Abstract Endophenotypes provide a powerful neurobiological platform from which we can understand the genomic and neural substrates of schizophrenia and other common complex neuropsychiatric ...disorders. The Consortium on the Genetics of Schizophrenia (COGS) has conducted multisite studies on carefully selected key neurocognitive and neurophysiological endophenotypes in 300 families (COGS-1) and then in a follow up multisite case–control study of 2471 subjects (COGS-2). Endophenotypes are neurobiologically informed quantitative measures that show deficits in probands and their first degree relatives. They are more amenable to statistical analysis than are “fuzzy” qualitative clinical traits or confoundingly heterogeneous diagnostic categories. Endophenotypes are also viewed as uniquely informative in traditional diagnosis-based as well as emerging NIMH Research Domain (RDoC) contexts, offering a bridge between the two approaches to psychopathology classification and research. Endo- or intermediate phenotypes are heritable, and in the COGS-1 cohort their level of heritability is in the same range as is the heritability of schizophrenia itself, using the same statistical methods and subjects to assess both. Because we can demonstrate endophenotypes link to both gene networks and neural circuits on the one hand and also to real-life function, endophenotypes provide a critically important bridge for “connecting the dots” between genes, cells, circuits, information processing, neurocognition and functional impairment and personalized treatment selection in schizophrenia patients. By connecting schizophrenia risk genes with neurobiologically informed endophenotypes, and via the use of association, linkage, sequencing, stem cell and other strategies, we can provide our field with new neurobiologically informed information in our efforts to understand and treat schizophrenia. Evolving views, data and new analytic strategies about schizophrenia risk, pathology and treatment are described in this Viewpoint and in the accompanying Special Issue reports.
Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in ...patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional coexpression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain.
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•De novo damaging mutations are enriched in schizophrenia•Schizophrenia genes are highly coexpressed in fetal prefrontal cortex•Schizophrenia genes operate in pathways important for brain development•Disruptions of fetal prefrontal cortical neurogenesis are critical to schizophrenia
Integrating sequencing data from persons with schizophrenia and their healthy siblings with transcript data from human brain samples at different points in development reveals a network of genes coexpressed specifically in the prefrontal cortex during fetal development. The findings contextualize disease-related mutations and implicate cortical neurogenesis defects in schizophrenia.
Endophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes ...exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1) associated with schizophrenia, 2) stable over time, independent of state-related changes, and 3) free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ) and nonpsychiatric comparison subjects (NCS). Stability of clinical and functional measures was also assessed.
Participants (SZ n = 341; NCS n = 205) completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade), neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II). In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF). 223 subjects (SZ n = 163; NCS n = 58) returned for retesting after 1 year.
Most neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS) was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria.
The majority of neurophysiological and neurocognitive measures exhibited deficits in patients, stability over a 1-year interval and did not demonstrate practice or time effects supporting their use as endophenotypes in neural substrate and genomic studies. These measures hold promise for informing the "gene-to-phene gap" in schizophrenia research.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
While it is clear that schizophrenia is highly heritable, the genetic basis of this heritability is complex. Human genetic, brain imaging, and model organism studies have met with only modest gains. ...A complementary research tactic is to evaluate the genetic substrates of quantitative endophenotypes with demonstrated deficits in schizophrenia patients. We used an Illumina custom 1,536-SNP array to interrogate 94 functionally relevant candidate genes for schizophrenia and evaluate association with both the qualitative diagnosis of schizophrenia and quantitative endophenotypes for schizophrenia. Subjects included 219 schizophrenia patients and normal comparison subjects of European ancestry and 76 schizophrenia patients and normal comparison subjects of African ancestry, all ascertained by the UCSD Schizophrenia Research Program. Six neurophysiological and neurocognitive endophenotype test paradigms were assessed: prepulse inhibition (PPI), P50 suppression, the antisaccade oculomotor task, the Letter-Number Span Test, the California Verbal Learning Test-II, and the Wisconsin Card Sorting Test-64 Card Version. These endophenotype test paradigms yielded six primary endophenotypes with prior evidence of heritability and demonstrated schizophrenia-related impairments, as well as eight secondary measures investigated as candidate endophenotypes. Schizophrenia patients showed significant deficits on ten of the endophenotypic measures, replicating prior studies and facilitating genetic analyses of these phenotypes. A total of 38 genes were found to be associated with at least one endophenotypic measure or schizophrenia with an empirical p-value<0.01. Many of these genes have been shown to interact on a molecular level, and eleven genes displayed evidence for pleiotropy, revealing associations with three or more endophenotypic measures. Among these genes were ERBB4 and NRG1, providing further support for a role of these genes in schizophrenia susceptibility. The observation of extensive pleiotropy for some genes and singular associations for others in our data may suggest both converging and independent genetic (and neural) pathways mediating schizophrenia risk and pathogenesis.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Cognitive impairment is a hallmark of schizophrenia and a robust predictor of functional outcomes. Impairments are found in all phases of the illness and are only moderately attenuated by ...currently approved therapeutics. Neurophysiological indices of sensory discrimination (ie, mismatch negativity (MMN) and P3a amplitudes) and gamma-band auditory steady-state response (ASSR; power and phase locking) are translational biomarkers widely used in the development of novel therapeutics for neuropsychiatric disorders. It is unclear whether laboratory-based EEG measures add explanatory power to well-established models that use only cognitive, clinical, and functional outcome measures. Moreover, it is unclear if measures of sensory discrimination and gamma-band ASSR uniquely contribute to putative causal pathways linking sensory discrimination, neurocognition, negative symptoms, and functional outcomes in schizophrenia. To answer these questions, hierarchical associations among sensory processing, neurocognition, clinical symptoms, and functional outcomes were assessed via structural equation modeling in a large sample of schizophrenia patients (n = 695) and healthy comparison subjects (n = 503). The results showed that the neurophysiologic indices of sensory discrimination and gamma-band ASSR both significantly contribute to and yield unique hierarchical, “bottom-up” effects on neurocognition, symptoms, and functioning. Measures of sensory discrimination showed direct effects on neurocognition and negative symptoms, while gamma-band ASSR had a direct effect on neurocognition in patients. Continued investigation of the neural mechanisms underlying abnormal networks of MMN/P3a and gamma-band ASSR is needed to clarify the pathophysiology of schizophrenia and the development of novel therapeutic interventions.
Our 1992 paper, ‘The neural substrates of sensorimotor gating of the startle reflex: a review of recent findings and their implications’, reviewed a series of (then) new and preliminary findings from ...cross-species studies of prepulse inhibition of the startle reflex, and commented on their implications. At the time that the report was composed, PubMed listed about 40 citations for studies using the search term ‘prepulse inhibition’. In the ensuing 25 years, the field has added about 2700 such reports, reflecting the substantial growth in interest in prepulse inhibition and its utility across a number of different experimental applications. The 30th anniversary of the Journal of Psychopharmacology provides an opportunity to comment briefly on what was described in that 1992 report, how the field has progressed in the subsequent decades, and the paths forward for studies of prepulse inhibition and its use as an operational measure of sensorimotor gating. Among these future paths, we highlight the use of prepulse inhibition as: an endophenotype for genomic studies, and a biomarker for healthy brain circuitry, which may predict sensitivity to psychotherapeutics. Our 1992 report was highly speculative and based on paper-thin empirical data, yet viewed in a certain light, it appears to have contained a basic roadmap for a journey spanning the next 25 years of prepulse inhibition research… and ‘what a long, strange trip it’s been’.
Since the mid-1970s, cross-species translational studies of prepulse inhibition (PPI) have increased at an astounding pace as the value of this neurobiologically informative measure has been ...optimized. PPI occurs when a relatively weak sensory event (the prepulse) is presented 30-500 ms before a strong startle-inducing stimulus, and reduces the magnitude of the startle response. In humans, PPI occurs in a robust, predictable manner when the prepulse and startling stimuli occur in either the same or different modalities (acoustic, visual, or cutaneous).
