Altered temporal, but intact spatial, features of transient network dynamics in psychosis.

Contemporary models of psychosis suggest that a continuum of severity of psychotic symptoms exists, with subthreshold psychotic experiences (PEs) potentially reflecting some genetic and environmental risk factors shared with clinical psychosis. Thus, identifying abnormalities in brain activity that manifest across this continuum can shed new light on the pathophysiology of psychosis. Here, we investigated the moment-to-moment engagement of brain networks ("states") in individuals with schizophrenia (SCZ) and PEs and identified features of these states that are associated with psychosis-spectrum symptoms. Transient brain states were defined by clustering "single snapshots" of blood oxygen level-dependent images, based on spatial similarity of the images. We found that individuals with SCZ (n = 35) demonstrated reduced recruitment of three brain states compared to demographically matched healthy controls (n = 35). Of these three illness-related states, one specific state, involving primarily the visual and salience networks, also occurred at a lower rate in individuals with persistent PEs (n = 22), compared to demographically matched healthy youth (n = 22). Moreover, the occurrence rate of this marker brain state was negatively correlated with the severity of PEs (r = -0.26, p = 0.003, n = 130). In contrast, the spatial map of this state appeared to be unaffected in the SCZ or PE groups. Thus, reduced engagement of a brain state involving the visual and salience networks was demonstrated across the psychosis continuum, suggesting that early disruptions of perceptual and affective function may underlie some of the core symptoms of the illness.

Distinct and opposite profiles of connectivity during self-reference task and rest in youth at clinical high risk for psychosis.

Self-reference is impaired in psychotic disorders such as schizophrenia, associated with disability, and closely related to characteristic patterns of aberrant brain connectivity. However, at present, it is unclear whether self-reference is impacted in pathogenesis of the disorder. Alterations in connectivity during a self-reference task or resting-state in the psychosis risk (i.e., prodromal) period may yield important clues for biomarker development, as well as for novel treatment targets. This study examined a task-based and resting-state functional magnetic resonance imaging in individuals at clinical high risk (CHR) for psychosis (n = 22) and healthy control unaffected peers (n = 20). The self-reference task comprised three task conditions where subjects were asked if an adjective was relevant to themselves (self), a designated other individual (other), or to evaluate the word's spelling (letter). Connectivity analyses examined medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC), regions commonly found in conjunction analyses of self-reference, during both the self-reference task and rest. In task connectivity analyses, CHR individuals exhibited decreased mPFC-PCC connectivity when compared to controls. In resting-state analyses, CHR participants showed greater mPFC-PCC connectivity. Taken together, results suggest that psychosis-like alterations in mPFC-PCC connectivity is present prior to psychosis onset across both task and rest.

Cerebellar networks in individuals at ultra high-risk of psychosis: impact on postural sway and symptom severity.

Despite known deficits in postural control in patients with schizophrenia, this domain has not been investigated in youth at ultra high-risk (UHR) for psychosis. This is particularly relevant as postural control implicates dysfunction in the cerebellum-a region implicated in cognitive dysmetria conceptions of schizophrenia but poorly understood in the prodrome. Here, we extended our understanding of movement abnormalities in UHR individuals to include postural control, and have linked these deficits to both symptom severity and cerebello-cortical network connectivity. UHR and healthy control participants completed an instrumentally based balance task to quantify postural control along with a resting state brain imaging scan to investigate cerebellar networks. We also quantified positive and negative symptom severity with structured clinical interviews. The UHR group showed overall increased postural sway and decreased cerebello-cortical resting state connectivity, relative to controls. The decreased cerebello-cortical connectivity was seen across multiple networks. Postural sway was also correlated with cerebellar connectivity in this population and uniquely positively correlated with the severity of negative symptoms. Finally, symptom severity was also associated with cerebellar connectivity. Together, our results point to a potential deficit in sensory integration as an underlying contributor to the increased postural sway, and provide evidence of cerebellar abnormalities in UHR individuals. These results extend our understanding of the motor abnormalities of UHR individuals beyond striatum-based dyskinesias to include postural control and sensory integration deficits, and implicate the cerebellum as a distinct neural substrate preceding the onset of psychosis. Taken together, our results extend the cognitive dysmetria framework to UHR populations.

Brain network connectivity during peer evaluation in adolescent females: Associations with age, pubertal hormones, timing, and status.

