Challenges and approaches to calibrating patient phenotype as evidence for cancer gene variant classification under ACMG/AMP guidelines.

Since first publication of the American College of Medical Genetics and Genomics/Association for Medical Pathology (ACMG/AMP) variant classification guidelines, additional recommendations for application of certain criteria have been released (https://clinicalgenome.org/docs/), to improve their application in the diagnostic setting. However, none have addressed use of the PS4 and PP4 criteria, capturing patient presentation as evidence towards pathogenicity. Application of PS4 can be done through traditional case-control studies, or "proband counting" within or across clinical testing cohorts. Review of the existing PS4 and PP4 specifications for Hereditary Cancer Gene Variant Curation Expert Panels revealed substantial differences in the approach to defining specifications. Using BRCA1, BRCA2 and TP53 as exemplar genes, we calibrated different methods proposed for applying the "PS4 proband counting" criterion. For each approach, we considered limitations, non-independence with other ACMG/AMP criteria, broader applicability, and variability in results for different datasets. Our findings highlight inherent overlap of proband-counting methods with ACMG/AMP frequency codes, and the importance of calibration to derive dataset-specific code weights that can account for potential between-dataset differences in ascertainment and other factors. Our work emphasizes the advantages and generalizability of logistic regression analysis over simple proband-counting approaches to empirically determine the relative predictive capacity and weight of various personal clinical features in the context of multigene panel testing, for improved variant interpretation. We also provide a general protocol, including instructions for data formatting and a web-server for analysis of personal history parameters, to facilitate dataset-specific calibration analyses required to use such data for germline variant classification.

Unveiling the potential of machine learning in schizophrenia diagnosis: A meta-analytic study of task-based neuroimaging data.

The emergence of machine learning (ML) techniques has opened up new avenues for identifying biomarkers associated with schizophrenia (SCZ) using task-related fMRI (t-fMRI) designs. To evaluate the effectiveness of this approach, we conducted a comprehensive meta-analysis of 31 t-fMRI studies using a bivariate model. Our findings revealed a high overall sensitivity of 0.83 and specificity of 0.82 for t-fMRI studies. Notably, neuropsychological domains modulated the classification performance, with selective attention demonstrating a significantly higher specificity than working memory (ß = 0.98, z = 2.11, P = 0.04). Studies involving older, chronic patients with SCZ reported higher sensitivity (P <0.015) and specificity (P <0.001) than those involving younger, first-episode patients or high-risk individuals for psychosis. Additionally, we found that the severity of negative symptoms was positively associated with the specificity of the classification model (ß = 7.19, z = 2.20, P = 0.03). Taken together, these results support the potential of using task-based fMRI data in combination with machine learning techniques to identify biomarkers related to symptom outcomes in SCZ, providing a promising avenue for improving diagnostic accuracy and treatment efficacy. Future attempts to deploy ML classification should consider the factors of algorithm choice, data quality and quantity, as well as issues related to generalization.

Revisiting reward impairments in schizophrenia spectrum disorders: a systematic review and meta-analysis for neuroimaging findings.

BACKGROUND: Abnormal reward functioning is central to anhedonia and amotivation symptoms of schizophrenia (SCZ). Reward processing encompasses a series of psychological components. This systematic review and meta-analysis examined the brain dysfunction related to reward processing of individuals with SCZ spectrum disorders and risks, covering multiple reward components. METHODS: After a systematic literature search, 37 neuroimaging studies were identified and divided into four groups based on their target psychology components (i.e. reward anticipation, reward consumption, reward learning, effort computation). Whole-brain Seed-based d Mapping (SDM) meta-analyses were conducted for all included studies and each component. RESULTS: The meta-analysis for all reward-related studies revealed reduced functional activation across the SCZ spectrum in the striatum, orbital frontal cortex, cingulate cortex, and cerebellar areas. Meanwhile, distinct abnormal patterns were found for reward anticipation (decreased activation of the cingulate cortex and striatum), reward consumption (decreased activation of cerebellum IV/V areas, insula and inferior frontal gyri), and reward learning processing (decreased activation of the striatum, thalamus, cerebellar Crus I, cingulate cortex, orbitofrontal cortex, and parietal and occipital areas). Lastly, our qualitative review suggested that decreased activation of the ventral striatum and anterior cingulate cortex was also involved in effort computation. CONCLUSIONS: These results provide deep insights on the component-based neuro-psychopathological mechanisms for anhedonia and amotivation symptoms of the SCZ spectrum.

