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Decades of research have highlighted the importance of optimal stimulation of cortical dopaminergic receptors, particularly the D1R receptor (D1R), for prefrontal-mediated cognition. This mechanism is particularly relevant to the cognitive deficits in schizophrenia, given the abnormalities in cortical dopamine (DA) neurotransmission and in the expression of D1R. Despite the critical need for D1R-based therapeutics, many factors have complicated their development and prevented this important therapeutic target from being adequately interrogated. Challenges include determination of the optimal level of D1R stimulation needed to improve cognitive performance, especially when D1R expression levels, affinity states, DA levels, and the resulting D1R occupancy by DA, are not clearly known in schizophrenia, and may display great interindividual and intraindividual variability related to cognitive states and other physiological variables. These directly affect the selection of the level of stimulation necessary to correct the underlying neurobiology. The optimal mechanism for stimulation is also unknown and could include partial or full agonism, biased agonism, or positive allosteric modulation. Furthermore, the development of D1R targeting drugs has been complicated by complexities in extrapolating from in vitro affinity determinations to in vivo use. Prior D1R-targeted drugs have been unsuccessful due to poor bioavailability, pharmacokinetics, and insufficient target engagement at tolerable doses. Newer drugs have recently become available, and these must be tested in the context of carefully designed paradigms that address methodological challenges. In this paper, we discuss how a better understanding of these challenges has shaped our proposed experimental design for testing a new D1R/D5R partial agonist, PF-06412562, renamed CVL-562.

At rest, human brain functional networks display striking modular architecture in which coherent clusters of brain regions are activated. The modular account of brain function is pervasive, reliable, and reproducible. Yet, a complementary perspective posits a core–periphery or rich-club account of brain function, where hubs are densely interconnected with one another, allowing for integrative processing. Unifying these two perspectives has remained difficult due to the fact that the methodological tools to identify modules are entirely distinct from the methodological tools to identify core–periphery structure. Here, we leverage a recently-developed model-based approach—the weighted stochastic block model—that simultaneously uncovers modular and core–periphery structure, and we apply it to functional magnetic resonance imaging data acquired at rest in 872 youth of the Philadelphia Neurodevelopmental Cohort. We demonstrate that functional brain networks display rich mesoscale organization beyond that sought by modularity maximization techniques. Moreover, we show that this mesoscale organization changes appreciably over the course of neurodevelopment, and that individual differences in this organization predict individual differences in cognition more accurately than module organization alone. Broadly, our study provides a unified assessment of modular and core–periphery structure in functional brain networks, offering novel insights into their development and implications for behavior.

Background Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world’s population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. Methods We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. Results Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10–30) and African American (P < .0005) participants in CSP #572. Conclusions We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.

Deep learning has emerged as a powerful approach to constructing imaging signatures of normal brain ageing as well as of various neuropathological processes associated with brain diseases. In particular, MRI-derived brain age has been used as a comprehensive biomarker of brain health that can identify both advanced and resilient ageing individuals via deviations from typical brain ageing. Imaging signatures of various brain diseases, including schizophrenia and Alzheimer’s disease, have also been identified using machine learning. Prior efforts to derive these indices have been hampered by the need for sophisticated and not easily reproducible processing steps, by insufficiently powered or diversified samples from which typical brain ageing trajectories were derived, and by limited reproducibility across populations and MRI scanners. Herein, we develop and test a sophisticated deep brain network (DeepBrainNet) using a large (n = 11 729) set of MRI scans from a highly diversified cohort spanning different studies, scanners, ages and geographic locations around the world. Tests using both cross-validation and a separate replication cohort of 2739 individuals indicate that DeepBrainNet obtains robust brain-age estimates from these diverse datasets without the need for specialized image data preparation and processing. Furthermore, we show evidence that moderately fit brain ageing models may provide brain age estimates that are most discriminant of individuals with pathologies. This is not unexpected as tightly-fitting brain age models naturally produce brain-age estimates that offer little information beyond age, and loosely fitting models may contain a lot of noise. Our results offer some experimental evidence against commonly pursued tightly-fitting models. We show that the moderately fitting brain age models obtain significantly higher differentiation compared to tightly-fitting models in two of the four disease groups tested. Critically, we demonstrate that leveraging DeepBrainNet, along with transfer learning, allows us to construct more accurate classifiers of several brain diseases, compared to directly training classifiers on patient versus healthy control datasets or using common imaging databases such as ImageNet. We, therefore, derive a domain-specific deep network likely to reduce the need for application-specific adaptation and tuning of generic deep learning networks. We made the DeepBrainNet model freely available to the community for MRI-based evaluation of brain health in the general population and over the lifespan.

