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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.

BackgroundPrior studies have shown that the auditory N1 event-related potential component elicited by self-generated vocalizations is reduced relative to played back vocalizations, putatively reflecting a corollary discharge mechanism. Schizophrenia patients and psychosis risk syndrome (PRS) youth show deficient N1 suppression during vocalization, consistent with corollary discharge dysfunction. Because N1 is an admixture of theta (4-7 Hz) power and phase synchrony, we examined their contributions to N1 suppression during vocalization, as well as their sensitivity, relative to N1, to corollary discharge dysfunction in schizophrenia and PRS individuals.MethodsTheta phase and power values were extracted from electroencephalography data acquired from PRS youth (n = 71), early illness schizophrenia patients (ESZ; n = 84), and healthy controls (HCs; n = 103) as they said "ah" (Talk) and then listened to the playback of their vocalizations (Listen). A principal component analysis extracted theta intertrial coherence (ITC; phase consistency) and event-related spectral power, peaking in the N1 latency range. Talk-Listen suppression scores were analyzed.ResultsTalk-Listen suppression was greater for theta ITC (Cohen's d = 1.46) than for N1 in HC (d = 0.63). Both were deficient in ESZ, but only N1 suppression was deficient in PRS. When deprived of variance shared with theta ITC suppression, N1 suppression no longer differentiated ESZ and PRS individuals from HC. Deficits in theta ITC suppression were correlated with delusions (P = .007) in ESZ. Theta power suppression did not differentiate groups.ConclusionsTheta ITC-suppression during vocalization is a more sensitive index of corollary discharge-mediated auditory cortical suppression than N1 suppression and is more sensitive to corollary discharge dysfunction in ESZ than in PRS individuals.

As a risk factor for psychosis, childhood trauma rates are elevated in the clinical-high-risk (CHR) syndrome compared to the general population. However, it is unknown whether trauma is typically experienced in childhood or adolescence/young adulthood, whether it occurred prior to CHR syndrome onset, and how severe trauma relates to presenting symptoms. In this study, we examined the relationship of trauma history to symptoms and functioning in individuals diagnosed with the CHR syndrome on the Structured Interview for Psychosis-Risk Syndromes (N = 103). Trauma, defined as meeting the DSM-IV A1 criterion of actual or threatened death or injury, was assessed by semi-structured interview. A large proportion of CHR participants (61%) reported trauma exposure, including interpersonal trauma, trauma prior to CHR onset, and childhood trauma prior to age 12. Those with a trauma history (versus those without trauma) were rated as having more severe perceptual disturbances, general/affective symptoms and more impairment on the Global Assessment of Functioning Scale. The number of traumatic events correlated with more severe ratings in those three domains. Additionally, the number of interpersonal traumas was correlated with ratings of suspiciousness. Trauma was unrelated to specific measures of social and role functioning. A small proportion of CHR participants were diagnosed with formal PTSD (14%), which was unrelated to symptom severity or functioning. Thus, we demonstrate that trauma exposure is often early in life (before age 12), occurs prior to the onset of the CHR syndrome, and is related to both positive and affective symptoms.

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.

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.

Self-generated speech produces a smaller N1 amplitude in the auditory-evoked potential than externally generated speech; this phenomenon is known as N1-suppression. Schizophrenia patients show less N1-suppression than healthy controls. This failure to self-suppress may underlie patients' characteristic tendency to misattribute self-generated thoughts and actions to external sources. While the cause of N1-suppression deficits to speech in schizophrenia remains unclear, structural damage to the arcuate fasciculus is a candidate, due to its ostensible role in transmitting the efference copy of the motor plan to speak. Fifty-one patients with early illness schizophrenia (ESZ), 40 individuals at clinical high-risk for psychosis (CHR), and 59 healthy control (HC) participants underwent an electroencephalogram while they spoke and then listened to a recording of their speech. N1-suppression to the spoken sounds was calculated. Participants also underwent a diffusion-tensor imaging (DTI) scan, from which the arcuate fasciculus and pyramidal tract were extracted with deterministic tractography. ESZ patients exhibited significantly less N1-suppression to self-generated speech than HC participants, with CHR participants exhibiting intermediate levels. ESZ patients also exhibited structural abnormalities in the arcuate fasciculus-specifically, reduced fractional anisotropy and increased radial diffusivity-relative to both HC and CHR. There were no between-group differences in the structural integrity of the pyramidal tract. Finally, level of N1-suppression was linearly related to the structural integrity of the arcuate fasciculus, but not the pyramidal tract, across groups. These results suggest that the self-suppression deficits to willed speech consistently observed in schizophrenia patients may be caused, at least in part, by structural damage to the arcuate fasciculus.