Anterior cingulate glutamate levels associate with functional activation and connectivity during sensory integration in schizophrenia: a multimodal 1H-MRS and fMRI study.

BACKGROUND: Glutamatergic dysfunction has been implicated in sensory integration deficits in schizophrenia, yet how glutamatergic function contributes to behavioural impairments and neural activities of sensory integration remains unknown. METHODS: Fifty schizophrenia patients and 43 healthy controls completed behavioural assessments for sensory integration and underwent magnetic resonance spectroscopy (MRS) for measuring the anterior cingulate cortex (ACC) glutamate levels. The correlation between glutamate levels and behavioural sensory integration deficits was examined in each group. A subsample of 20 pairs of patients and controls further completed an audiovisual sensory integration functional magnetic resonance imaging (fMRI) task. Blood Oxygenation Level Dependent (BOLD) activation and task-dependent functional connectivity (FC) were assessed based on fMRI data. Full factorial analyses were performed to examine the Group-by-Glutamate Level interaction effects on fMRI measurements (group differences in correlation between glutamate levels and fMRI measurements) and the correlation between glutamate levels and fMRI measurements within each group. RESULTS: We found that schizophrenia patients exhibited impaired sensory integration which was positively correlated with ACC glutamate levels. Multimodal analyses showed significantly Group-by-Glutamate Level interaction effects on BOLD activation as well as task-dependent FC in a 'cortico-subcortical-cortical' network (including medial frontal gyrus, precuneus, ACC, middle cingulate gyrus, thalamus and caudate) with positive correlations in patients and negative in controls. CONCLUSIONS: Our findings indicate that ACC glutamate influences neural activities in a large-scale network during sensory integration, but the effects have opposite directionality between schizophrenia patients and healthy people. This implicates the crucial role of glutamatergic system in sensory integration processing in schizophrenia.

Negative schizotypal traits predict the reduction of reward motivation in effort-reward imbalance.

The schizotypy construct is useful for studying the effects of environmental stress on development of subclinical negative symptoms. The relationship among self-report motivation, effort-reward imbalance (ERI), and schizotypal features has seldom been studied. We aimed to examine the possible moderation effect of schizotypal traits on ERI and reward motivation. Eight-hundred-and-forty-three college students were recruited online to complete a set of self-reported measures capturing schizotypal traits, effort-reward imbalance and reward motivation, namely the Schizotypal Personality Questionnaire (SPQ), the Effort-Reward Imbalance-School Version Questionnaire (C-ERI-S) and the Motivation and Pleasure Scale-Self Report (MAP-SR). We conducted multiple linear regression to construct models to investigate the moderating effects of schizotypal traits on the relationship between ERI and reward motivation. Stressful ERI situation predicted the reduction of reward motivation. Negative schizotypal traits showed a significant negative moderating effect on the relationship between ERI and reward motivation, while positive and disorganized schizotypal traits had significant positive moderating effects. Schizotypal traits subtypes differently moderate the relationship between ERI and reward motivation. Only negative schizotypal traits and stressful ERI situation together have negative impact on reward motivation.

Reward motivation adaptation in people with negative schizotypal features: development of a novel behavioural paradigm and identifying its neural correlates using resting-state functional connectivity analysis.

