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.
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.
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.
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.
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.
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.
The interpretability of results in psychiatric neuroimaging is significantly limited by an overreliance on correlational relationships. Purely correlational studies cannot alone determine whether ...behavior-imaging relationships are causal to illness, functionally compensatory processes, or purely epiphenomena. Negative symptoms (e.g., anhedonia, amotivation, and expressive deficits) are refractory to current medications and are among the foremost causes of disability in schizophrenia. The authors used a two-step approach in identifying and then empirically testing a brain network model of schizophrenia symptoms.
In the first cohort (N=44), a data-driven resting-state functional connectivity analysis was used to identify a network with connectivity that corresponds to negative symptom severity. In the second cohort (N=11), this network connectivity was modulated with 5 days of twice-daily transcranial magnetic stimulation (TMS) to the cerebellar midline.
A breakdown of connectivity in a specific dorsolateral prefrontal cortex-to-cerebellum network directly corresponded to negative symptom severity. Restoration of network connectivity with TMS corresponded to amelioration of negative symptoms, showing a statistically significant strong relationship of negative symptom change in response to functional connectivity change.
These results demonstrate that a connectivity breakdown between the cerebellum and the right dorsolateral prefrontal cortex is associated with negative symptom severity and that correction of this breakdown ameliorates negative symptom severity, supporting a novel network hypothesis for medication-refractory negative symptoms and suggesting that network manipulation may establish causal relationships between network markers and clinical phenomena.
Early detection and intervention are key principles in clinical medicine and psychiatry. In this issue of Neuron, Cabungcal et al. (2014) demonstrate that prophylactic treatment with antioxidants in ...adolescence prevents adult deficits in a rat model relevant to schizophrenia.
Cognitive dysfunction is a hallmark feature of schizophrenia and is evident across all phases of the illness. While prior meta-analyses have elucidated the level and pattern of cognitive deficits in ...the premorbid and post-onset periods of psychosis, no meta-analyses of studies of the putative prodromal period have been published. Our primary aim is to provide a meta-analysis of neurocognitive findings from 14 studies of psychosis risk syndrome (PRS) individuals published through February 2011, and compare the resulting profile with that synthesized by meta-analyses from other periods of the disorder. Meta-analysis of 1215 PRS individuals with a mean age of 19.2 (± 3.3) and 851 healthy control subjects yielded small-to-medium impairments across nine of 10 neurocognitive domains (Cohen's d = -0.26 to -0.67). Seven studies reported on PRS individuals who later developed psychosis (n = 175) and their baseline performance level generally yielded moderate-to-large ESs (d = -0.35 to -0.84). Mild cognitive deficits are reliably and broadly present in PRS individuals, falling at a level that is intermediate between healthy individuals and those diagnosed with schizophrenia, and at a level that is comparable to those at familial ("genetic") risk and with premorbid data. Moreover, baseline neurocognition in PRS individuals who converted to psychosis showed more severe deficits than non-converters in nearly all domains. However, considerable heterogeneity of ESs across studies in many domains underscores variability in phenotypic expression and/or measurement sensitivity, and a critical need for improved reporting of sample characteristics to support moderator variable analyses.
ADHD is defined by behavioral characteristics similar to neuropsychological disorders of executive dysfunction. This paper is a literature review of the neurocognitive characteristics of ADHD from ...early childhood through adulthood. The author addresses the development of the concept of attention and executive function (EF) deficits in ADHD, clinical neuropsychological studies of pre-teenage children, teenagers and adults with ADHD, gender and the role of psychiatric co-morbidity including the relationship of learning disabilities to ADHD, heterogeneity of neuropsychological dysfunctions, experimental neuropsychological studies, the relationship of brain structure to function, psychopharmacology of ADHD, and clinical neuropsychological assessment. The group data clearly supports the hypothesis that executive dysfunctions are correlates of ADHD regardless of gender and age, and these EF deficits are exacerbated by co-morbidity with learning disabilities such as dyslexia. However, there is limited data on children under the age of 5, teenagers from age 13–18, and adults with ADHD over the age of 40. Studies of individual classification of people with ADHD compared to healthy, non-psychiatric controls do not support the use of neuropsychological tests for the clinical diagnosis of ADHD, and indicate that not all persons with ADHD have EF deficits. Some persons with ADHD may have deficits in brain reward systems that are relatively independent of EF impairments. Future research should clarify the multiple sources of ADHD impairments, continue to refine neuropsychological tools optimized for assessment, and incorporate longitudinal, developmental designs to understand ADHD across the lifespan.
Over the past three decades, there have been significant changes in the diagnostic criteria for schizophrenia as well as changes in measurement of IQ. The last quantitative review of the literature ...on premorbid IQ in schizophrenia was published more than two decades ago. Since that time, there have been many published studies of data sets pertaining to this issue. The purpose of the present review was to provide an updated meta-analysis of premorbid IQ in individuals who later develop schizophrenia.
The authors performed a systematic literature search, which yielded 18 studies that met criteria for the meta-analysis. Inclusion criteria were 1) premorbid psychometric measures of IQ in subjects who were later diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder, 2) similar comparison data, and 3) sufficient data for calculation of an effect size. The analogue to the analysis of variance method was used to model between-study variance due to key study-design features.
