trials, and therefore meet the criteria for treatment-resistant depression (TRD). Mindfulness-based cognitive therapy (MBCT) is one promising treatment; however, the extent to which MBCT influences clinical outcomes relative to baseline neural activation remains unknown. In the present study we investigated baseline differences in amygdala activation between TRD patients and healthy controls (HCs), related amygdala activation to depression symptoms, and examined the impacts of MBCT and amygdala activation on longitudinal depression outcomes. At baseline, TRD patients (n = 80) and HCs (n = 37) participated in a functional magnetic resonance imaging task in which they identified either the emotion (affect labeling) or the gender (gender labeling) of faces, or passively viewed faces (observing). The TRD participants then completed eight weeks of MBCT or a health enhancement program (HEP). Relative to HCs, the TRD patients demonstrated less amygdala activation during affect labeling, and marginally less during gender labeling. Blunted amygdala activation in TRD patients during affect labeling was associated with greater depression severity. MBCT was associated with greater depression reductions than was HEP directly following treatment; however, at 52 weeks the treatment effect was not significant, and baseline amygdala activation across the task conditions predicted depression severity in both groups. TRD patients have blunted amygdala responses during affect labeling that are associated with greater concurrent depression. Furthermore, although MBCT produced greater short-term improvements in depression than did HEP, overall baseline amygdala reactivity was predictive of long-term clinical outcomes in both groups.