Reward motivation in individuals with high levels of negative schizotypal traits (NS) has been found to be lower than that in their counterparts. But it is unclear that whether their reward motivation adaptively changes with external effort-reward ratio, and what resting-state functional connectivity (rsFC) is associated with this change. Thirty-five individuals with high levels of NS and 44 individuals with low levels of NS were recruited. A 3T resting-state functional brain scan and a novel reward motivation adaptation behavioural task were administrated in all participants. The behavioural task was manipulated with three conditions (effort > reward condition vs. effort < reward condition vs. effort = reward condition). Under each condition were rated 'wanting' and 'liking' for rewards. The seed-based voxel-wise rsFC analysis was conducted to explore the rsFCs associated with the 'wanting' and 'liking' ratings in individuals with high levels of NS. 'Wanting' and 'liking' ratings of individuals with high levels of NS significantly declined in the effort > reward condition but did not rebound as high as their counterparts in the effort < reward condition. The rsFCs in NS group associated with these ratings were altered. The altered rsFCs in NS group involved regions in the prefrontal lobe, dopaminergic brain regions (ventral tegmental area, substantia nigra), hippocampus, thalamus and cerebellum. Individuals with high levels of NS manifested their reward motivation adaptation impairment as a failure of adjustment adaptively during effort-reward imbalance condition and altered rsFCs in prefrontal, dopaminergic and other brain regions.

Altered neural mechanism of social reward anticipation in individuals with schizophrenia and social anhedonia.

Altered social reward anticipation could be found in schizophrenia (SCZ) patients and individuals with high levels of social anhedonia (SA). However, few research investigated the putative neural processing for altered social reward anticipation in these populations on the SCZ spectrum. This study aimed to examine the underlying neural mechanisms of social reward anticipation in these populations. Twenty-three SCZ patients and 17 healthy controls (HC), 37 SA individuals and 50 respective HCs completed the Social Incentive Delay (SID) imaging task while they were undertaking MRI brain scans. We used the group contrast to examine the alterations of BOLD activation and functional connectivity (FC, psychophysiological interactions analysis). We then characterized the beta-series social brain network (SBN) based on the meta-analysis results from NeuroSynth and examined their prediction effects on real-life social network (SN) characteristics using the partial least squared regression analysis. The results showed that SCZ patients exhibited hypo-activation of the left medial frontal gyrus and the negative FCs with the left parietal regions, while individuals with SA showed the hyper-activation of the left middle frontal gyrus when anticipating social reward. For the beta-series SBNs, SCZ patients had strengthened cerebellum-temporal FCs, while SA individuals had strengthened left frontal regions FCs. However, such FCs of the SBN failed to predict the real-life SN characteristics. These preliminary findings suggested that SCZ patients and SA individuals appear to exhibit altered neural processing for social reward anticipation, and such neural activities showed a weakened association with real-life SN characteristics.

Bridge centrality network structure of negative symptoms in people with schizophrenia.

Negative symptoms are complex psychopathology. Although evidence generally supported the NIMH five consensus domains, research seldom examined measurement invariance of this model, and domain-specific correspondence across multiple scales. This study aimed to examine the interrelationship between negative symptom domains captured by different rating scales, and to examine the domain-specific correspondence across multiple scales. We administered the Brief Negative Symptom Scale (BNSS), the Self-evaluation of Negative Symptoms (SNS), and the Scale for Assessment of Negative Symptoms (SANS) to 204 individuals with schizophrenia. We used network analysis to examine the interrelationship between negative symptom domains. Besides regularized partial correlation network, we estimated bridge centrality indices to investigate domain-specific correspondence, while taking each scale as an independent community. The regularized partial correlation network showed that the SNS nodes clustered together, whereas the SANS and the BNSS nodes intermingled together. The SANS attention domain lied at the periphery of the network according to the Fruchterman-Reingold algorithm. The SANS anhedonia-asociality (strength = 1.48; EI = 1.48) and the SANS affective flattening (strength = 1.06; EI = 1.06) had the highest node strength and EI. Moreover, the five nodes of the BNSS bridged the nodes of the SANS and the SNS. BNSS blunted affect (strength = 0.76; EI = 0.76) and SANS anhedonia-asociality (strength = 0.76; EI = 0.74) showed the highest bridge strength and bridge EI. The BNSS captures negative symptoms and bridges the symptom domains measured by the SANS and the SNS. The three scales showed domain-specific correspondence.

The impact of childhood trauma on thalamic functional connectivity in patients with obsessive-compulsive disorder.