BACKGROUND: The Philadelphia Neurodevelopmental Cohort (PNC), a community sample of ~9,500 youth (8–21 years) ascertained through pediatric services, ~1600 had neuroimaging. Psychosis spectrum (PS) symptoms at intake were associated with neurocognitive deficits and abnormalities in brain structure and function. Follow-up allows examining associations between intake parameters, environmental adversity, polygenic risk score (PRS) and outcome. METHODS: We developed an environmental risk score (ERS), which was based on geocoding and traumatic stressful events. We compared symptoms, neurocognitive and neuroimaging parameters in PS to typically developing (TD) youths in relation to PRS and ERS. We followed 639 participants with 2 sets of measures and 322 with 3. RESULTS: We divided the sample by the ERS into those who grew up in benign environment and those with adverse environment. We found that participants with PS had higher PRS only in benign environment. Adverse environment was associated with more severe psychotic symptoms, as well as greater neurocognitive deficits at intake, especially in working memory, complex cognition and social cognition. MRI showed lower gray matter volume at intake in those with persistent psychotic symptoms across cortical regions. In individuals who entered at TD, emergence of PS in follow-up was also related to intake volumes across cortical regions and thalamus. DISCUSSION: Genetic vulnerability and environmental stressors are important in the evolution of psychosis during a dynamic period of brain maturation. Genetic effects are more influential in youth growing up in a benign environment while adversity is associated with emergence of psychosis even with lower genetic vulnerability.

OBJECTIVE: 22q11.2 Deletion Syndrome (22q11.2DS) is associated with increased risk for schizophrenia in adulthood while Attention Deficit Hyperactivity Disorder (ADHD) is the most prevalent diagnosis in childhood. Inattention symptoms are pronounced in 22q11.2DS and given that attentional impairment is a core feature of schizophrenia, inattention symptoms may reflect underlying ADHD, psychosis, or both. We investigate whether inattention is associated with psychosis in 22q11.2DS and in other groups at risk for psychosis but without the deletion (ND) (idiopathic clinical risk and first degree family members of individuals with schizophrenia). METHODS: One hundred thirty-seven individuals with 22q11.2DS (mean age: 14.0), 84 ND individuals with subthreshold psychosis (mean age: 16.9) and 31 ND individuals with family history of psychosis (mean age: 17.0) were included in the study. Psychopathology was assessed using research diagnostic assessments. RESULTS: ADHD total symptoms were associated with overall levels of subthreshold psychosis symptoms in 22q11.2DS (β = .8, P = .04). Inattention symptoms were specifically associated with positive (β = .5, P = .004), negative (β = .5, P = .03), and disorganized (β = .5, P < .001) symptoms, while hyperactivity-impulsivity symptoms were associated with disorganized symptoms (β = .5, P = .01). The prevalence of ADHD inattention symptoms was higher in 22q11.2DS with subthreshold psychosis compared to ND individuals with subthreshold psychosis (P < .001), even when adjusting for cognitive impairment and overall psychopathology. The pattern was similar when comparing individuals with 22q11.2DS and ND individuals with family history of psychosis. CONCLUSIONS: This is the first study to examine the associations between ADHD symptoms and psychosis in 22q11.2DS. Our findings support a potentially important role of ADHD inattention symptoms in psychosis in 22q11.2DS.

