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Research indicates that high utilizers of the health care system are more likely to have mental illness, to be from socially disadvantaged groups, and to have limited access to community-based services. In this retrospective study, three definitions of high utilization were examined: (1) across time: non-high utilization versus high-utilization, (2) single year versus multi-year, and (3) year-to-year. Univariate logistic regression models were fit to a set of 20 theory-selected predictors of high utilization. An optimal multiple predictor model was then derived via penalized multiple logistic regression (via elastic net, a machine learning algorithm). Three factors were identified in the optimized model as increasing the likelihood of high utilization: having a diagnosis of schizophrenia, having a co-occurring personality disorder diagnosis, and having less than a high school education. Given the complex needs of psychiatric high utilizers, innovative approaches should be considered to improve patient outcomes and reduce costly psychiatric hospitalizations.

Working memory dysfunction may be central to neurocognitive deficits in schizophrenia. Maintenance of visual information in working memory, or visual short-term memory (vSTM), is linked to general cognitive dysfunction and predicts functional outcome. Lateralized change-detection tasks afford investigation of the contralateral delay activity (CDA), a useful tool for investigating vSTM dysfunction. Previous work suggests "hyperfocusing" of attention in schizophrenia, such that CDA is increased when a single item is maintained in vSTM but reduced for multiple items. If observed early in the disease, vSTM dysfunction may be a key feature of schizophrenia or target for intervention. We investigated CDA during lateralized vSTM of one versus three items using sensor-level electroencephalography and source-level magnetoencephalography in 26 individuals at their first episode of schizophrenia-spectrum psychosis (FESz) and 26 matched healthy controls. FESz were unable to modulate CDA with increased memory load - high-load CDA was reduced and low-load CDA was increased compared to controls. Further, sources of CDA in posterior parietal cortex were reduced in FESz and indices of working memory were correlated with neurocognitive deficits and symptom severity. These results support working memory maintenance dysfunction as a central and early component to the disorder. Targeted intervention focusing on vSTM deficits may be warranted to alleviate downstream effects of this disability.

Memory dysfunction and associated hippocampal disturbances play crucial roles in cognitive impairment of schizophrenia. To examine the relationships between cognitive function and the hippocampal subfields (HSs) in first-episode never-treated (FENT) schizophrenia patients, the HSs were segmented in 39 FENT patients and 30 healthy controls using a state-of the-art automated algorithm. We found no significant differences in any HSs between the patients and controls. However, multivariate regression analysis showed that the left cornu ammonis 1 (CA1), left hippocampal tail, left presubiculum, and right molecular layer contributed 40% to the variance of the PANSS negative symptom score. After adjusting for sex, age, education, and intracranial volume, the partial correlation analysis showed that the volumes of left CA1, CA3, CA4, molecular layer, granule cell layer and both left and right subiculum were negatively correlated with the MATRICS consensus cognitive battery (MCCB) Hopkins Verbal Learning Test (HVLT). Multiple regression analysis showed that the left CA1 and CA3 hippocampal abnormalities contributed 66% to the variance of the HVLT. Our results suggest no detectable HS deficits were found in FENT schizophrenia patients. However, the HSs may be involved in the symptoms and cognitive deficits of schizophrenia patients in the early phase of their illness.

Obsessive-compulsive disorder (OCD) is a common psychiatric disorder that can be chronic and debilitating if not properly treated. Current first-line treatments for OCD include cognitive-behavioral therapy with exposure and response prevention and serotonin uptake inhibitor medications; however, these therapies are not effective for all individuals.Deep transcranial magnetic stimulation (dTMS) has been hypothesized to be an effective alternative for individuals with treatment-resistant OCD. dTMS has thought to be favorable due to its low side effect profile and its minimally invasive nature.This review evaluates the current research on effectiveness of dTMS therapy for individuals with treatment-resistant OCD. This review also investigates shortcomings in current dTMS research and the hypothesized future of dTMS therapy.

Brain neuromodulation effectively treats neurological diseases and psychiatric disorders such as Depression. However, due to patient heterogeneity, neuromodulation treatment outcomes are often highly variable, requiring patient-specific stimulation protocols throughout the recovery stages to optimize treatment outcomes. Therefore, it is critical to personalize neuromodulation protocol to optimize the patient-specific stimulation targets and parameters by accommodating inherent interpatient variability and intersession alteration during treatments. The study aims to develop a personalized repetitive transcranial magnetic stimulation (rTMS) protocol and evaluate its feasibility in optimizing the treatment efficiency using an existing dataset from an antidepressant experimental imaging study in depression. The personalization of the rTMS treatment protocol was achieved by personalizing both stimulation targets and parameters via a novel approach integrating the functional brain network controllability analysis and optimal control analysis. First, the functional brain network controllability analysis was performed to identify the optimal rTMS stimulation target from the effective connectivity network constructed from patient-specific resting-state functional magnetic resonance imaging data. The optimal control algorithm was then applied to optimize the rTMS stimulation parameters based on the optimized target. The performance of the proposed personalized rTMS technique was evaluated using datasets collected from a longitudinal antidepressant experimental imaging study in depression (n = 20). Simulation models demonstrated that the proposed personalized rTMS protocol outperformed the standard rTMS treatment by efficiently steering a depressive resting brain state to a healthy resting brain state, indicated by the significantly less control energy needed and higher model fitting accuracy achieved. The node with the maximum average controllability of each patient was designated as the optimal target region for the personalized rTMS protocol. Our results also demonstrated the theoretical feasibility of achieving comparable neuromodulation efficacy by stimulating a single node compared to stimulating multiple driver nodes. The findings support the feasibility of developing personalized neuromodulation protocols to more efficiently treat depression and other neurological diseases.