BACKGROUND: Childhood trauma is a vulnerability factor for the development of obsessive-compulsive disorder (OCD). Empirical findings suggest that trauma-related alterations in brain networks, especially in thalamus-related regions, have been observed in OCD patients. However, the relationship between childhood trauma and thalamic connectivity in patients with OCD remains unclear. The present study aimed to examine the impact of childhood trauma on thalamic functional connectivity in OCD patients. METHODS: Magnetic resonance imaging resting-state scans were acquired in 79 patients with OCD, including 22 patients with a high level of childhood trauma (OCD_HCT), 57 patients with a low level of childhood trauma (OCD_LCT) and 47 healthy controls. Seven thalamic subdivisions were chosen as regions of interest (ROIs) to examine the group difference in thalamic ROIs and whole-brain resting-state functional connectivity (rsFC). RESULTS: We found significantly decreased caudate-thalamic rsFC in OCD patients as a whole group and also in OCD_LCT patients, compared with healthy controls. However, OCD_HCT patients exhibited increased thalamic rsFC with the prefrontal cortex when compared with both OCD_LCT patients and healthy controls. CONCLUSIONS: Taken together, OCD patients with high and low levels of childhood trauma exhibit different pathological alterations in thalamic rsFC, suggesting that childhood trauma may be a predisposing factor for some OCD patients.

Altered brain structural and functional connectivity in schizotypy.

BACKGROUND: Schizotypy refers to schizophrenia-like traits below the clinical threshold in the general population. The pathological development of schizophrenia has been postulated to evolve from the initial coexistence of 'brain disconnection' and 'brain connectivity compensation' to 'brain connectivity decompensation'. METHODS: In this study, we examined the brain connectivity changes associated with schizotypy by combining brain white matter structural connectivity, static and dynamic functional connectivity analysis of diffusion tensor imaging data and resting-state functional magnetic resonance imaging data. A total of 87 participants with a high level of schizotypal traits and 122 control participants completed the experiment. Group differences in whole-brain white matter structural connectivity probability, static mean functional connectivity strength, dynamic functional connectivity variability and stability among 264 brain sub-regions of interests were investigated. RESULTS: We found that individuals with high schizotypy exhibited increased structural connectivity probability within the task control network and within the default mode network; increased variability and decreased stability of functional connectivity within the default mode network and between the auditory network and the subcortical network; and decreased static mean functional connectivity strength mainly associated with the sensorimotor network, the default mode network and the task control network. CONCLUSIONS: These findings highlight the specific changes in brain connectivity associated with schizotypy and indicate that both decompensatory and compensatory changes in structural connectivity within the default mode network and the task control network in the context of whole-brain functional disconnection may be an important neurobiological correlate in individuals with high schizotypy.

A network analysis of interoception, self-awareness, empathy, alexithymia, and autistic traits.

Altered interoception has been consistently found in people with autism spectrum disorder (ASD), and this impairment may contribute to social cognitive dysfunctions. However, little is known regarding the intercorrelations between interoceptive sensibility, autistic, alexithymic, empathic, and self-related traits. We recruited 1360 non-clinical college students and adults to investigate the complex inter-relationship between these variables using network analysis. The resultant network revealed patterns connecting autistic traits to interoceptive sensibility, empathy, alexithymia, and self-awareness, with reasonable stability and test-retest consistency. The node of alexithymia exhibited the highest centrality and expected influence. As revealed by the network comparison test, networks constructed in high- and low-autistic subgroups were comparable in global strength and structure. Our findings suggested that alexithymia serves as an important node, bridging interoceptive deficits, self-awareness, and empathic impairments of autism spectrum disorder. The co-morbidity of alexithymia should be considered carefully in future studies of interoceptive impairments and social deficits in ASD.

Co-occurrence of schizo-obsessive traits and its correlation with altered executive control network functional connectivity.