This chapter starts by showing how interest in psychological treatments for schizophrenia have increased recently, especially in Europe and Australia. However, the issue is that there is a paucity of data concerning the application of approaches to adolescents suffering from schizophrenia. This means that inferences need to be drawn mainly from studies of adult populations. The chapter looks at how patients respond in terms of positive symptoms to antipsychotic treatment for schizophrenia. However, cognitive and negative symptoms are often slower to respond or refractory to treatment, leaving many individuals with significant social disability. The chapter concludes by arguing that sequential trials of adequate dose and duration of antipsychotics and adjunctive treatments should be employed to help patients achieve their optimal response. Psychosocial therapies such as cognitive behavioral therapy and education groups may be helpful in addressing residual symptoms and helping patients to adhere to their medication regimens.

This chapter introduces the topic with an overview of the current thinking on preventative measures for schizophrenia. It states that there are currently recognized precursors of schizophrenia that are apparent during adolescence. A wide variety of early intervention techniques have been developed, which draw on the knowledge of these precursors to identify individuals at risk for the illness and to prevent the predisposition toward schizophrenia from developing into the full disorder. However, prevention efforts have necessarily lagged behind studies of the risk factors, detection, and early intervention of the disease. The chapter ends by asking the question: do early intervention and prevention efforts work?

This chapter begins by describing exactly what schizophrenia is. It also defines what is meant by adolescent and adult in terms of this condition. It goes on to look at the diagnostic criteria for schizophrenia. It then considers the relationship of phenomenology to neural mechanisms. Finally, it looks at the use of phenomenology to assist in identifying the phenotype for genetic studies. Research into this area is continuous. However, some early trends are noteworthy. Some potential gene discoveries have now been replicated enough times that it is increasingly unlikely that they are false positive findings. We can also expect that the biochemical pathways represented by these genes will be explored at the level of basic cell biology and new leads about pathogenesis and potential new targets for prevention and treatment will be found. In addition, we should expect a number of studies to emerge that will try to understand whether expression of these genes are changed in the brains of schizophrenia patients. Also, efforts are already underway to try to understand how these genes influence psychological functions such as attention, sensory gating, and memory that are disturbed in schizophrenia. Finally, intense efforts will be made to try to determine whether these different genes are acting through a common pathway as, for example, has been postulated for the known genes for Alzheimer's disease.

Background: Most data sets currently included in genomic analyses of schizophrenia are comprised of case–control design that focuses on diagnostic categorization on those who meet diagnostic criteria for schizophrenia and of healthy participants. A hallmark of schizophrenia is impaired cognitive functioning. The goal of the study was to examine cognitive endophenotypes in 3 large-scale consortia that differ in recruitment and assess the pattern of neurocognitive performance across consortia.

© The Author 2017. Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a fullblown psychotic episode is usually preceded by subthreshold symptoms. In the current study, 760 participants (aged 6-55 years) with a confirmed hemizygous 22q11.2 microdeletion have been recruited through 10 medical sites worldwide, as part of an international research consortium. Of them, 692 were nonpsychotic and with complete measurement data. Subthreshold psychotic symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). Nearly one-third of participants met criteria for positive subthreshold psychotic symptoms (32.8%), less than 1% qualified for acute positive subthreshold symptoms, and almost a quarter met criteria for negative/disorganized subthreshold symptoms (21.7%). Adolescents and young adults (13-25 years) showed the highest rates of subthreshold psychotic symptoms. Additionally, higher rates of anxiety disorders and attention deficit/hyperactivity disorder (ADHD) were found among the study participants with subthreshold psychotic symptoms compared to those without. Full-scale IQ, verbal IQ, and global functioning (GAF) scores were negatively associated with participants' subthreshold psychotic symptoms. This study represents the most comprehensive analysis reported to date on subthreshold psychosis in 22q11.2DS. Novel findings include age-related changes in subthreshold psychotic symptoms and evidence that cognitive deficits are associated with subthreshold psychosis in this population. Future studies should longitudinally follow these symptoms to detect whether and how early identification and treatment of these manifestations can improve long-term outcomes in those that eventually develop a psychotic disorder.