Clinic-based transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that has been shown to improve pain. However, no published studies have reported using home-based self-administered tDCS in older adults with knee osteoarthritis (OA). The present study aimed to evaluate the preliminary efficacy and feasibility of home-based self-administered tDCS with real-time remote supervision on clinical pain, anxiety, depression, and sleep disturbances in older adults with knee OA. Twenty 50- to 85-year-old community-dwelling participants with knee OA received 10 daily home-based sessions of 2 mA tDCS for 20 min with real-time remote supervision. We measured clinical pain severity via the Visual Analog Scale, Western Ontario and McMaster Universities Osteoarthritis Index, and Short-Form McGill Pain Questionnaire. We assessed anxiety, depression, and sleep disturbances using the Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety-short form, depression-short form, and sleep disturbance-short form, respectively. All 20 participants completed all 10 home-based tDCS sessions without serious adverse effects. Both clinical pain severity and sleep disturbances were improved after completion of the 10 tDCS sessions. Anxiety and depression scores were not significantly improved. We demonstrated that home-based self-administered tDCS with real-time remote supervision was feasible and beneficial in alleviating clinical pain in older adults with knee OA. These findings support future studies with larger samples and longer-term follow-up evaluations.

BACKGROUND: Knowledge is lacking regarding deficits in selective attention and their underlying biological mechanisms during early stages of schizophrenia. The present study examined the N2pc, a neurophysiological index of covert spatial attention, and its cortical sources at first psychotic episode in the schizophrenia spectrum (FESz). METHODS: Neurophysiological responses measured simultaneously with magnetoencephalography (MEG) and electroencephalography (EEG) during pop-out and serial search tasks were compared between 32 FESz and 32 matched healthy controls (HC). Mean scalp-recorded N2pc was measured from a cluster of posterior-lateral EEG electrodes. Cortical source-resolved MEG activity contributing to the N2pc signal was derived for the intraparietal sulcus (IPS) and lateral occipital complex (LOC). RESULTS: Group differences in EEG N2pc varied by task demand. FESz exhibited reduced N2pc amplitude during pop-out (p

Background/objectives Micro-induction is a novel buprenorphine induction approach that seeks to avoid withdrawal and minimize precipitated withdrawal, both barriers to standard inductions. We aimed to synthesize evidence on micro-induction effectiveness, and regimens described. Methods We searched scientific databases and grey literature for studies including adolescents or adults with opioid use disorder who received buprenorphine micro-induction. Study selection, data extraction and quality assessments occurred in duplicate. We narratively synthesized results. Results We screened 4,752 citations and included 19 case studies/series and one feasibility study (n = 57 patients; mean age 38 years [SD 12.0]; 57.9% male [33/57]). Studies described 26 regimens; starting and maintenance doses ranged from 0.03 to 1.0 mg, and 8 to 32 mg, respectively. We calculated rate of increase to 8 mg. All patients achieved the desired maintenance dose. Among 54 patients in whom precipitated withdrawal was not reported, mean increases were 1.36 mg/day (SD 0.41). For three patients in whom precipitated withdrawal was specifically reported, mean increase was 1.17 mg/day (SD 0.11). All studies were low quality. Discussion Described regimens are highly variable. Inconsistent reporting, selection bias, and poor quality evidence limit conclusions regarding optimal dosing, and patient characteristics and clinical settings in which micro-induction is likely beneficial. Conclusions This systematic review provides the most up-to-date synthesis on buprenorphine micro-induction regimens. Rigorous studies evaluating effectiveness and safety of micro-induction, and patient and clinical factors influencing its success, are needed.

Increased anticholinergic activity resulting from pharmacotherapies used to treat schizophrenia is associated with poorer cognition. However the neural mechanisms underlying this effect are unknown. In this study of 39 early course schizophrenia outpatients, we demonstrate that increased serum anticholinergic activity is associated with reduced activation across the prefrontal cortex, including the dorsolateral, anterior, and medial prefrontal cortices, during two tasks of cognitive control. Lower activation in the dorsolateral and anterior prefrontal cortices mediated the association between increased anticholinergicity and poorer neurocognitive function. Such findings provide preliminary insight into how anticholinergic medications may impact cognition through reduced prefrontal cortical function in schizophrenia.

U.S. Hispanics, now the single largest minority group in the country, face unique mental health disparities. The current study utilizes Andersen's Behavioral Model of Health Service Use to examine ethnic disparities in receiving a schizophrenia or mood disorder diagnosis at psychiatric hospital admission. Our retrospective cohort study examined electronic health record data at an academic safety-net psychiatric hospital for adult patients (n = 5571) admitted between 2010 and 2013. Logistic regression with block-wise entry of predisposing, enabling and need variables was used to examine ethnic disparities in receiving a schizophrenia diagnosis at admission. The block of need factors was the strongest predictor of receiving a schizophrenia diagnosis compared to predisposing and enabling factors. Compared to non-Hispanic whites, Hispanics and African Americans had a greater likelihood of receiving a schizophrenia diagnosis at admission. Additionally, patients diagnosed with schizophrenia had elevated positive and negative symptoms and were more likely to be male, single/unmarried, homeless, high inpatient service utilizers, involuntarily hospitalized, and to exhibit functional impairment at psychiatric hospital admission. To address elevated positive and negative symptoms of schizophrenia, functional impairment, social withdrawal, and high inpatient service utilization, promising psychosocial interventions should be adapted for racial and ethnic minority populations and utilized as an adjuvant to antipsychotic medication.

Young adults experiencing first-episode psychosis have historically been difficult to retain in mental health treatment. Communities across the United States are implementing Coordinated Specialty Care to improve outcomes for individuals experiencing first-episode psychosis. This mixed-methods research study examined the relationship between program services and treatment retention, operationalized as the likelihood of remaining in the program for 9 months or more. In the adjusted analysis, male gender and participation in home-based cognitive behavioral therapy were associated with an increased likelihood of remaining in treatment. The key informant interview findings suggest the shared decision-making process and the breadth, flexibility, and focus on functional recovery of the home-based cognitive behavioral therapy intervention may have positively influenced treatment retention. These findings suggest the use of shared decision-making and improved access to home-based cognitive behavioral therapy for first-episode psychosis patients may improve outcomes for this vulnerable population.