Overall, schizophrenia samples demonstrated a reliable, medium-sized impairment in premorbid IQ. The heterogeneity of effect sizes was minimal and almost exclusively the result of one study. Methodological differences, such as diagnostic criteria, type of IQ measure, sample ascertainment, and age at premorbid testing, contributed minimally to the effect size variance. A cross-sectional analysis of all studies by age and a descriptive review of studies that used repeated measures of IQ in a single sample did not support the presence of a relative decline in IQ during the premorbid period in individuals with schizophrenia. However, all studies with pre- and post-onset testing within the same sample suggested that a significant decline in the IQ of individuals with schizophrenia, relative to comparison subjects, was associated with the onset of frank psychosis.
Years before the onset of psychotic symptoms, individuals with schizophrenia, as a group, demonstrate mean IQ scores approximately one-half of a standard deviation below that of healthy comparison subjects.
Hypertrophic cardiomyopathy (HCM) is caused primarily by pathogenic variants in genes encoding sarcomere proteins. We report genetic testing results for HCM in 2,912 unrelated individuals with ...nonsyndromic presentations from a broad referral population over 10 years.
Genetic testing was performed by Sanger sequencing for 10 genes from 2004 to 2007, by HCM CardioChip for 11 genes from 2007 to 2011 and by next-generation sequencing for 18, 46, or 51 genes from 2011 onward.
The detection rate is ~32% among unselected probands, with inconclusive results in an additional 15%. Detection rates were not significantly different between adult and pediatric probands but were higher in females compared with males. An expanded gene panel encompassing more than 50 genes identified only a very small number of additional pathogenic variants beyond those identifiable in our original panels, which examined 11 genes. Familial genetic testing in at-risk family members eliminated the need for longitudinal cardiac evaluations in 691 individuals. Based on the projected costs derived from Medicare fee schedules for the recommended clinical evaluations of HCM family members by the American College of Cardiology Foundation/American Heart Association, our data indicate that genetic testing resulted in a minimum cost savings of about $0.7 million.
Clinical HCM genetic testing provides a definitive molecular diagnosis for many patients and provides cost savings to families. Expanded gene panels have not substantively increased the clinical sensitivity of HCM testing, suggesting major additional causes of HCM still remain to be identified.
Abstract Mismatch negativity (MMN) and P3a are auditory event-related potential (ERP) components that show robust deficits in schizophrenia (SZ) patients and exhibit qualities of endophenotypes, ...including substantial heritability, test–retest reliability, and trait-like stability. These measures also fulfill criteria for use as cognition and function-linked biomarkers in outcome studies, but have not yet been validated for use in large-scale multi-site clinical studies. This study tested the feasibility of adding MMN and P3a to the ongoing Consortium on the Genetics of Schizophrenia (COGS) study. The extent to which demographic, clinical, cognitive, and functional characteristics contribute to variability in MMN and P3a amplitudes was also examined. Participants (HCS n = 824, SZ n = 966) underwent testing at 5 geographically distributed COGS laboratories. Valid ERP recordings were obtained from 91% of HCS and 91% of SZ patients. Highly significant MMN (d = 0.96) and P3a (d = 0.93) amplitude reductions were observed in SZ patients, comparable in magnitude to those observed in single-lab studies with no appreciable differences across laboratories. Demographic characteristics accounted for 26% and 18% of the variance in MMN and P3a amplitudes, respectively. Significant relationships were observed among demographically-adjusted MMN and P3a measures and medication status as well as several clinical, cognitive, and functional characteristics of the SZ patients. This study demonstrates that MMN and P3a ERP biomarkers can be feasibly used in multi-site clinical studies. As with many clinical tests of brain function, demographic factors contribute to MMN and P3a amplitudes and should be carefully considered in future biomarker-informed clinical studies.
Many investigators have hypothesized that attention-deficit/hyperactivity disorder (ADHD) involves structural and functional brain abnormalities in frontal-striatal circuitry. Although our review ...suggests that there is substantial support for this hypothesis, a growing literature demonstrates widespread abnormalities affecting other cortical regions and the cerebellum. Because there is only one report studying adults with ADHD, this summary is based on children. A key limitation of the literature is that most of the studies until recently have been underpowered, using samples of fewer than 20 subjects per group. Nevertheless, these studies are largely consistent with the most comprehensive and definitive study(
Castellanos et al 2002). Moreover, studies differ in the degree to which they address the influence of medications, comorbidities, or gender, and most have not addressed potentially important sources of heterogeneity such as family history of ADHD, subtype, or perinatal complications. Despite these limitations, a relatively consistent picture has emerged. The most replicated alterations in ADHD in childhood include significantly smaller volumes in the dorsolateral prefrontal cortex, caudate, pallidum, corpus callosum, and cerebellum. These results suggest that the brain is altered in a more widespread manner than has been previously hypothesized. Developmental studies are needed to address the evolution of this brain disorder into adulthood.
Over the past few decades, functional neuroimaging techniques have begun to provide unprecedented windows on the neurobiology of attention-deficit/hyperactivity disorder (ADHD) and the neural effects ...of medications used to treat the disorder. Convergent data from neuroimaging, neuropsychological, genetics, and neurochemical studies have implicated dysfunction of fronto-striatal structures (lateral prefrontal cortex, dorsal anterior cingulate cortex, caudate, and putamen) as likely contributing to the pathophysiology of ADHD. This review 1) provides an overview of the main imaging techniques being used to study ADHD; 2) discusses their relative strengths and weaknesses, highlighting how they can complement one another; 3) shows how the functional imaging literature, which has built on the structural imaging data, is now being used to test focused hypotheses regarding the neurobiological substrate of ADHD; and 4) suggests guidelines for improving future functional imaging studies. Although at present there are no accepted uses for functional imaging in diagnosing ADHD, this article mentions possible future clinical uses of imaging in ADHD.
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