Despite copious data linking brain function with changes to social behavior and mental health, little is known about how puberty relates to brain functioning. We investigated the specificity of brain network connectivity associations with pubertal indices and age to inform neurodevelopmental models of adolescence. We examined how brain network connectivity during a peer evaluation fMRI task related to pubertal hormones (dehydroepiandrosterone and testosterone), pubertal timing and status, and age. Participants were 99 adolescents assigned female at birth aged 9-15 (M = 12.38, SD = 1.81) enriched for the presence of internalizing symptoms. Multivariate analysis revealed that within Salience, between Frontoparietal - Reward and Cinguloopercular - Reward network connectivity were associated with all measures of pubertal development and age. Specifically, Salience connectivity linked with age, pubertal hormones, and status, but not timing. In contrast, Frontoparietal - Reward connectivity was only associated with hormones. Finally, Cinguloopercular - Reward connectivity related to age and pubertal status, but not hormones or timing. These results provide evidence that the salience processing underlying peer evaluation is jointly influenced by various indices of puberty and age, while coordination between cognitive control and reward circuitry is related to pubertal hormones, pubertal status, and age in unique ways.

Negative Symptom Inventory-Self-Report (NSI-SR): Initial development and validation.

Negative symptoms (i.e., anhedonia, avolition, asociality, blunted affect, alogia) are frequently observed in the schizophrenia-spectrum (SZ) and associated with functional disability. While semi-structured interviews of negative symptoms represent a gold-standard approach, they require specialized training and may be vulnerable to rater biases. Thus, brief self-report questionnaires measuring negative symptoms may be useful. Existing negative symptom questionnaires demonstrate that this approach may be promising in schizophrenia, but no measure has been devised for use across stages of psychotic illness. The present study reports initial psychometric validation of the Negative Symptom Inventory-Self-Report (NSI-SR), the self-report counterpart of the Negative Symptom Inventory-Psychosis Risk clinical interview. The NSI-SR is a novel transphasic negative symptoms measure assessing the domains of anhedonia, avolition, and asociality. The NSI-SR and related measures were administered to two samples: 1) undergraduates (n = 335), 2) community participants, including: SZ (n = 32), clinical-high risk for psychosis (CHR, n = 25), and healthy controls matched to SZ (n = 31) and CHR (n = 30). The psychometrically trimmed 11-item NSI-SR showed good internal consistency and a three-factor solution reflecting avolition, asociality, and anhedonia. The NSI-SR demonstrated convergent validity via moderate to large correlations with clinician-rated negative symptoms and related constructs in both samples. Discriminant validity was supported by lower correlations with positive symptoms in both samples; however, correlations with positive symptoms were still significant. These initial psychometric findings suggest that the NSI-SR is a reliable and valid brief questionnaire capable of measuring negative symptoms across phases of psychotic illness.

Development and Validation of the Negative Symptom Inventory-Psychosis Risk.

BACKGROUND AND HYPOTHESES: Early identification and prevention of psychosis is limited by the availability of tools designed to assess negative symptoms in those at clinical high-risk for psychosis (CHR). To address this critical need, a multi-site study was established to develop and validate a clinical rating scale designed specifically for individuals at CHR: The Negative Symptom Inventory-Psychosis Risk (NSI-PR). STUDY DESIGN: The measure was developed according to guidelines recommended by the NIMH Consensus Conference on Negative Symptoms using a transparent, iterative, and data-driven process. A 16-item version of the NSI-PR was designed to have an overly inclusive set of items and lengthier interview to support the ultimate intention of creating a new briefer measure. Psychometric properties of the 16-item NSI-PR were evaluated in a sample of 218 CHR participants. STUDY RESULTS: Item-level analyses indicated that men had higher scores than women. Reliability analyses supported internal consistency, inter-rater agreement, and temporal stability. Associations with measures of negative symptoms and functioning supported convergent validity. Small correlations with positive, disorganized, and general symptoms supported discriminant validity. Structural analyses indicated a 5-factor structure (anhedonia, avolition, asociality, alogia, and blunted affect). Item response theory identified items for removal and indicated that the anchor range could be reduced. Factor loadings, item-level correlations, item-total correlations, and skew further supported removal of certain items. CONCLUSIONS: These findings support the psychometric properties of the NSI-PR and guided the creation of a new 11-item NSI-PR that will be validated in the next phase of this multi-site scale development project.

Neural Markers of Emotion Reactivity and Regulation Before and After a Targeted Social Rejection: Differences Among Girls With and Without Suicidal Ideation and Behavior Histories.