Previous studies consistently showed that IL-3 signaling may be involved in the pathophysiology of schizophrenia. However, investigations of associations between IL-3 and the neurocognitive impairments are lacking, including the study of how this may vary with stage of illness. We recruited 45 first-episode drug-naïve (FE-Sz), 35 chronic medicated schizophrenia (Ch-Sz) and 40 healthy controls (HC) and examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum IL-3. Altered serum IL-3 levels were found in both patient groups compared with HC group (both p 0.001). There were significantly lower neurocognitive scores on the RBANS and nearly all of its five subscales, except for Visuospatial/Constructional index in both FE-Sz and Ch-Sz patients vs healthy controls. Moreover, a significant reduction in Immediate memory index (p = 0.021) and a trend-level reduction in RBANS total score (p = 0.094) in Ch-Sz than FE-Sz patients. Interestingly, there was a significant negative correlation between IL-3 and the Immediate memory index only in Ch-Sz patients (p = 0.03). Our findings showed that neurocognitive impairments present in schizophrenia emerge during the first episode with further diminished functioning with disease progression, and IL-3 may be involved in the immediate memory deficits in the chronic phase of schizophrenia.

Renpenning syndrome (OMIM: 309500) is a rare X-linked disorder that causes intellectual disability, microcephaly, short stature, a variety of eye anomalies, and characteristic craniofacial features. This condition results from pathogenic variation of PQBP1, a polyglutamine-binding protein involved in transcription and pre-mRNA splicing. Renpenning syndrome has only been reported in affected males. Carrier females do not usually have clinical features, and in reported families with Renpenning syndrome, most female carriers exhibit favorable skewing of X-chromosome inactivation. We describe a female with syndromic features typical of Renpenning syndrome. She was identified by exome sequencing to have a de novo heterozygous c.459_462delAGAG mutation in PQBP1 (Xp11.23), affecting the AG hexamer in exon 4, which is the most common causative mutation in this syndrome. Streaky hypopigmentation of the skin was observed, supporting a hypothesized presence of an actively expressed, PQBP1 mutation-bearing X-chromosome in some cells. X-inactivation studies on peripheral blood cells demonstrated complete skewing in both the proband and her mother with preferential inactivation of the maternal X chromosome in the child. We demonstrated expression of the PQBP1 mutant transcript in leukocytes of the affected girl. Therefore, it is highly likely that the PQBP1 mutation arose from the paternal X chromosome.

Multiple lines of evidence indicate that patients with chronic schizophrenia (SCZ) display executive dysfunction across the illness course. However, the potential molecular pathophysiologic mechanisms remain poorly elucidated. Neurodevelopmental changes caused by alterations of inflammatory mediators and neurotrophins have been shown to occur in the earliest stages of SCZ, and be associated with executive dysfunction (ED) in SCZ. Therefore, the current study was to investigate whether the interplay between BDNF and inflammatory mediators was involved in the disruption of executive function of long-term hospitalized patients with chronic SCZ. Serum cytokines and BDNF levels were measured in 112 long-term hospitalized patients with chronic SCZ and 44 healthy normal controls. Executive functions were assessed by verbal fluency tests (VFT), the Stroop word-color test (Stroop), and the Wisconsin card sorting tests (WCST).The results showed that the patients had higher IL-2, IL-6, IL-8, but lower TNF-α and BDNF compared to control subjects. In the patient group, BDNF was positively associated with IL-2 and IL-8 levels, while lower BDNF levels were correlated with ED measured by VFT and WCST tests. Multiple stepwise regression analyses confirmed that BDNF × IL-8 and BDNF × TNF-α were factors influencing the total score of VFT, while BDNF × IL-8 and BDNF × TNF-α were recognized as influencing factors for WCST scores. Our results suggest complex interactions between BDNF and cytokines were involved in the pathophysiology of executive function impairments in patients with SCZ.

Background Dysregulation of the inositol cycle is implicated in a wide variety of human diseases, including developmental defects and neurological diseases. A homozygous frameshift mutation in IMPA1, coding for the enzyme inositol monophosphatase 1 (IMPase), has recently been associated with severe intellectual disability (ID) in a geographically isolated consanguineous family in Northeastern Brazil (Figueredo et al., 2016). However, the neurophysiologic mechanisms that mediate the IMPA1 mutation and associated ID phenotype have not been characterized. To this end, resting EEG (eyes-open and eyes-closed) was collected from the Figueredo et al. pedigree. Quantitative EEG measures, including mean power, dominant frequency and dominant frequency variability, were investigated for allelic associations using multivariate family-based association test using generalized estimating equations. Results We found that the IMPA1 mutation was associated with relative decreases in frontal theta band power as well as altered alpha-band variability with no regional specificity during the eyes-open condition. For the eyes-closed condition, there was altered dominant theta frequency variability in the central and parietal regions. Conclusions These findings represent the first human in vivo phenotypic assessment of brain function disturbances associated with a loss-of-function IMPA1 mutation, and thus an important first step towards an understanding the pathophysiologic mechanisms of intellectual disability associated with the mutation that affects this critical metabolic pathway.