The prevalence of obsessive-compulsive symptoms (OCS) in schizophrenia patients is as around 30%. Evidence suggested that mild OCS could reduce symptoms of schizophrenia, supporting the presence of compensatory functions. However, severe OCS could aggravate various impairments in schizophrenia patients, supporting the "double jeopardy hypothesis". Patients with schizo-obsessive comorbidity, schizophrenia patients and obsessive-compulsive disorder patients have been found to have similarities in executive dysfunctions and altered resting-state functional connectivity within the executive control network (ECN). Executive functions could be associated with the ECN. However, little is known as to whether such overlap exists in the subclinical populations of individuals with schizo-obsessive traits (SOT), schizotypal individuals and individuals with high levels of obsessive-compulsive symptoms (OCS). In this study, we recruited 30 schizotypal individuals, 25 individuals with OCS, 29 individuals with SOT and 29 controls for a resting-state ECN-related functional connectivity (rsFC) and a go/shift/no-go task. We found that individuals with SOT exhibited increased rsFC within the ECN compared with controls, while schizotypal individuals exhibited the opposite. Individuals with OCS exhibited decreased rsFC within the ECN and between the ECN and the default mode network (DMN), relative to controls. No significant correlational results between altered rsFC related to the ECN with executive function performance were found after corrections for multiple comparisons in three subclinical groups. Our findings showed that individuals with SOT had increased rsFC within the ECN, while schizotypal individuals and individuals with OCS showed the opposite. Our findings provide evidence for possible neural substrates of subclinical comorbidity of OCS and schizotypy.

Hub-connected functional connectivity within social brain network weakens the association with real-life social network in schizophrenia patients.

Hubs in the brain network are the regions with high centrality and are crucial in the network communication and information integration. Patients with schizophrenia (SCZ) exhibit wide range of abnormality in the hub regions and their connected functional connectivity (FC) at the whole-brain network level. Study of the hubs in the brain networks supporting complex social behavior (social brain network, SBN) would contribute to understand the social dysfunction in patients with SCZ. Forty-nine patients with SCZ and 27 healthy controls (HC) were recruited to undertake the resting-state magnetic resonance imaging scanning and completed a social network (SN) questionnaire. The resting-state SBN was constructed based on the automatic analysis results from the NeuroSynth. Our results showed that the left temporal lobe was the only hub of SBN, and its connected FCs strength was higher than the remaining FCs in both two groups. SCZ patients showed the lower association between the hub-connected FCs (compared to the FCs not connected to the hub regions) with the real-life SN characteristics. These results were replicated in another independent sample (30 SCZ and 28 HC). These preliminary findings suggested that the hub-connected FCs of SBN in SCZ patients exhibit the abnormality in predicting real-life SN characteristics.

Altered empathy-related resting-state functional connectivity in patients with bipolar disorder.

Empathy is the ability to generate emotional responses (i.e., cognitive empathy) and to make cognitive inferences (i.e., affective empathy) to other people's emotions. Empirical evidence suggests that patients with bipolar disorder (BD) exhibit impairment in cognitive empathy, but findings on affective empathy are inconsistent. Few studies have examined the neural mechanisms of cognitive and affective empathy in patients with BD. In this study, we examined the empathy-related resting-state functional connectivity (rsFC) in BD patients. Thirty-seven patients with BD and 42 healthy controls completed the self-report Questionnaires of Cognitive and Affective Empathy (QCAE), the Yoni behavioural task, and resting-sate fMRI brain scans. Group comparison of empathic ability was conducted. The interactions between group and empathic ability on seed-based whole brain rsFC were examined. BD patients scored lower on the Online Simulation subscale of the QCAE and showed positive correlations between cognitive empathy and the rsFC of the dorsal Medial Prefrontal Cortex (dmPFC) with the lingual gyrus. The correlations between cognitive empathy and the rsFC of the temporal-parietal junction (TPJ) with the fusiform gyrus, the cerebellum and the parahippocampus were weaker in BD patients than that in healthy controls. These findings highlight the underlying neural mechanisms of empathy impairments in BD patients.

Shared and distinct reward neural mechanisms among patients with schizophrenia, major depressive disorder, and bipolar disorder: an effort-based functional imaging study.