Structural brain abnormalities have been amply demonstrated in schizophrenia. These include volume decrements in the perirhinal/entorhinal regions of the ventromedial temporal lobe, which comprise the primary olfactory cortex. Olfactory impairments, which are a hallmark of schizophrenia, precede the onset of illness, distinguish adolescents experiencing prodromal symptoms from healthy youths, and may predict the transition from the prodrome to frank psychosis. We therefore examined temporal lobe regional volumes in a large adolescent sample to determine if structural deficits in ventromedial temporal lobe areas were associated, not only with schizophrenia, but also with a heightened risk for psychosis. Seven temporal lobe regional volumes (amygdala [AM], hippocampus, inferior temporal gyrus, parahippocampal gyrus, superior temporal gyrus, temporal pole, and entorhinal cortex [EC]) were measured in 386 psychosis spectrum adolescents, 521 adolescents with other types of psychopathology, and 359 healthy adolescents from the Philadelphia Neurodevelopment Cohort. Total intracranial and left EC volumes, which were both smallest among the psychosis spectrum, were the only measures that distinguished all 3 groups. Left AM was also smaller in psychosis spectrum compared with healthy subjects. EC volume decrement was strongly correlated with impaired cognition and less robustly associated with heightened negative/disorganized symptoms. AM volume decrement correlated with positive symptoms (persecution/special abilities). Temporal lobe volumes classified psychosis spectrum youths with very high specificity but relatively low sensitivity. These MRI measures may therefore serve as important confirmatory biomarkers denoting a worrisome preclinical trajectory among at-risk youths, and the specific pattern of deficits may predict specific symptom profiles.

Attenuated psychotic symptoms characterize the prodromal phase of schizophrenia spectrum disorders. Becausemany help-seeking individuals who manifest such symptoms do not transition to psychosis, the incorporation of brain behavior measures that canidentify psychosis proneness may help understand potentially contributing neurobiological mechanisms. Neurobehavioral studiesin clinical risk groups show diffuse deficits across multiple domains.The pattern is similar, but less severe, than that observed in schizophrenia. Neuroimaging studies of brain structure, connectivity and activation, also indicate abnormalities in a pattern similar to that evident in schizophrenia. Limited longitudinal studies suggest that transition to psychosis is associated with greater aberrations of neurobehavioral and neuroimaging measures. These findings pave the way to developing models that can predict progression and offer avenues for interventions.

Certain cognitive measures are heritable and differentiate individuals at risk for schizophrenia from unaffected family members and healthy comparison subjects. These deficits in neurocognitive performance in patients with schizophrenia appear stable in the short-term. However, the duration of most, but not all, longitudinal studies is modest and the majority have relied on traditional average performance measures to examine stability. Using a computerized neurocognitive battery (CNB), we assessed mean performance (accuracy and speed) and intra-individual variability (IIV) in a longitudinal study aimed to examine neurocognitive stability in European-American multiplex families with schizophrenia. Thirty-four patients with schizophrenia, 65 unaffected relatives, and 45 healthy comparison subjects completed the same computerized neurocognitive assessment over approximately 5 years. Measures of mean performance showed that patients had stable accuracy performance but were slower in many neurocognitive domains over time as compared with unaffected family members and healthy subjects. Furthermore, patients and family members showed dissociable patterns of change in IIV for speed across cognitive domains: compared with controls, patients showed higher across-task IIV in performance compared with family members, who showed lower across-task IIV. Patients showed an increase in IIV over time, whereas family members showed a decrease. These findings suggest that measures of mean performance and IIV of speed during a CNB may provide useful information about the genetic susceptibility in schizophrenia.