BackgroundSchizophrenia patients have a higher prevalence of type 2 diabetes mellitus with impaired glucose tolerance (IGT) than normals. We examined the relationship between IGT and clinical phenotypes or cognitive deficits in first-episode, drug-naïve (FEDN) Han Chinese patients with schizophrenia.MethodA total of 175 in-patients were compared with 31 healthy controls on anthropometric measures and fasting plasma levels of glucose, insulin and lipids. They were also compared using a 75 g oral glucose tolerance test and the homeostasis model assessment of insulin resistance (HOMA-IR). Neurocognitive functioning was assessed using the MATRICS Consensus Cognitive Battery (MCCB). Patient psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS).ResultsOf the patients, 24.5% had IGT compared with none of the controls, and they also had significantly higher levels of fasting blood glucose and 2-h glucose after an oral glucose load, and were more insulin resistant. Compared with those patients with normal glucose tolerance, the IGT patients were older, had a later age of onset, higher waist or hip circumference and body mass index, higher levels of low-density lipoprotein and triglycerides and higher insulin resistance. Furthermore, IGT patients had higher PANSS total and negative symptom subscale scores, but no greater cognitive impairment except on the emotional intelligence index of the MCCB.ConclusionsIGT occurs with greater frequency in FEDN schizophrenia, and shows association with demographic and anthropometric parameters, as well as with clinical symptoms but minimally with cognitive impairment during the early course of the disorder.

Electroconvulsive therapy (ECT) is one of the most effective treatments for major depression disorder (MDD). ECT can induce neurogenesis and synaptogenesis in hippocampus, which contains distinct subfields, e.g., the cornu ammonis (CA) subfields, a granule cell layer (GCL), a molecular layer (ML), and the subiculum. It is unclear which subfields are affected by ECT and whether we predict the future treatment response to ECT by using volumetric information of hippocampal subfields at baseline? In this study, 24 patients with severe MDD received the ECT and their structural brain images were acquired with magnetic resonance imaging before and after ECT. A state-of-the-art hippocampal segmentation algorithm from Freesurfer 6.0 was used. We found that ECT induced volume increases in CA subfields, GCL, ML and subiculum. We applied a machine learning algorithm to the hippocampal subfield volumes at baseline and were able to predict the change in depressive symptoms (r = 0.81; within remitters, r = 0.93). Receiver operating characteristic analysis also showed robust prediction of remission with an area under the curve of 0.90. Our findings provide evidence for particular hippocampal subfields having specific roles in the response to ECT. We also provide an analytic approach for generating predictions about clinical outcomes for ECT in MDD.

Identifying biomarkers in schizophrenia during the first episode without the confounding effects of treatment has been challenging. Leveraging these biomarkers to establish diagnosis and make individualized predictions of future treatment responses to antipsychotics would be of great value, but there has been limited progress. In this study, by using machine learning algorithms and the functional connections of the superior temporal cortex, we successfully identified the first-episode drug-naive (FEDN) schizophrenia patients (accuracy 78.6%) and predict their responses to antipsychotic treatment (accuracy 82.5%) at an individual level. The functional connections (FC) were derived using the mutual information and the correlations, between the blood-oxygen-level dependent signals of the superior temporal cortex and other cortical regions acquired with the resting-state functional magnetic resonance imaging. We also found that the mutual information and correlation FC was informative in identifying individual FEDN schizophrenia and prediction of treatment response, respectively. The methods and findings in this paper could provide a critical step toward individualized identification and treatment response prediction in first-episode drug-naive schizophrenia, which could complement other biomarkers in the development of precision medicine approaches for this severe mental disorder.

Atherosclerotic cardiovascular disease (ASCVD) is highly heritable, particularly when it occurs at a young age. The screening of individuals with premature ASCVD, although often recommended, is not routinely performed. Strategies to address this gap in care are essential. We designed the Study to Avoid CardioVascular Events in British Columbia (SAVE BC) as a prospective, observational study of individuals with a new diagnosis of very premature ASCVD (defined as age ≤ 50 years in males and age ≤ 55 years in females) and their first-degree relatives (FDRs) and spouses. FDRs and spouses will undergo screening for cardiovascular (CV) risk factors and subclinical ASCVD using a structured screening algorithm. All subjects will be followed longitudinally for ≥10 years. The overall goal of SAVE BC is to evaluate the yield of a structured screening program for identifying individuals at risk of premature ASCVD. The primary objectives of SAVE BC are to identify and follow index cases with very premature ASCVD and their FDRs and to determine the diagnostic yield of a structured screening program for these individuals. We will collect data on CV risk factors, medication use, CV events, and healthcare costs in these individuals. SAVE BC will provide insight regarding approaches to identify individuals at risk for premature ASCVD with implications for prevention and treatment in this population.

Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm.The binding of [(11)C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [(11)C]flumazenil tissue distribution volume (VT).[(11)C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [(11)C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [(11)C]flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [(11)C]flumazenil ΔVT was positively associated with gamma-band oscillation power.This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.

Multiple studies confirm that African Americans are less likely than non-Hispanic whites to receive needed mental health services. Research has consistently shown that African Americans are under-represented in outpatient mental health treatment settings and are over-represented in inpatient psychiatric settings. Further, African Americans are more likely to receive a diagnosis of schizophrenia and are less likely receive an affective disorder diagnosis during inpatient psychiatric hospitalization compared to non-Hispanic white patients, pointing to a need for examining factors contributing to mental health disparities. Using Andersen's Behavioral Model of Health Service Use, this study examined predisposing, enabling and need factors differentially associated with health service utilization among African American and non-Hispanic white patients (n = 5183) during psychiatric admission. We conducted univariate and multivariate logistic regression analyses to examine both main effects and interactions. In the multivariate model, African American race at admission was predicted by multiple factors including younger age, female gender, multiple psychiatric hospitalizations, elevated positive and negative symptoms of psychosis, a diagnosis of schizophrenia and substance use, as well as having housing and commercial insurance. Additionally, screening positive for cannabis use at intake was found to moderate the relationship between being female and African American. Our study findings highlight the importance of examining mental health disparities using a conceptual framework developed for vulnerable populations (such as racial minorities and patients with co-occurring substance use).