Unwillingness to exert effort for rewards has been found in patients with schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BD), but the underlying shared and distinct reward neural mechanisms remain unclear. This study aimed to compare the neural correlates of such impairments across different diagnoses. The neural responses in an effort-expenditure for reward task (EEfRT) were assessed in 20 SCZ patients, 23 MDD patients, 17 BD patients, and 30 healthy controls (HC). The results found shared activation in the cingulate gyrus, the medial frontal gyrus, and the middle frontal gyrus during the EEfRT administration. Compared to HC, SCZ patients exhibited stronger variations of functional connectivity between the right caudate and the left amygdala, the left hippocampus and the left putamen, with increase in reward magnitude. In MDD patients, an enhanced activation compared to HC in the right superior temporal gyrus was found with the increase of reward magnitude. The variations of functional connectivity between the caudate and the right cingulate gyrus, the left postcentral gyrus and the left inferior parietal lobule with increase in reward magnitude were weaker than that found in HC. In BD patients, the degree of activation in the left precuneus was increased, but that in the left dorsolateral prefrontal cortex was decreased with increase in reward probability compared to HC. These findings demonstrate both shared and distinct reward neural mechanisms associated with EEfRT in patients with SCZ, MDD, and BD, implicating potential intervention targets to alleviate amotivation in these clinical disorders.

Distinct clinical manifestations of obsessive-compulsive disorder are associated with cortical thickness alteration.

BACKGROUND: Although brain structural changes have been reported in patients with obsessive-compulsive disorder (OCD), results from previous studies have been inconsistent. A growing number of studies have focused on obsessive beliefs and impulsivity which could be involved in the occurrence and maintenance of OCD symptoms. The present study aimed to examine whether there are distinct brain structural changes in patients with different OCD subgroups. METHODS: Eighty-nine patients with OCD and 42 healthy controls were recruited to undergo structural magnetic resonance imaging brain scan. OCD patients were classified into subgroups according to scores of the Obsessive Belief Questionnaire (OBQ-44) and the Barratt Impulsiveness Scale (BIS-11) using cluster analysis. Group comparisons in cortical thickness and subcortical volumes between all OCD patients and healthy controls, as well as between subgroups of OCD patients and healthy controls, were carried out. RESULTS: OCD patients with more obsessive beliefs and attentional impulsivity (OCD_OB_AT) had reduced cortical thickness at the inferior parietal gyrus, the superior and middle temporal gyrus and the insula compared with OCD patients with higher score on the non-planning impulsivity (OCD_NP, corrected p < 0.05). The whole group of OCD patients and both subgroups showed reduced cortical thickness at the superior parietal gyrus compared with controls (uncorrected p < 0.01, number of vertices > 100). CONCLUSION: Our results suggest that apart from distinct phenomenology, there are distinct neural correlates of different OCD subgroups based on obsessive beliefs and impulsivity. These neural correlates may have clinical significance and should be considered in future research.

Validity and normative data of the Chinese Prospective and Retrospective Memory Questionnaire (PRMQ) across adolescence, adults and elderly people.

The Prospective and Retrospective Memory Questionnaire (PRMQ) is a widely-used questionnaire for evaluating individuals' memory failures in everyday life. However, whether the scale is valid for different age groups and gender, and how memory complaints change with age and gender remains less clear. This study aimed to validate the self-report PRMQ in a large Chinese sample across adolescence and adulthood and investigate age-related changes and gender differences in self-report prospective memory (PM) and retrospective memory (RM). A total of 2528 healthy individuals aged from 13 to 96 completed the Chinese version of the PRMQ. Results revealed that the PM-RM correlated factor model was the best fit model with satisfactory reliability and had measurement invariance across gender and adjacent age groups. Adolescents and adults reported similar memory complaints, while older people stated more memory difficulties. Female participants reported more PM errors than male participants, but this gender difference only showed in adolescents and adults. Taken together, these findings not only support the Chinese version of the PRMQ as a valid tool for evaluating prospective and retrospective memory difficulties across gender and adjacent age groups, but also reveal age-related changes and gender difference on self-report memory.

Negative belief-updating bias for positive daily life events in individuals with schizophrenia and social anhedonia.

