Attentiveness and mental health in adolescents with moderate-to-severe atopic dermatitis without ADHD.

Patients with moderate-to-severe atopic dermatitis (AD) experience intense chronic itch and impaired sleep. Reports from parents and teachers suggest that AD patients may also have attention problems. However, attention has not yet been directly assessed in AD patients. We utilized an objective, computer-based continuous performance test (CPT) validated for use in attention-deficit/hyperactivity disorder (ADHD) diagnosis to formally evaluate attention in adolescent AD subjects. This was a single-visit, cross-sectional, non-interventional study of moderate-to-severe (Investigator's Global Assessment [IGA] ≥ 3) AD subjects aged 12-17 years without clinician-diagnosed ADHD. Attention was evaluated using two performance-based measures: Conners, CPT-3 and the Stroop Color and Word Test. The primary parameter was CPT-3 detectability (d') measure. Lesional severity measures included Eczema Area and Severity Index (EASI) and body surface area (BSA) involvement. Subjects completed self-report rating scales assessing sensory responsiveness patterns (Adult/Adolescent Sensory Profile [AASP]), itch (Peak Pruritus Numerical Rating Scale [PP-NRS]), skin pain, quality of life, sleep, anxiety, and depressive symptoms. A total of 44 subjects were included in the study (61.4% female; mean age 15.0 [SD 1.78] years; mean EASI 20.4 [SD 7.8]; mean PP-NRS 7.0 [SD 1.8]). Results indicated substantial disease impact on sleep, quality of life, and comorbid anxiety and depressive symptoms. The mean (SD) Conners, CPT-3 d' T-score was 48.7 (SD 10.7), similar to the expected mean from a randomly selected age/gender-matched sample of the general population (50 [SD 10], by definition). Overall, 13.6% of subjects exhibited a d' T-score ≥ 60 (clinically significant poor performance), which was not greater than the expected general population value (15.9%). Subject-level data review by two psychologists determined that only 2 subjects demonstrated an overall response pattern that clearly indicated attention deficit. Many subjects had atypical sensory responsiveness profiles: sensory hypersensitivity (38.6%), sensory avoidance (50%), and low registration (hypo-sensitivity, 36.4%). Adolescents with moderate-to-severe AD without existing ADHD diagnosis did not demonstrate greater attention problems on performance-based measures than would be expected in age/gender-matched peers.Trial registration NCT05203380.

Atopic dermatitis (often shortened to AD) is a long-term skin disease that causes intense itching. It affects patients' lives in many ways, including interrupting their sleep. Parents and teachers of young people with AD have sometimes suggested that AD may also cause attention problems. But this has never been tested properly.We measured the attention of 44 adolescents aged between 12 and 17 years who all had moderate-to-severe AD. We used computerized tests of attention that were developed for young people with ADHD (attention deficit hyperactivity disorder). Also, we made sure that none of the 44 patients had also been diagnosed with ADHD. The severity and extent of the patients' AD was measured by doctors. We also used some measures that allowed the patients to report how AD affected their lives, including things like itch, skin pain, quality of life, sleep, anxiety, and depression.The adolescent patients reported that AD had a negative effect on various areas of their lives, including sleep and quality of life, and that it resulted in anxiety and symptoms of depression. However, the results of the attention tests in adolescents with AD were similar to what would usually be expected in adolescents without AD. Only 2 of the 44 patients with AD were found to have clear evidence of attention problems.The study concluded that adolescents with moderate-to-severe AD did not have any greater attention problems than would usually be expected in adolescents without AD.

Methods for Neuroscience Drug Development: Guidance on Standardization of the Process for Defining Clinical Outcome Strategies in Clinical Trials.

Neurosciences clinical trials continue to have notoriously high failure rates. Appropriate outcomes selection in early clinical trials is key to maximizing the likelihood of identifying new treatments in psychiatry and neurology. The field lacks good standards for designing outcome strategies, therefore The Outcomes Research Group was formed to develop and promote good practices in outcome selection. This article describes the first published guidance on the standardization of the process for clinical outcomes in neuroscience. A minimal step process is defined starting as early as possible, covering key activities for evidence generation in support of content validity, patient-centricity, validity requirements and considerations for regulatory acceptance. Feedback from expert members is provided, regarding the risks of shortening the process and examples supporting the recommended process are summarized. This methodology is now available to researchers in industry, academia or clinics aiming to implement consensus-based standard practices for clinical outcome selection, contributing to maximizing the efficiency of clinical research.