This review covers three areas of interest in human PPI studies. First, we review the normal influences on PPI related to the underlying construct of sensori- (prepulse) motor (startle reflex) gating. Second, we review PPI studies in psychopathological disorders that form a family of gating disorders. Third, we review the relatively limited but interesting and rapidly expanding literature on pharmacological influences on PPI in humans.
All studies identified by a computerized literature search that addressed the three topics of this review were compiled and evaluated. The principal studies were summarized in appropriate tables.
The major influences on PPI as a measure of sensorimotor gating can be grouped into 11 domains. Most of these domains are similar across species, supporting the value of PPI studies in translational comparisons across species. The most prominent literature describing deficits in PPI in psychiatrically defined groups features schizophrenia-spectrum patients and their clinically unaffected relatives. These findings support the use of PPI as an endophenotype in genetic studies. Additional groups of psychopathologically disordered patients with neuropathology involving cortico-striato-pallido-pontine circuits exhibit poor gating of motor, sensory, or cognitive information and corresponding PPI deficits. These groups include patients with obsessive compulsive disorder, Tourette's syndrome, blepharospasm, temporal lobe epilepsy with psychosis, enuresis, and perhaps posttraumatic stress disorder (PTSD). Several pharmacological manipulations have been examined for their effects on PPI in healthy human subjects. In some cases, the alterations in PPI produced by these drugs in animals correspond to similar effects in humans. Specifically, dopamine agonists disrupt and nicotine increases PPI in at least some human studies. With some other compounds, however, the effects seen in humans appear to differ from those reported in animals. For example, the PPI-increasing effects of the glutamate antagonist ketamine and the serotonin releaser MDMA in humans are opposite to the PPI-disruptive effects of these compounds in rodents.
Considerable evidence supports a high degree of homology between measures of PPI in rodents and humans, consistent with the use of PPI as a cross-species measure of sensorimotor gating. Multiple investigations of PPI using a variety of methods and parameters confirm that deficits in PPI are evident in schizophrenia-spectrum patients and in certain other disorders in which gating mechanisms are disturbed. In contrast to the extensive literature on clinical populations, much more work is required to clarify the degree of correspondence between pharmacological effects on PPI in healthy humans and those reported in animals.
Introduction
Under specific conditions, a weak lead stimulus, or “prepulse”, can inhibit the startling effects of a subsequent intense abrupt stimulus. This startle-inhibiting effect of the prepulse, ...termed “prepulse inhibition” (PPI), is widely used in translational models to understand the biology of brain‑based inhibitory mechanisms and their deficiency in neuropsychiatric disorders. In 1981, four published reports with “prepulse inhibition” as an index term were listed on Medline; over the past 5 years, new published Medline reports with “prepulse inhibition” as an index term have appeared at a rate exceeding once every 2.7 days (
n
= 678). Most of these reports focus on the use of PPI in translational models of impaired sensorimotor gating in schizophrenia. This rapid expansion and broad application of PPI as a tool for understanding schizophrenia has, at times, outpaced critical thinking and falsifiable hypotheses about the relative strengths vs. limitations of this measure.
Objectives
This review enumerates the realistic expectations for PPI in translational models for schizophrenia research, and provides cautionary notes for the future applications of this important research tool.
Conclusion
In humans, PPI is not “diagnostic”; levels of PPI do not predict clinical course, specific symptoms, or individual medication responses. In preclinical studies, PPI is valuable for evaluating models or model organisms relevant to schizophrenia, “mapping” neural substrates of deficient PPI in schizophrenia, and advancing the discovery and development of novel therapeutics. Across species, PPI is a reliable, robust quantitative phenotype that is useful for probing the neurobiology and genetics of gating deficits in schizophrenia.