Context processing involves a flexible and continually updated representation of task relevant information and is a core aspect of cognitive control. The expectancy AX Continuous Performance Test (AXCPT) was designed to specifically measure context processing and has been widely applied to elucidate mechanisms of cognitive control and their impairments in conditions such as aging and schizophrenia. Here we present a large-sample, cross-sectional study of context processing aimed at characterizing its normal development from childhood to early adulthood (8 to 22 years old). We track the age-related changes in the standard AXCPT performance measures and also investigate their validity using detailed data-driven method. We show how critical maturational changes in context processing can be validly tracked from mid-adolescence onward with increasing reliance on preparatory, proactive strategies well into early adulthood. However, the early maturation from childhood into adolescence showed a sharp, two-fold discontinuity: while standard measures provide partially conflicting results suggesting an early worsening of proactive strategies, further analyses do not support their validity during this period. Our findings advocate the existence of multiple preparatory strategies that cannot be captured by indices that assume a simple dichotomy of proactive vs. reactive strategies. When evaluating context processing differences over development or in clinical populations, we advocate the explicit testing of the assumptions underlying standard AXCPT indices through complementary data-driven methods.

Repeated viewing of an image over days and weeks induces a marked reduction in the strength with which neurons in monkey inferotemporal cortex respond to it. The processing advantage that attaches to this reduction is unknown. One possibility is that truncation of the response to a familiar image leaves neurons in a state of readiness to respond to ensuing images and thereby enhances their ability to track rapidly changing displays. We explored this possibility by assessing neuronal responses to familiar and novel images in rapid serial visual displays. Inferotemporal neurons responded more strongly to familiar than to novel images in such displays. The effect was stronger among putative inhibitory neurons than among putative excitatory neurons. A comparable effect occurred at the level of the scalp potential in humans. We conclude that long-term familiarization sharpens the response dynamics of neurons in both monkey and human extrastriate visual cortex.

Background: Evidence from preclinical and human studies indicates the presence of reduced dopamine-1 receptor (D1R) signaling in the cortex, where D1Rs predominate, in patients with schizophrenia (SCZ), which may contribute to their cognitive deficits. Furthermore, studies in nonhuman primates (NHP) have suggested that intermittent administration of low doses of D1R agonists produce long-lasting reversals in cognitive deficits. The purpose of this trial was to test whether a similar design, involving subacute intermittent administration of low doses of a full, selective agonist at D1Rs, DAR-0100A, would improve cognitive deficits in SCZ. Methods: We randomized 49 clinically stable individuals with SCZ to three weeks of intermittent treatment with 0.5 mg or 15 mg of DAR-0100A, or placebo (normal saline). Functional magnetic resonance imaging (fMRI) BOLD was used to evaluate the effects of drug administration on brain activity during a working memory (WM) task. Effects on cognition were also assessed using the MATRICS and the N-back task as primary endpoints. The CogState battery was used as a secondary endpoint. Results: There were no observed treatment effects on either the BOLD fMRI signal during WM tasks or the WM domains of the MATRICS. Moderate improvement was detected on the CogState battery and on the attention domain of the MATRICS. Conclusion: These results suggest that low doses of D1 agonists that do not result in measureable occupancy of the D1R do not reliably improve cognition in SCZ, unlike the observations in NHP. As this drug is limited by its pharmacokinetic profile, better D1R agonists that can achieve adequate levels of D1R occupancy are needed to test the efficacy of this mechanism for cognitive enhancement in SCZ.

Objective Schizophrenia is characterized by impaired -social and non social cognition both of which lead to functional deficits. These deficits may benefit from cognitive remediation, but the neural underpinnings of such improvements have not been clearly delineated. Methods We conducted a functional magnetic resonance (fMRI) study in early course schizophrenia patients randomly assigned to cognitive enhancement therapy (CET) or enriched supportive therapy (EST) and treated for two years. Imaging data over three time points including fMRI blood oxygen level dependent (BOLD) data were acquired during performance of a cognitive control paradigm, the Preparing to Overcome Prepotency (POP) task, and functional connectivity data, were analyzed. Results During the two years of treatment, CET patients showed a continual increase in BOLD activity in the right dorsolateral prefrontal cortex (DLPFC), whereas EST patients tended to show no change in prefrontal brain function throughout treatment. Increases in right DLPFC activity were modestly associated with improved neurocognition (β = .14, p = .041), but not social cognition. Functional connectivity analyses showed reduced connectivity between the DLPFC and the anterior cingulate cortex (ACC) in CET compared to EST over the two years of treatment, which was associated with neurocognitive improvement. Conclusions. These findings suggest that CET leads to enhanced neural activity in brain regions mediating cognitive control and increased efficiency in prefrontal circuits; such changes may be related to the observed therapeutic effects of CET on neurocognitive function.

Mechanisms by which the brain monitors and modulates performance are an important focus of recent research. The conflict-monitoring hypothesis posits that the ACC detects conflict between competing response pathways which, in turn, signals for enhanced control. The N2, an ERP component that has been localized to ACC, has been observed after high conflict stimuli. As a candidate index of the conflict signal, the N2 would be expected to be sensitive to the degree of response conflict present, a factor that depends on both the features of external stimuli and the internal control state. In the present study, we sought to explore the relationship between N2 amplitude and these variables through use of a modified Eriksen flankers task in which target–distracter compatibility was parametrically varied. We hypothesized that greater target–distracter incompatibility would result in higher levels of response conflict, as indexed by both behavior and the N2 component. Consistent with this prediction, there were parametric degradations in behavioral performance and increases in N2 amplitudes with increasing incompatibility. Further, increasingly incompatible stimuli led to the predicted parametric increases in control on subsequent incompatible trials as evidenced by enhanced performance and reduced N2 amplitudes. These findings suggest that the N2 component and associated behavioral performance are finely sensitive to the degree of response conflict present and to the control adjustments that result from modulations in conflict.