An adapted clinical global Impression of improvement for use in Angelman syndrome: Validation analyses utilizing data from the NEPTUNE study.

PURPOSE: Angelman Syndrome (AS) is a rare, severe neurogenetic disorder that causes symptoms such as intellectual disability and motor impairments and is typically diagnosed in early childhood. The complexity and heterogeneity of AS confound characterization of disease severity and pose unique challenges when determining an individual's response to treatment. There is therefore a substantial unmet need for rating scales specifically designed for complex conditions such as AS. To address this, the Clinical Global Impressions (CGI) scale, which has components for both symptom severity (CGI-S) and improvement (CGI-I) was specifically adapted to measure severity (CGI-S-AS) and improvement (CGI-I-AS) in AS. METHODS: The modified CGI-S/I-AS was used in the NEPTUNE trial of gaboxadol for the treatment of AS. Here we report on the validation of the CGI-I-AS using data from NEPTUNE and discuss insights for its potential use in future trials. RESULTS: Improvements in the CGI-I-AS rating tended to be consistent with changes on other relevant rating scales. Sleep-related symptoms were particularly well represented, while communication-related symptoms were not. CONCLUSIONS: Our validation analysis of the CGI-I-AS demonstrates its usefulness along with possible areas of improvement. The CGI-I-AS is a potential tool for use in other trials of AS drug candidates, and the process for its development can serve as a road map for the development of assessment tools for other neuropsychiatric disorders with similar complexities and heterogeneity.

Development of a cognitive composite for measuring change in progressive supranuclear palsy.

INTRODUCTION: Individuals with progressive supranuclear palsy (PSP) experience cognitive changes that are challenging to follow without a validated neuropsychological test battery to measure progression. This study describes a composite measure to evaluate cognition in individuals with PSP. METHODS: Baseline cognitive test data from 486 participants with PSP in the PASSPORT (NCT03068468) study included the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), Color Trails Test (CTT) parts 1 and 2, letter-number sequencing, and letter fluency. Data were analyzed using summary statistics and a matrix of Pearson correlations. A hypothetical factor structure was constructed and validated. RESULTS: Observed correlations were highest for scores between story memory and story recall (correlation coefficient = 0.78) and lowest for scores between letter fluency and picture naming (correlation coefficient = 0.11), and picture naming and figure copy (correlation coefficient = 0.12). After excluding picture naming and Color Trails Test (CTT) parts 1 and 2, a 3-factor structure was hypothesized for the remaining 13 tests. Confirmatory factor analysis demonstrated goodness of fit within acceptable limits (comparative fit index and Tucker-Lewis index = 0.98, standardized root-mean-square residual and root-mean-square error of approximation = 0.05-0.06). Mixed-model repeated-measures analysis of change from baseline to week 52 in RBANS and PSP cognitive composite score produced mean-to-standard-deviation ratios of 0.418 and 0.780, respectively. CONCLUSIONS: This novel composite endpoint, based on RBANS and designed to account for motor impairments in PSP, improves on current cognitive assessments PSP.

Behaviour and Experience: The Two Sides of the Negative Syndrome - A Comparison of Andreasen's Negative Syndrome and Huber's Basic Symptoms.

Negative symptoms in schizophrenia and schizoaffective disorder are present both in behavior and in the subjective experience of the patients, however the relationships between these two components have not been sufficiently studied. Standardized assessment methods were utilized in a study of 96 acutely exacerbated inpatients and 26 stabilized outpatients with the diagnosis of schizophrenia and schizoaffective disorder for the measurement of nega tive symptoms, subjective experiences, depression, general psychopathology and neurological side effects. Halo - peridol blood levels were controlled in the inpatient group. Results of this study suggest that the behavioral symptoms and the subjective experiences of the negative syndrome are not correlated with each other. The subjective experiences of negative symptoms were highly correlated with depression in the acutely exacerbated inpatients, but not in the outpatients. Medication levels and neurological side effects were not related either to the behavioral or the experiential aspects of the negative syndrome.

A randomized, multicenter, crossover psychometric evaluation study of an iPad-administered cognitive test battery in participants with major depressive disorder who responded to treatment with oral antidepressants.