INTRODUCTION: Low-pleasure beliefs are found in both patients with schizophrenia (SZ) and individuals with high social anhedonia (SocAnh), and are associated with anhedonia. However, little is known about the development and maintenance of these low-pleasure beliefs in the clinical and subclinical populations. We investigated whether patients with SZ and individuals with high SocAnh have deficits in updating their beliefs, which may contribute to the understanding of the formation and maintenance of low-pleasure beliefs. METHODS: The Modified Belief Updating Task was administered to assess belief-updating patterns in a clinical sample (36 SZ patients and 30 matched controls) and a subclinical sample (27 individuals with high SocAnh and 30 matched controls). RESULTS: We found that compared with controls, SZ patients updated their beliefs to a greater extent and more frequently when receiving bad news for positive life events, but not for negative life events. Moreover, individuals with high SocAnh also exhibited similar patterns in updating their beliefs for positive life events after controlling depressive symptoms. CONCLUSIONS: Our findings suggest that negative belief-updating patterns for positive events may play an important role in the formation and maintenance of low-pleasure beliefs in patients with SZ and individuals with high SocAnh.

Altered activation and functional connectivity in individuals with social anhedonia when envisioning positive future episodes.

BACKGROUND: Anticipatory pleasure deficits are closely correlated with negative symptoms in schizophrenia, and may be found in both clinical and subclinical populations along the psychosis continuum. Prospection, which is an important component of anticipatory pleasure, is impaired in individuals with social anhedonia (SocAnh). In this study, we examined the neural correlates of envisioning positive future events in individuals with SocAnh. METHODS: Forty-nine individuals with SocAnh and 33 matched controls were recruited to undergo functional MRI scanning, during which they were instructed to simulate positive or neutral future episodes according to cue words. Two stages of prospection were distinguished: construction and elaboration. RESULTS: Reduced activation at the caudate and the precuneus when prospecting positive (v. neutral) future events was observed in individuals with SocAnh. Furthermore, compared with controls, increased functional connectivity between the caudate and the inferior occipital gyrus during positive (v. neutral) prospection was found in individuals with SocAnh. Both groups exhibited a similar pattern of brain activation for the construction v. elaboration contrast, regardless of the emotional context. CONCLUSIONS: Our results provide further evidence on the neural mechanism of anticipatory pleasure deficits in subclinical individuals with SocAnh and suggest that altered cortico-striatal circuit may play a role in anticipatory pleasure deficits in these individuals.

Dissociation of Proactive and Reactive Cognitive Control in Individuals with Schizotypy: An Event-Related Potential Study.

OBJECTIVE: Patients with schizophrenia and individuals with schizotypy, a subclinical group at risk for schizophrenia, have been found to have impairments in cognitive control. The Dual Mechanisms of Cognitive Control (DMC) framework hypothesises that cognitive control can be divided into proactive and reactive control. However, it is unclear whether individuals with schizotypy have differential behavioural impairments and neural correlates underlying these two types of cognitive control. METHOD: Twenty-five individuals with schizotypy and 26 matched healthy controls (HCs) completed both reactive and proactive control tasks with electroencephalographic data recorded. The proportion of congruent and incongruent trials was manipulated in a classic colour-word Stroop task to induce proactive or reactive control. Proactive control was induced in a context with mostly incongruent (MI) trials and reactive control in a context with mostly congruent (MC) trials. Two event-related potential (ERP) components, medial frontal negativity (MFN, associated with conflict detection) and conflict sustained potential (conflict SP, associated with conflict resolution) were examined. RESULTS: There was no significant difference between the two groups in terms of behavioural results. In terms of ERP results, in the MC context, HC exhibited significantly larger MFN (360-530 ms) and conflict SP (600-1000 ms) amplitudes than individuals with schizotypy. The two groups did not show any significant difference in MFN or conflict SP in the MI context. CONCLUSIONS: The present findings provide initial evidence for dissociation of neural activation between proactive and reactive cognitive control in individuals with schizotypy. These findings help us understand cognitive control deficits in the schizophrenia spectrum.