Objective Multiscale entropy (MSE) is a recently proposed entropy-based index of physiological complexity, evaluating signals at multiple temporal scales. To test this method as an aid to elucidating the pathophysiology of Alzheimer’s disease (AD), we examined MSE in resting state EEG activity in comparison with traditional EEG analysis. Methods We recorded EEG in medication-free 15 presenile AD patients and 18 age- and sex-matched healthy control (HC) subjects. MSE was calculated for continuous 60-s epochs for each group, concurrently with power analysis. Results The MSE results from smaller and larger scales were associated with higher and lower frequencies of relative power, respectively. Group analysis demonstrated that the AD group had less complexity at smaller scales in more frontal areas, consistent with previous findings. In contrast, higher complexity at larger scales was observed across brain areas in AD group and this higher complexity was significantly correlated with cognitive decline. Conclusions MSE measures identified an abnormal complexity profile across different temporal scales and their relation to the severity of AD. Significance These findings indicate that entropy-based analytic methods with applied at temporal scales may serve as a complementary approach for characterizing and understanding abnormal cortical dynamics in AD.

This study was intended to examine variations in electroencephalographic (EEG) complexity in response to photic stimulation (PS) during aging to test the hypothesis that the aging process reduces physiologic complexity and functional responsiveness.Multiscale entropy (MSE), an estimate of time-series signal complexity associated with long-range temporal correlation, is used as a recently proposed method for quantifying EEG complexity with multiple coarse-grained sequences. We recorded EEG in 13 healthy elderly subjects and 12 healthy young subjects during pre-PS and post-PS conditions and estimated their respective MSE values.For the pre-PS condition, no significant complexity difference was found between the groups. However, a significant MSE change (complexity increase) was found post-PS only in young subjects, thereby revealing a power-law scaling property, which means long-range temporal correlation.Enhancement of long-range temporal correlation in young subjects after PS might reflect a cortical response to stimuli, which was absent in elderly subjects. These results are consistent with the general "loss of complexity/diminished functional response to stimuli" theory of aging.Our findings demonstrate that application of MSE analysis to EEG is a powerful approach for studying age-related changes in brain function.

Deficits in working memory and cognitive control in schizophrenia are associated with impairments in prefrontal cortical function, including altered gamma band oscillations. These abnormalities are thought to reflect a deficiency in the synchronization of pyramidal cell activity that is dependent, in part, on gamma-aminobutyric acid (GABA) neurotransmission through GABA type A (GABA(A)) receptors containing alpha(2) subunits. The authors conducted a proof-of-concept clinical trial designed to test the hypothesis that a novel compound with relatively selective agonist activity at GABA(A) receptors containing alpha(2) subunits would improve cognitive function and gamma band oscillations in individuals with schizophrenia.Participants were male subjects (N=15) with chronic schizophrenia who were randomly assigned to receive 4 weeks of treatment with the study drug MK-0777, a benzodiazepine-like agent with selective activity at GABA(A) receptors containing alpha(2) or alpha(3) subunits, or a matched placebo in a double-blind fashion. Outcome measures were the Brief Psychiatric Rating Scale (BPRS), Repeatable Battery for the Assessment of Neuropsychological Status, three tests of working memory and/or cognitive control (N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency), and EEG measures of gamma band oscillations induced during the Preparing to Overcome Prepotency task.Compared with placebo, the MK-0777 compound was associated with improved performance on the N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency tasks. The compound was also associated with increased frontal gamma band power during the Preparing to Overcome Prepotency task. No effects of the MK-0777 compound were detected in BPRS or Repeatable Battery for the Assessment of Neuropsychological Status scores, with the exception of improvement on the Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index. The MK-0777 agent was well-tolerated.These findings provide preliminary support for the hypothesis that enhanced GABA activity at alpha(2) subunit containing GABA(A) receptors improves behavioral and electrophysiological measures of prefrontal function in individuals with schizophrenia.

A growing body of evidence from functional neuroimaging and computational modeling studies indicates that the anterior cingulate cortex (ACC) detects the presence of response conflict and conveys this information to other brain regions, enabling subsequent adjustments in cognitive control. The present study examined previous empirical findings of increased ACC for low-frequency stimuli across three distinct speeded response tasks (two-alternative forced choice, go/no-go, and oddball). Simulations conducted in a neural network model incorporating sequential priming mechanisms (developed in Cho et al., 2002) confirmed that a computational measure of response conflict was higher on low-frequency trials across all three tasks. In addition, the model captured detailed aspects of behavioral reaction time and accuracy data, predicted the dynamics of ACC activity related to trial sequence effects, and provided evidence for the functional role of conflict information in performance monitoring and optimization. The results indicate that the conflict-monitoring hypothesis, augmented by mechanisms for encoding stimulus history, can explain key phenomena associated with performance in sequential speeded response tasks.

In choice reaction time tasks, response times and error rates demonstrate differential dependencies on the identities of up to four stimuli preceding the current one. Although the general profile of reaction times and error rates, when plotted against the stimulus histories, may seem idiosyncratic, we show that it can result from simple underlying mechanisms that take account of the occurrence of stimulus repetitions and alternations. Employing a simple connectionist model of a two-alternative forced-choice task, we explored various combinations of repetition and alternation detection schemes in an attempt to account for empirical results from the literature and from our own studies. We found that certain combinations of the repetition and the alternation schemes provided good fits to the data, suggesting that simple mechanisms may serve to explain the complicated but highly reproducible higher order dependencies of task performance on stimulus history.

Cognitive deficits are a core clinical feature of schizophrenia but respond poorly to available medications. Thus, understanding the neural basis of these deficits is crucial for the development of new therapeutic interventions. The types of cognitive processes affected in schizophrenia are thought to depend on the precisely timed transmission of information in cortical regions via synchronous oscillations at gamma band frequency. Here, we review 1) data from clinical studies suggesting that induction of frontal cortex gamma oscillations during tasks that engage cognitive or complex perceptual functions is attenuated in schizophrenia; 2) findings from basic neuroscience studies highlighting the features of parvalbumin-positive interneurons that are critical for gamma oscillation production; and 3) results from recent postmortem human brain studies providing additional molecular bases for parvalbumin-positive interneuron alterations in prefrontal cortical circuitry in schizophrenia.