BACKGROUND: Performance validity and test-retest reliability of ReVeRe.D, an iPad-administered cognitive test battery in major depressive disorder (MDD) were analyzed. METHODS: Participants aged 18-59 years had DSM-5 diagnosis of MDD with adequate visual and hearing acuity. All had responded to oral antidepressant treatment for a major depressive episode within the most recent 24-months and were stable with no greater than mild depressive symptoms as evidenced by Montgomery Asberg Depression Rating Scale total score <17. Participants were randomly assigned to 1 of 2 test sequences (AABB or BBAA; A=ReVeRe.D; B=examiner-administered tests) in a crossover design. RESULTS: 244 randomized participants (AABB: n=123; BBAA: n=121) had mean age of 38.3 years; 54.9% had a college, baccalaureate, or higher education. At first administration, Pearson correlation coefficients (PCC) for 6/10 pairs of corresponding ReVeRe.D vs examiner-administered tests exceeded the pre-specified acceptance criterion (PCC=0.53) for the primary analysis; 8 test score pairs had PCC exceeding 0.40. At second administration, PCC for 9/10 test scores pairs exceeded PCC=0.53. Together, the series of PCCs supports the concurrent validity for ReVeRe.D. Test-retest reliability for ReVeRe.D test scores was generally moderate to high. LIMITATIONS: The study included stable participants with MDD who had responded to oral antidepressant treatment, with most in at least partial remission. The sample was limited to English-speaking participants, and skewed towards white, college-educated women. Further studies in acutely ill MDD patients who represent a broader demographic, are warranted. CONCLUSIONS: iPad-administered ReVeRe.D is a valid and reliable computerized test battery for assessment of cognitive performance in MDD.

Markers of early changes in cognition across cohorts of adults with Down syndrome at risk of Alzheimer's disease.

INTRODUCTION: Down syndrome (DS), a genetic variant of early onset Alzheimer's disease (AD), lacks a suitable outcome measure for prevention trials targeting pre-dementia stages. METHODS: We used cognitive test data collected in several longitudinal aging studies internationally from 312 participants with DS without dementia to identify composites that were sensitive to change over time. We then conducted additional analyses to provide support for the utility of the composites. The composites were presented to an expert panel to determine the most optimal cognitive battery based on predetermined criteria. RESULTS: There were common cognitive domains across site composites, which were sensitive to early decline. The final composite consisted of memory, language/executive functioning, selective attention, orientation, and praxis tests. DISCUSSION: We have identified a composite that is sensitive to early decline and thus may have utility as an outcome measure in trials to prevent or delay symptoms of AD in DS.

Diagnostic criteria for apathy in neurocognitive disorders.

INTRODUCTION: Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed. METHODS: The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019. RESULTS: The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies. DISCUSSION: These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research.

Value-Generating Exploratory Trials in Neurodegenerative Dementias.

Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and face common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof of concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof of concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development.

Development of an adapted Clinical Global Impression scale for use in Angelman syndrome.

BACKGROUND: The Clinical Global Impression-Severity (CGI-S) and CGI-Improvement (CGI-I) scales are widely accepted tools that measure overall disease severity and change, synthesizing the clinician's impression of the global state of an individual. Frequently employed in clinical trials for neuropsychiatric disorders, the CGI scales are typically used in conjunction with disease-specific rating scales. When no disease-specific rating scale is available, the CGI scales can be adapted to reflect the specific symptom domains that are relevant to the disorder. Angelman syndrome (AS) is a rare, clinically heterogeneous condition for which there is no disease-specific rating scale. This paper describes efforts to develop standardized, adapted CGI scales specific to AS for use in clinical trials. METHODS: In order to develop adapted CGI scales specific to AS, we (1) reviewed literature and interviewed caregivers and clinicians to determine the most impactful symptoms, (2) engaged expert panels to define and operationalize the symptom domains identified, (3) developed detailed rating anchors for each domain and for global severity and improvement ratings, (4) reviewed the anchors with expert clinicians and established minimally clinically meaningful change for each symptom domain, and (5) generated mock patient vignettes to test the reliability of the resulting scales and to standardize rater training. This systematic approach to developing, validating, and training raters on a standardized, adapted CGI scale specifically for AS is described herein. RESULTS: The resulting CGI-S/I-AS scales capture six critical domains (behavior, gross and fine motor function, expressive and receptive communication, and sleep) defined by caregivers and expert clinicians as the most challenging for patients with AS and their families. CONCLUSIONS: Rigorous training and careful calibration for clinicians will allow the CGI-S/-I-AS scales to be reliable in the context of randomized controlled trials. The CGI-S/-I-AS scales are being utilized in a Phase 3 trial of gaboxadol for the treatment of AS.