Objective There is increasing evidence that schizophrenia patients have difficulties in the hedonic appraisal of odors. In a prior study, we assessed olfactory hedonic perception birhinally and found that males with schizophrenia failed to attach the appropriate hedonic valence to a pleasant odor, despite correctly perceiving changes in odor intensity. Female patients, in contrast, exhibited normal responses. The current study extends this work by examining odor valence processing in unaffected first-degree relatives of schizophrenia patients, to determine the extent to which this abnormality may be genetically mediated. We also examine odor valence processing unirhinally, rather than birhinally, to probe possible lateralized differences in patients' hedonic processing deficits. Method Individuals with schizophrenia (n = 54), first-degree unaffected family members (n = 22), and demographically matched controls (n = 45) were administered the Suprathreshold Amyl Acetate Odor Intensity and Odor Pleasantness Rating Test. Results In contrast to family members and controls, both male and female schizophrenia probands underevaluated the hedonic characteristics of amyl acetate at lower concentrations and overevaluated its pleasantness at concentrations perceived as unpleasant by both controls and relatives. These patient-specific differences could not be explained by differences in smoking habit, medication use, or subjective ratings of odor intensity. However, they were associated with increased levels of anhedonia/asociality and negative symptomatology. Conclusions Our findings suggest that both male and female schizophrenia patients have difficulties in the unirhinal appraisal of hedonic valence. Normal responses in unaffected first-degree relatives suggest that this is an environmentally, rather than genetically, mediated abnormality denoting negative symptomatology.

Schizophrenia is a chronic and disabling disorder that is characterized by significant impairments in social and nonsocial cognition. Individuals with schizophrenia have for some time been shown to have marked neurocognitive deficits in attention, working memory, and executive functioning;1 and growing evidence indicates that deficits are also prominent in such social cognitive domains as emotion perception,2 social cue recognition,3 interpersonal attribution,4 and perspective taking and theory of mind.5 Longitudinal studies have shown that many of these domains of cognitive impairment are stable over time and are present even after the remission of psychotic symptoms.6,7 Recent investigations have not only highlighted the presence and stability of deficits in social and nonsocial cognition in schizophrenia but also underscored the centrality of these impairments in schizophrenic illness by showing consistent and robust relations between cognition and functional outcome in this population.8,9 The frequency, pervasiveness, and stability of cognitive impairment in schizophrenia have led investigators to posit endophenotypic models of the illness with neurobiologically based impairments in cognitive function as a core component.10,11 Support has been garnered for such models in recent years from studies documenting the presence of similar cognitive deficits in patients with schizophrenia and their unaffected relatives,12 although cognitive dysfunction in unaffected relatives appears to be milder than in schizophrenia.13 Unfortunately, the majority of these investigations have focused primarily on the heritability of neurocognitive impairments in attention, working memory, and executive functioning, whereas deficits in social cognition have received little attention in the endophenotyping literature. Although impairments in social cognition have been increasingly recognized as separate, but related to neurocognitive dysfunction,14,15 and convincing theoretical and empirical models suggest that social cognitive impairment may underlie the development of schizophrenic symptoms and disability,16,17 little is known about the degree to which impairments in social cognitive functioning represent endophenotypic markers of the illness. To date, only a few studies have examined the heritability of social cognitive impairment in schizophrenia through the use of samples at heightened genetic risk for the illness. One study by Kee et al18 found that siblings of patients with schizophrenia performed moderately worse on a series of emotion perception tasks (particularly in facial emotion perception tasks) than healthy controls but slightly better than their affected relatives. Another study of unaffected siblings of patients with schizophrenia by Leppanen et al19 was consistent with these findings, where these investigators demonstrated significant performance impairments in the recognition of facial displays of anger in unaffected siblings relative to healthy controls, further supporting social cognitive deficits in emotion perception as a potential endophenotype for schizophrenia. Recently, Addington et al20 extended this line of investigation to the schizophrenia prodrome, where they found that individuals at clinical high risk for developing schizophrenia performed as poorly as first-episode schizophrenia patients on an emotion identification task. Taken together, these findings increasingly suggest that impairments in perhaps the most widely studied domain of social cognition in schizophrenia, emotion perception, may be a marker of genetic liability for the disorder and eventually portend who will develop the illness. While these studies have provided promising results pointing to social cognitive impairment in emotion perception as a potential endophenotype for schizophrenia, several critical questions remain that preclude firm conclusions from these findings. Perhaps, most importantly, none of these investigations have evaluated the independence of this finding relative to the well-replicated deficits in neurocognitive functioning seen between unaffected relatives and healthy controls.12 Although research has supported the notion that social cognition and neurocognition are distinct constructs,15,21 a clear relationship does exist in individuals with the illness.15 The extent of this relationship in unaffected relatives is largely unknown, but if present, it is possible that neurocognitive impairment alone could account for the sometimes subtle poorer performance of unaffected relatives on social cognitive tasks. Further, even if social cognitive impairment exists independent of deficits in neurocognition among genetically predisposed samples, little is known about the degree to which these impairments are associated with manifestations of schizophrenia-spectrum symptoms in at-risk samples. Answers to these 2 questions are critical for solidifying social cognitive impairment as a robust and independent endophenotypic marker of schizophrenia. To begin to address these questions, we conducted a study of social cognitive impairment in relatives of schizophrenia probands and healthy controls to identify the presence of deficits in social cognition, their independence from neurocognitive dysfunction, and their relation to schizophrenia-spectrum psychopathology. Specifically, we aimed to determine whether individuals at familial high risk for schizophrenia would display impairments in social cognition that were independent of neurocognitive dysfunction and, if present, determine whether such impairments would be associated with schizophrenia psychopathology. We hypothesized that at-risk individuals would display impairments in social cognition that were independent of neurocognitive function and that such impairments would be significantly related to prodromal psychopathology portending the development of schizophrenia.