Christopher P. Walkerand Nicola R. Polizzotto contributed equally to the manuscript.Given the importance of gamma oscillations in normal and disturbedcognition, there has beengrowing interestin their developmentaltra-jectory. In the current study, age-related changes in sensory corticalgamma were studied using the auditory steady-state response(ASSR), indexing cortical activity entrained to a periodic auditorystimulus.Alargesample(n=188) aged8–22years hadelectroence-phalography recording of ASSR during 20-, 30-, and 40-Hz clicktrains, analyzed forevoked amplitude, phase-locking factor (PLF) andcross-frequency coupling (CFC) with lower frequency oscillations.Both 40-Hz evoked power and PLF increased monotonically from 8through 16 years, and subsequently decreased toward ages 20–22years. CFC followed a similar pattern, with strongest age-relatedmodulation of 40-Hz amplitude by the phase of delta oscillations. Incontrast, the evoked power, PLFand CFCfor the 20- and 30-Hz stimu-lation were distinct from the 40-Hz condition, with flat or decreasingprofiles fromchildhood toearlyadulthood. The inverted U-shaped de-velopmental trajectoryof gamma oscillations may be consistent withinteracting maturational processes—such as increasing fast GABAinhibition that enhances gamma activity and synaptic pruning thatdecreases gamma activity—that may continue from childhoodthrough to adulthood.Keywords: cross-frequency coupling, development, GABA, gammaoscillations, phase-locking factor, synaptic pruningIntroductionSynchronous gamma-band (30–80 Hz) oscillations are animportant mechanism for coordinating neural activity in theservice of cognitive and sensory processing. Altered gammaoscillations have also been implicated in the pathophysiologyof neuropsychiatric disorders such as schizophrenia andautism. Accordingly, investigating the normal developmentaltrajectoryofgamma oscillations isof vital importanceto under-standing the neurophysiologic underpinnings of normal cogni-tive development and how pathophysiologic disturbances ingamma activity in neurodevelopmental disorders can give riseto deviations from thistrajectory.Gamma oscillations have been most studied in humansusing electroencephalography (EEG), which records at thescalp the summed effect of the synchronous postsynapticactivity in a large number of cortical pyramidal neurons(Nunez and Srinivasan 2005). As various structural and func-tional processesthat support gamma oscillations involve a pro-tracted neurodevelopmental course from childhood through toadulthood, the development of gamma oscillations would beexpected to followa similarlyextended trajectory before reach-ing the mature state. For instance, structural magnetic reson-ance imaging (MRI) studies find that gray matter thickness inauditory cortical areas (posterior superior temporal gyrus) de-crease linearly from childhood into early adulthood (Gogtayet al. 2004). Such macro-level observations of gray matterchanges are thought to reflect synaptic pruning over develop-ment. Early studies by Huttenlocher and Dabholkar (1997)suggested that auditory and visual regions completed pruningprocesses in early adolescence while prefrontal cortex had amore extended course into mid-adolescence. However, theseinterpretations were limited by sparse sampling over the ado-lescence and adulthood periods, and more recent studies withdenser sampling over this range have indicated that synapticelimination continues beyond adolescence into the thirddecade of life (Petanjek et al. 2011). Such structural changesare accompanied by extensive changes in components ofGABA neurotransmission (Beneyto and Lewis 2011) that couldcritically change the functional capacity to produce gammaoscillations. Parvalbumin (PV) fast-spiking cells are a subclassof GABA interneurons that, given their nonadapting firing andpostsynaptic GABA-A receptors that possess fast kinetics, cansupport sustained, high-frequency firing. These propertiesallow PV fast-spiking interneurons to play their critical role inthe temporal regulation of gamma oscillations through feed-back inhibitory coupling with pyramidal cells (Bartos et al.2007; Buzsaki and Wang 2012). Interestingly, during develop-ment, GABA-A receptors shift their subunit composition fromalpha-2 to alpha-1 subtypes, resulting in a shift from slower tofaster inhibitory decay kinetics (Hashimoto et al. 2009). Sincethe frequency of gamma oscillations depends critically on thedecay time course for inhibition (Bartos et al. 2007), such ashift could increasingly provide the means to support higherfrequency oscillations. This developmental shift also follows aprotracted temporal course, beginning postnatally and conti-nuing through to adulthood (Hashimoto et al. 2009). Thus,both structural refinements and molecular changes occur witha protracted course but exactly how these interact and give riseto physiologic changes over development in the form ofgamma oscillations requires explicit investigation.Steady-state responses to trains of periodic stimuli havebeen extensively used to examine oscillations in auditory,visual, and somatosensory modalities (Colon et al. 2012) andhave the advantage of a high signal-to-noise ratio (Vialatteet al. 2010). Auditory steady-state responses (ASSRs) havebeen used to study the development of gamma oscillations

The primary aim of the present research was to determine how stimulus-set and response-set components of task-set contribute to switch costs and conflict processing. Three experiments are described wherein participants completed an explicitly cued task-switching procedure. Experiment 1 established that task switches requiring a reconfiguration of both stimulus- and response-set incurred larger residual switch costs than task switches requiring the reconfiguration of stimulus-set alone. Between-task interference was also drastically reduced for response-set conflict compared with stimulus-set conflict. A second experiment replicated these findings and demonstrated that stimulus- and response-conflict have dissociable effects on the "decision time" and "motor time" components of total response time. Finally, a third experiment replicated Experiment 2 and demonstrated that the stimulus- and response- components of task switching and conflict processing elicit dissociable neural activity as evidence by event-related brain potentials.