Practical algorithms for amyloid ß probability in subjective or mild cognitive impairment.

INTRODUCTION: Practical algorithms predicting the probability of amyloid pathology among patients with subjective cognitive decline or mild cognitive impairment may help clinical decisions regarding confirmatory biomarker testing for Alzheimer's disease. METHODS: Algorithm feature selection was conducted with Alzheimer's Disease Neuroimaging Initiative and Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing data. Probability algorithms were developed in Alzheimer's Disease Neuroimaging Initiative using nested cross-validation accompanied by stratified subsampling to obtain 1000 internally validated decision trees. Semi-independent validation was conducted using Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. Independent external validation was conducted in the population-based Mayo Clinic Study of Aging. RESULTS: Two algorithms were developed using age and normalized immediate recall z-scores, with or without apolipoprotein E ε4 carrier status. Both algorithms had robust performance across data sets and when substituting different recall memory tests. DISCUSSION: The statistical framework resulted in robust probability estimation. Application of these algorithms may assist in clinical decision-making for further testing to diagnose amyloid pathology.

Associating Cognition With Amyloid Status Using Partially Ordered Set Analysis.

Background: The presence of brain amyloid-beta positivity is associated with cognitive impairment and dementia, but whether there are specific aspects of cognition that are most linked to amyloid-beta is unclear. Analysis of neuropsychological test data presents challenges since a single test often requires drawing upon multiple cognitive functions to perform well. It can thus be imprecise to link performance on a given test to a specific cognitive function. Our objective was to provide insight into how cognitive functions are associated with brain amyloid-beta positivity among samples consisting of cognitively normal and mild cognitively impaired (MCI) subjects, by using partially ordered set models (POSETs). Methods: We used POSET classification models of neuropsychological test data to classify samples to detailed cognitive profiles using ADNI2 and AIBL data. We considered 3 gradations of episodic memory, cognitive flexibility, verbal fluency, attention and perceptual motor speed, and performed group comparisons of cognitive functioning stratified by amyloid positivity (yes/no) and age (<70, 70-80, 81-90 years). We also employed random forest methods stratified by age to assess the effectiveness of cognitive testing in predicting amyloid positivity, in addition to demographic variables, and APOE4 allele count. Results: In ADNI2, differences in episodic memory and attention by amyloid were found for <70, and 70-80 years groups. In AIBL, episodic memory differences were found in the 70-80 years age group. In both studies, no cognitive differences were found in the 81-90 years group. The random forest analysis indicates that variable importance in classification depends on age. Cognitive testing that targets an intermediate level of episodic memory and delayed recall, in addition to APOE4 allele count, are the most important variables in both studies. Conclusions: In the ADNI2 and AIBL samples, the associations between specific cognitive abilities and brain amyloid-beta positivity depended on age, but in general episodic memory was most consistently predictive of brain amyloid-beta positivity. Random forest methods and OOB error rates establish the feasibility of predicting the presence of brain beta-amyloid using cognitive testing, APOE4 genotyping and demographic variables.

Digit Symbol Substitution Test: The Case for Sensitivity Over Specificity in Neuropsychological Testing.

PURPOSE/BACKGROUND: Development of the Digit Symbol Substitution Test (DSST) was initiated over a century ago as an experimental tool to understand human associative learning. Its clinical utility, owing to its brevity and high discriminant validity, was first recognized in the 1940s, and now the DSST is among the most commonly used tests in clinical neuropsychology. METHODS: Specific studies and articles were reviewed to illustrate what the test measures, to evaluate its sensitivity to change, and to discuss its use in clinical practice. RESULTS: The DSST is a valid and sensitive measure of cognitive dysfunction impacted by many domains. Performance on the DSST correlates with real-world functional outcomes (eg, the ability to accomplish everyday tasks) and recovery from functional disability in a range of psychiatric conditions including schizophrenia and major depressive disorder. Importantly, the DSST has been demonstrated to be sensitive to changes in cognitive functioning in patients with major depressive disorder and offers promise as a clinical decision-making tool for monitoring treatment effects in this and other disorders affecting cognition. IMPLICATIONS/CONCLUSIONS: The DSST is sensitive to the presence of cognitive dysfunction as well as to change in cognitive function across a wide range of clinical populations but has low specificity to determine exactly which cognitive domain has been affected. However, the DSST offers a practical and effective method to monitor cognitive functions over time in clinical practice.