The experience of childhood trauma (CT) and stressful life events (SLEs) is associated with subsequent development of a variety of mental health conditions, including psychotic illness. Recent research identifying adolescents and young adults at clinical high risk (CHR) for psychosis allows for prospective evaluation of the impact of trauma and adverse life events on psychosis onset and other outcomes, addressing etiological questions that cannot be answered in studies of fully psychotic or non-clinical populations. This article provides a comprehensive review of the current emerging literature on trauma and adverse life events in the CHR population. Up to 80% of CHR youth endorse a lifetime history of childhood traumatic events and victimization (e.g., bullying). Several studies have shown that the experience of CT predicts psychosis onset among CHR individuals, while the literature on the influence of recent SLEs (e.g., death of a loved one) remains inconclusive. Multiple models have been proposed to explain the link between trauma and psychosis, including the stress-vulnerability and stress-sensitivity hypotheses, with emphases on both cognitive processes and neurobiological mechanisms (e.g., the hypothalamic-pituitary-adrenal axis). Despite the preponderance of CHR individuals who endorse either CT or SLEs, no clinical trials have been conducted evaluating interventions for trauma in CHR youth to date. Furthermore, the current process of formal identification and assessment of trauma, SLEs, and their impact on CHR youth is inconsistent in research and clinical practice. Recommendations for improving trauma assessment, treatment, and future research directions in the CHR field are provided.

A priority for improving outcome in individuals at clinical high risk (CHR) is enhancing our understanding of predictors of psychosis as well as psychosocial functioning. Social functioning, in particular, is a unique indicator of risk as well as an important outcome in itself. Negative symptoms are a significant determinant of social functioning in CHR individuals; yet, it is unclear which specific negative symptoms drive functional outcome and how these symptoms function relative to other predictors, such as neurocognition and mood/anxiety symptoms. In a sample of 85 CHR individuals, we examined whether a two-factor negative symptom structure that is found in schizophrenia (experiential vs expressive symptoms) would be replicated in a CHR sample; and tested the degree to which specific negative symptoms predict social functioning, relative to neurocognition and mood/anxiety symptoms, which are known to predict functioning. The two-factor negative symptom solution was replicated in this CHR sample. Negative symptom severity was found to be uniquely predictive of social functioning, above and beyond depression/anxiety and neurocognition. Experiential symptoms were more strongly associated with social functioning, relative to expression symptoms. In addition, experiential symptoms mediated the relationship between expressive negative symptoms and social functioning. These results suggest that experiences of motivational impairment are more important in determining social functioning, relative to affective flattening and alogia, in CHR individuals, thereby informing the development of more precise therapeutic targets. Developing novel interventions that stimulate goal-directed behavior and reinforce rewarding experiences in social contexts are recommended.

Functional impairment is a defining feature of psychotic disorders and usually appears well before their onset. Negative symptoms play a prominent role in the impaired functioning of individuals with schizophrenia and those at clinical-high-risk (CHR) for psychosis. Despite high rates of depression and anxiety in early psychosis, few studies have examined the contribution of these symptoms to functioning in the putative 'prodrome.' In the current study, we tested the hypotheses that 1) worse negative and disorganized, but not positive, symptoms would be significantly related to impaired social and role functioning in two cohorts of CHR individuals (combined N=98) and a separate sample of individuals with recent-onset (RO) psychotic disorders (N=88); and 2) worse anxiety and depression would be significantly related to impaired functioning in both samples, above and beyond the contributions of negative and disorganized symptoms. Findings largely supported our hypotheses that more severe negative and disorganized symptoms were related to poorer social and role functioning in both samples. Anxiety and depression severity were significantly related to poorer functioning in both samples. In addition, depression, but not anxiety, predicted poorer global and social functioning above and beyond that explained by negative symptoms in the CHR sample. These results suggest the need for phase-specific treatment in early psychosis, with a focus on symptom dimensions to improve functional outcomes for CHR individuals.

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. [ABSTRACT FROM AUTHOR]

Background: During vocalization, efference copy/corollary discharge mechanisms suppress the auditory cortical response to self-generated sounds. Previously, we found attenuated vocalization-related auditory cortical suppression in psychosis and a similar trend in the psychosis risk syndrome. Here, we report data from the final sample of early illness schizophrenia patients (ESZ), individuals at clinical high risk for psychosis (CHR), and healthy controls (HC). Methods: Event-related potentials (ERP) were recorded from ESZ (n = 84), CHR (n = 71), and HC (n = 103) participants during a vocalization paradigm. The N1 ERP component was elicited during production (Talk) and playback (Listen) of vocalization. Age effects on N1 suppression (Talk–Listen), Talk N1, and Listen N1 were compared across groups. N1 measures were adjusted for normal aging before testing for group differences. Results: Both ESZ and CHR groups showed reduced Talk–Listen N1 suppression relative to HC, but did not differ from each other. Listen N1 was reduced in ESZ, but not in CHR, relative to HC. Deficient Talk–Listen N1 suppression was associated with greater unusual thought content in CHR individuals. N1 suppression increased with age in HC (12–36 years), and while CHR individuals showed a similar age-related increase, no such relationship was evident in ESZ. Conclusions: Putative efference copy/corollary discharge-mediated auditory cortical suppression during vocalization is deficient in ESZ and precedes psychosis onset, particularly in CHR individuals with greater unusual thought content. Furthermore, this suppression increases from adolescence through early adulthood, likely reflecting the effects of normal brain maturation. This maturation effect is disrupted in ESZ, presumably due to countervailing illness effects. [ABSTRACT FROM AUTHOR]