Polymorphisms of the gene encoding the regulator of G protein signaling, subtype 4 (RGS4), may be associated with schizophrenia. Among first-episode schizophrenia patients, they are also associated with dorsolateral prefrontal cortex (DLPFC) volume. The DLPFC is a key region that regulates heritable cognitive functions implicated in schizophrenia pathogenesis. To further understand the relationship of RGS4 variants to schizophrenia, we examined their associations with cognitive functions among schizophrenia patients and their relatives. We analyzed 31 multiplex, multigenerational Caucasian families with schizophrenia recruited on the basis of 2 affected first-degree relatives. All participants underwent a computerized neurocognitive battery that evaluates accuracy and speed (response time) of performance on abstraction/mental flexibility; attention; verbal, spatial, and face memory; and spatial ability. "Tag" single-nucleotide polymorphisms (SNPs) representing common polymorphisms were genotyped. Measured genotype analyses accounting for family relationships were performed using Sequential Oligogenic Linkage Analysis Routines. SNPs rs10917670 ("SNP1") and rs951439 ("SNP7") were associated with face memory speed (P = .0003) at a significance level that survived Bonferroni correction (P = .039). The same SNPs have earlier been reported to be associated with schizophrenia. There also were uncorrected associations with rs10917670 ("SNP1") and rs951439 ("SNP7") on face memory efficiency (P = .03) and verbal memory efficiency (P = 0.02), rs28757217 on abstraction/mental flexibility speed (P = .02) and verbal memory efficiency (P = .03), SNP18 (rs2661319) on spatial memory accuracy (P = 0.02) and face memory speed (P = .03). RGS4 polymorphisms are associated with variations in cognitive functions and contribute a small but statistically significant proportion of variance in a family-based sample.

This article describes the results and recommendations of the third Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia meeting related to measuring treatment effects on social and affective processing. At the first meeting, it was recommended that measurement development focuses on the construct of emotion identification and responding. Five Tasks were nominated as candidate measures for this construct via the premeeting web-based survey. Two of the 5 tasks were recommended for immediate translation, the Penn Emotion Recognition Task and the Facial Affect Recognition and the Effects of Situational Context, which provides a measure of emotion identification and responding as well as a related, higher level construct, context-based modulation of emotional responding. This article summarizes the criteria-based, consensus building analysis of each nominated task that led to these 2 paradigms being recommended as priority tasks for development as measures of treatment effects on negative symptoms in schizophrenia.