Episodic Memory and Learning Dysfunction Over an 18-Month Period in Preclinical and Prodromal Alzheimer's Disease.

Recent meta-analyses suggest that episodic memory impairment associated with preclinical Alzheimer's disease (AD) equates to 0.15-0.24 standard deviations below that of cognitively healthy older adults. The current study aimed to characterize impairments in verbal acquisition and recall detectable at a single assessment, and investigate how verbal learning and episodic memory deteriorates in preclinical AD. A verbal list-learning task, the International Shopping List Test (ISLT), was administered multiple times over an 18-month period, to three groups of participants: amyloid-beta negative healthy older adults (Aß- CN; n = 50); Aß+ positive healthy older adults (preclinical AD; n = 25); and Aß+ positive individuals diagnosed with mild cognitive impairment (prodromal AD; n = 22). At baseline, there was no significant difference between the preclinical AD and control groups rate of acquisition, or total and delayed recall, however all indices were impaired in prodromal AD. Performance on ISLT total score improved in the control group over the 18-month period, but showed a moderate magnitude decline in the preclinical AD group (Cohen's d = - 0.63, [- 1.12, - 0.14]) and the prodromal AD group (Cohen's d = - 0.36, [- 0.94, 0.22]). No significant impairment in acquisition associated with preclinical AD was seen at baseline. Individuals with preclinical AD showed a significantly different performance on the ISLT total score over an 18-month period, compared to those without abnormal Aß. Individuals with prodromal AD showed substantial impairment on the ISLT at baseline and declined to a greater extent over time.

What is the overlap between subjective and objective cognitive impairments in MDD?

BACKGROUND: Cognitive impairments, such as memory deficits and executive impairment, are common among patients with major depressive disorder (MDD) and can be captured with objective or subjective assessments. The aim of this post-hoc analysis of the CONNECT study was to assess the degree of overlap between subjective and objective cognitive impairment among MDD patients, and to evaluate associated clinical characteristics. METHODS: The study was conducted from April 2012 to February 2014 and enrolled a total of 602 patients with MDD who reported subjective cognitive impairment. Efficacy was assessed using a battery of objective tests of cognitive function representing multiple domains: Digit Symbol Substitution Test performance, Trail Making Test A, Trail Making Test B, Congruent and Incongruent Stroop Test, Groton Maze Learning Test, Detection Task, Identification Task, and One-Back Task. The Cognitive and Physical Functioning Questionnaire (CPFQ) was used to capture patient-reported assessments of cognitive function. RESULTS: Although 48% of patients with MDD met our conservative criteria for subjectively defined marked cognitive impairment, 64% of patients with MDD met our conservative criteria for objectively defined cognitive impairment. Therefore, the proportion of patients defined as having impaired cognition was somewhat similar regardless of methodology. Overall, 80% of patients with MDD in this study reported either subjective or objective cognitive impairment per subjective and objective scales. However, the proportion of patients meeting criteria for both subjectively and objectively defined cognitive impairment was only 31%. This could be explained by the fact that the CPFQ total score was only modestly-although significantly-correlated with all but one of the objective tests. CONCLUSIONS: This post-hoc study shows that approximately 80% of patients with MDD participating in an antidepressant trial reported either subjective or objective cognitive impairment.

Measuring cognition and function in the preclinical stage of Alzheimer's disease.

The Alzheimer's Association's Research Roundtable met in November 2016 to explore how best to measure changes in cognition and function in the preclinical stage of Alzheimer's disease. This review will cover the tools and instruments currently available to identify populations for prevention trials, and measure subtle disease progression in the earliest stages of Alzheimer's disease, and will include discussions of suitable cognitive, behavioral, functional, composite, and biological endpoints for prevention trials. Current prevention trials are reviewed including TOMMOROW, Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Trial, the Alzheimer's Prevention Initiative Generation Study, and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's to compare current approaches and tools that are being developed.