Background Schizophrenia patients have deficits across a broad range of important cognitive and clinical domains. Synchronization of oscillations in the gamma frequency range (∼40 Hz) is associated ...with many normal cognitive functions and underlies at least some of the deficits observed in schizophrenia patients. Recent studies have demonstrated that gamma oscillations are modulated by the phase of theta waves, and this cross-frequency coupling indicates that a complex and hierarchical organization governs neural oscillatory dynamics. The aims of the present study were to determine if schizophrenia patients have abnormalities in the amplitude, synchrony, and cross-frequency coupling of gamma and theta oscillations in response to gamma-frequency steady-state stimulation and if abnormal neural oscillatory dynamics are associated with cognitive deficits in schizophrenia. Methods Schizophrenia patients ( n = 234) and healthy control subjects ( n = 188) underwent electroencephalography testing in response to 40-Hz auditory steady-state stimulation. Cognitive functions were assessed with a battery of neuropsychological tests. Results Schizophrenia patients had significantly reduced gamma intertrial phase coherence, increased theta amplitude, and intact cross-frequency coupling relative to healthy control subjects. In schizophrenia patients, increased theta amplitude was associated with poor verbal memory performance. Conclusions Results suggest that schizophrenia patients have specific alterations in both gamma and theta oscillations, but these deficits occur in the context of an intact hierarchical organization of their cross-frequency modulation in response to 40-Hz steady-state stimulation. Cortical oscillatory dynamics may be useful for understanding the neural mechanisms that underlie the disparate cognitive and functional impairments of schizophrenia.
IMPORTANCE: Neurophysiologic measures of early auditory information processing (EAP) are used as endophenotypes in genomic studies and biomarkers in clinical intervention studies. Research in ...schizophrenia has established correlations among measures of EAP, cognition, clinical symptoms, and functional outcome. Clarifying these associations by determining the pathways through which deficits in EAP affect functioning would suggest when and where to therapeutically intervene. OBJECTIVES: To characterize the pathways from EAP to outcome and to estimate the extent to which enhancement of basic information processing might improve cognition and psychosocial functioning in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional data were analyzed using structural equation modeling to examine the associations among EAP, cognition, negative symptoms, and functional outcome. Participants were recruited from the community at 5 geographically distributed laboratories as part of the Consortium on the Genetics of Schizophrenia 2 from July 1, 2010, through January 31, 2014. This well-characterized cohort of 1415 patients with schizophrenia underwent EAP, cognitive, and thorough clinical and functional assessment. MAIN OUTCOME AND MEASURES: Mismatch negativity, P3a, and reorienting negativity were used to measure EAP. Cognition was measured by the Letter Number Span test and scales from the California Verbal Learning Test–Second Edition, the Wechsler Memory Scale–Third Edition, and the Penn Computerized Neurocognitive Battery. Negative symptoms were measured by the Scale for the Assessment of Negative Symptoms. Functional outcome was measured by the Role Functioning Scale. RESULTS: Participants included 1415 unrelated outpatients diagnosed with schizophrenia or schizoaffective disorder (mean SD age, 46 11 years; 979 males 69.2% and 619 white 43.7%). Early auditory information processing had a direct effect on cognition (β = 0.37, P < .001), cognition had a direct effect on negative symptoms (β = −0.16, P < .001), and both cognition (β = 0.26, P < .001) and experiential negative symptoms (β = −0.75, P < .001) had direct effects on functional outcome. The indirect effect of EAP on functional outcome was significant as well (β = 0.14, P < .001). Overall, EAP had a fully mediated effect on functional outcome, engaging general rather than modality-specific cognition, with separate pathways that involved or bypassed negative symptoms. CONCLUSIONS AND RELEVANCE: The data support a model in which EAP deficits lead to poor functional outcome via impaired cognition and increased negative symptoms. Results can be used to help guide mechanistically informed, personalized treatments and support the strategy of using EAP measures as surrogate end points in early-stage procognitive intervention studies.
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