BACKGROUND: Suicidal thoughts and behaviors (STBs) are common among adolescent girls and increase risk for suicide death. Emotion regulation difficulties are linked with STBs, particularly in response to targeted social rejection. However, neural correlates of this link have not been investigated and may identify novel targets for interventions. Here, we examined neural correlates of emotion regulation before and after an experimentally delivered targeted social rejection in adolescent girls with STBs and girls without STBs (i.e., control participants). METHODS: Girls (N = 138; age range, 9-15 years; mean [SD] age = 11.6 [1.79] years) completed a functional neuroimaging emotion regulation task. In the middle of the task, participants were socially rejected by an unfamiliar confederate whom the participants had elected to meet. Participants also completed a multimethod STB assessment. RESULTS: Before rejection, girls with a history of STBs, compared with control participants, showed greater activation in the right superior frontal gyrus when passively viewing negative stimuli, and girls with suicidal behavior (SB) versus those without SB showed less activation in the right frontal pole during emotion regulation attempts. Following the rejection, girls with STBs, compared with control participants, showed greater activation in the right inferior frontal gyrus during emotion regulation. CONCLUSIONS: Before social rejection, girls with SB versus without SB may not activate brain regions implicated in emotion regulation, suggesting a vulnerability to poor regulation at their baseline emotional state. After social rejection, girls with any history of STBs showed altered activation in a brain region strongly associated with inhibition and emotion regulation success, possibly reflecting increased effort at inhibiting emotional responses during regulation following stress exposure.

Social goals in girls transitioning to adolescence: associations with psychopathology and brain network connectivity.

The motivation to socially connect with peers increases during adolescence in parallel with changes in neurodevelopment. These changes in social motivation create opportunities for experiences that can impact risk for psychopathology, but the specific motivational presentations that confer greater psychopathology risk are not fully understood. To address this issue, we used a latent profile analysis to identify the multidimensional presentations of self-reported social goals in a sample of 220 girls (9-15 years old, M = 11.81, SD = 1.81) that was enriched for internalizing symptoms, and tested the association between social goal profiles and psychopathology. Associations between social goals and brain network connectivity were also examined in a subsample of 138 youth. Preregistered analyses revealed four unique profiles of social goal presentations in these girls. Greater psychopathology was associated with heightened social goals such that higher clinical symptoms were related to a greater desire to attain social competence, avoid negative feedback and gain positive feedback from peers. The profiles endorsing these excessive social goals were characterized by denser connections among social-affective and cognitive control brain regions. These findings thus provide preliminary support for adolescent-onset changes in motivating factors supporting social engagement that may contribute to risk for psychopathology in vulnerable girls.

Individual differences in frontal alpha asymmetry moderate the relationship between acute stress responsivity and state and trait anxiety in adolescents.

Stress is a risk factor in the development and maintenance of psychopathology, particularly anxiety. Despite theory suggesting differences in stress responsivity may explain heterogeneity in anxiety, findings remain contradictory. This may be due to failure to account for individuals' neurobiological states and outdated methodologic analyses which confound conceptually and biologically distinct stress response pathways. In 145 adolescents, this study examined whether individual differences in neural activation underlying motivational states, indexed by resting frontal alpha asymmetry (FAA) before and after the Trier Social Stress Test (TSST), moderate the relationship between stress responsivity (measured by cortisol) and anxiety. Adolescents with rightward FAA activation (indexed by changes in resting FAA pre-to-post TSST) and high trait anxiety showed blunted cortisol reactivities while those with leftward FAA activation and high state anxiety showed prolonged cortisol recoveries. Our work reveals individual differences in vulnerability to psychosocial stressors and is the first study to show that FAA activation moderates the relationships between anxiety and distinct phases of the stress response in adolescents.

Triple Network Functional Connectivity During Acute Stress in Adolescents and the Influence of Polyvictimization.

BACKGROUND: Exposure to both chronic and acute stressors can disrupt functional connectivity (FC) of the default mode network (DMN), salience network (SN), and central executive network (CEN), increasing risk for negative health outcomes. During adolescence, these stress-sensitive triple networks undergo critical neuromaturation that is altered by chronic exposure to general forms of trauma or victimization. However, no work has directly examined how acute stress affects triple network FC in adolescents or whether polyvictimization-exposure to multiple categories/subtypes of victimization-influences adolescent triple network neural acute stress response. METHODS: This functional magnetic resonance imaging study examined seed-to-voxel FC of the DMN, SN, and CEN during the Montreal Imaging Stress Task. Complete data from 73 participants aged 9 to 16 years (31 female) are reported. RESULTS: During acute stress, FC was increased between DMN and CEN regions and decreased between the SN and the DMN and CEN. Greater polyvictimization was associated with reduced FC during acute stress exposure between the DMN seed and a cluster containing the left insula of the SN. CONCLUSIONS: These results indicate that acute stress exposure alters FC between the DMN, SN, and CEN in adolescents. In addition, FC changes during stress between the DMN and SN are further moderated by polyvictimization exposure.