Affective and emotional dysregulation as pre-dementia risk markers: exploring the mild behavioral impairment symptoms of depression, anxiety, irritability, and euphoria.

BACKGROUND: Affective and emotional symptoms such as depression, anxiety, euphoria, and irritability are common neuropsychiatric symptoms (NPS) in pre-dementia and cognitively normal older adults. They comprise a domain of Mild Behavioral Impairment (MBI), which describes their emergence in later life as an at-risk state for cognitive decline and dementia, and as a potential manifestation of prodromal dementia. This selective scoping review explores the epidemiology and neurobiological links between affective and emotional symptoms, and incident cognitive decline, focusing on recent literature in this expanding field of research. METHODS: Existing literature in prodromal and dementia states was reviewed, focusing on epidemiology, and neurobiology. Search terms included: "mild cognitive impairment," "dementia," "prodromal dementia," "preclinical dementia," "Alzheimer's," "depression," "dysphoria," "mania," "euphoria," "bipolar disorder," and "irritability." RESULTS: Affective and emotional dysregulation are common in preclinical and prodromal dementia syndromes, often being harbingers of neurodegenerative change and progressive cognitive decline. Nosological constraints in distinguishing between pre-existing psychiatric symptomatology and later life acquired NPS limit historical data utility, but emerging research emphasizes the importance of addressing time frames between symptom onset and cognitive decline, and age of symptom onset. CONCLUSION: Affective symptoms are of prognostic utility, but interventions to prevent dementia syndromes are limited. Trials need to assess interventions targeting known dementia pathology, toward novel pathology, as well as using psychiatric medications. Research focusing explicitly on later life onset symptomatology will improve our understanding of the neurobiology of NPS and neurodegeneration, enrich the study sample, and inform observational and clinical trial design for prevention and treatment strategies.

Mismatch Negativity But Not P300 Is Associated With Functional Disability in Schizophrenia.

Mismatch negativity (MMN) and P300 event-related potential (ERP) reductions in schizophrenia (SZ) reflect preattentive and attention-mediated auditory processing deficits, respectively. Although both have been linked to cognitive deficits in SZ, their relative contributions to real-world functioning are unclear. We sought to determine the functional significance of disrupted auditory processing in SZ by examining MMN and P300 in typically disabled low-functioning patients and in patients with high levels of independent role functioning. MMN to auditory deviants and P300 to infrequent auditory target and nontarget novel stimuli were assessed in 20 high-functioning SZ patients (HF-SZ), 17 low-functioning patients (LF-SZ), and 35 healthy comparison (HC) subjects. There was a group effect on MMN and P300 amplitudes across stimulus types. MMN was significantly diminished in LF-SZ compared to HF-SZ and HC, and HF-SZ demonstrated comparable MMN to HC. In contrast, P300 was significantly reduced in both LF-SZ and HF-SZ compared to HC. Logistic regression suggested independent sensitivity of MMN to functioning in SZ over and above P300 measures. Neither MMN nor P300 were associated with positive or negative symptom severity. Results replicate MMN and P300 abnormalities in SZ, and also suggest that the neural mechanisms associated with the preattentive detection of auditory deviance are most compromised in patients with functional disability. MMN may index pathophysiological processes that are critical for optimal functioning in SZ.

Role of N-Methyl-D-Aspartate Receptors in Action-Based Predictive Coding Deficits in Schizophrenia.

BACKGROUND: Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia. METHODS: In two separate studies, the N1 component of the event-related potential elicited by speech sounds during vocalization (talk) and passive playback (listen) were compared to assess the degree of N1 suppression during vocalization, a putative measure of auditory predictive coding. In the crossover study, 31 healthy volunteers completed two randomly ordered test days, a saline day and a ketamine day. Event-related potentials during the talk/listen task were obtained before infusion and during infusion on both days, and N1 amplitudes were compared across days. In the case-control study, N1 amplitudes from 34 schizophrenia patients and 33 healthy control volunteers were compared. RESULTS: N1 suppression to self-produced vocalizations was significantly and similarly diminished by ketamine (Cohen's d = 1.14) and schizophrenia (Cohen's d = .85). CONCLUSIONS: Disruption of NMDARs causes dysfunction in predictive coding during vocalization in a manner similar to the dysfunction observed in schizophrenia patients, consistent with the theorized contribution of NMDAR hypofunction to predictive coding deficits in schizophrenia.