Context-processing deficits have been shown in schizophrenia during first-episode, medication-naïve status, that persist after short-term antipsychotic treatment and also in first-degree relatives of individuals with schizophrenia. To confirm longer term persistence of deficits, we examined schizophrenia patients (n=63) during first-episode, medication-naïve status through to one-year follow-up, compared to healthy control (n=83) and non-schizophrenia psychosis comparison (n=47) groups, as well as unaffected first-degree relatives of individuals with schizophrenia (n=31). Context-processing ability assessed by performance on the AX-CPT (Continuous Performance Test) at baseline, 8 weeks, 6 months, and 1 year (relatives only at baseline). Reaction time, error rates and signal detection indices (d′-context) of context processing were analyzed. Linear discriminant analyses (LDA) on early timepoints (baseline, 8 weeks) were conducted to predict confirmatory diagnosis (schizophrenia vs. psychosis control) at 6 months. Schizophrenia patients showed evidence of impaired context-processing relative to both the healthy and psychosis comparator groups at baseline and continued through to 1 year. While context-processing impairments persisted in schizophrenia patients through one year, the impairments in psychosis controls, which were more modest at baseline, remitted at follow-up. First-degree relatives showed deficits that were intermediate between the schizophrenia and healthy control groups. LDA showed 67% classification rates for distinguishing schizophrenia from non-schizophrenia psychosis. The persistence, diagnostic specificity and association with genetic liability give support for context processing impairments serving as a cognitive endophenotype for schizophrenia and that evaluation of context processing could contribute to diagnostic assessments.

Dopamine modulates cortical circuit activity in part through its actions on GABAergic interneurons, including increasing the excitability of fast-spiking interneurons. Though such effects have been demonstrated in single cells, there are no studies that examine how such mechanisms may lead to the effects of dopamine at a neural network level. With this motivation, we investigated the effects of dopamine on synchronization in a simulated neural network composed of excitatory and fast-spiking inhibitory Wang-Buzsaki neurons. The effects of dopamine were implemented through varying leak K+ conductance of the fast-spiking interneurons and the network synchronization within the gamma band (∼40 Hz) was analyzed. Parametrically varying the leak K+ conductance revealed an inverted-U shaped relationship, with low gamma band power at both low and high conductance levels and optimal synchronization at intermediate conductance levels. We also examined the effects of modulating excitability of the inhibitory neurons more generically using an idealized model with theta neurons, with similar findings. Moreover, such a relationship holds when the external input is both tonic and periodic. Our computational results mirror our empirical study of dopamine modulation in schizophrenia and healthy controls, which showed that amphetamine administration increased gamma power in patients but decreased it in controls. Together, our computational and empirical investigations indicate that dopamine can modulate cortical gamma band synchrony in an inverted-U fashion and that the physiologic effects of dopamine on single fast-spiking interneurons can give rise to such non-monotonic effects at the network level.

Evidence indicates that synchronization of cortical activity at gamma-band frequencies, mediated through GABA-A receptors, is important for perceptual/cognitive processes. To study GABA signaling in vivo, we recently used a novel positron emission tomography (PET) paradigm measuring the change in binding of the benzodiazepine (BDZ) site radiotracer [(11)C]flumazenil associated with increases in extracellular GABA induced via GABA membrane transporter (GAT1) blockade with tiagabine. GAT1 blockade resulted in significant increases in [(11)C]flumazenil binding potential (BPND) over baseline in the major functional domains of the cortex, consistent with preclinical studies showing that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands. In the current study we sought to replicate our previous results and to further validate this approach by demonstrating that the magnitude of increase in [(11)C]flumazenil binding observed with PET is directly correlated with tiagabine dose. [(11)C]flumazenil distribution volume (VT) was measured in 18 healthy volunteers before and after GAT1 blockade with tiagabine. Two dose groups were studied (n = 9 per group; Group I: tiagabine 0.15 mg/kg; Group II: tiagabine 0.25 mg/kg). GAT1 blockade resulted in increases in mean (± SD) [(11)C]flumazenil VT in Group II in association cortices (6.8 ± 0.8 mL g-1 vs. 7.3 ± 0.4 mL g-1;p = 0.03), sensory cortices (6.7 ± 0.8 mL g-1 vs. 7.3 ± 0.5 mL g-1;p = 0.02) and limbic regions (5.2 ± 0.6 mL g-1 vs. 5.7 ± 0.3 mL g-1;p = 0.03). No change was observed at the low dose (Group I). Increased orbital frontal cortex binding of [(11)C]flumazenil in Group II correlated with the ability to entrain cortical networks (r = 0.67, p = 0.05) measured via EEG during a cognitive control task. These data provide a replication of our previous study demonstrating the ability to measure in vivo, with PET, acute shifts in extracellular GABA.

Previous research suggests that synchronous cortical gamma-band oscillations reflect the implementation of cognitive control in anticipation of the need to overcome prepotent responses. These studies often require participants to link task instructions with task cues signaling the need (or lack thereof ) for cognitive control. Thus, the oscillatory response elicited by these cues may also reflect the implementation of explicit task instructions. The aim of this research was to determine whether gamma-band oscillations would also be increased in preparation for cognitive control when the need for that control was only made implicitly available to the participant. Using a task-ambiguous cue to indicate the position of a subsequent probe stimulus, we manipulated the need for cognitive control by varying the probability of high- and low-control probes appearing in each of two positions. Results show that participants developed the anticipated expectancies regarding probe identity in the two positions and that the anticipation of a high-control probe was associated with an increase in the power of induced cortical gamma band over frontal scalp recording sites.

Multiscale entropy (MSE) analysis is a novel entropy-based approach for measuring dynamical complexity in physiological systems over a range of temporal scales. To evaluate this analytic approach as an aid to elucidating the pathophysiologic mechanisms in schizophrenia, we examined MSE in EEG activity in drug-naïve schizophrenia subjects pre- and post-treatment with antipsychotics in comparison with traditional EEG analysis. We recorded eyes-closed resting state EEG from frontal, temporal, parietal and occipital regions in drug-naïve 22 schizophrenia and 24 age-matched healthy control subjects. Fifteen patients were re-evaluated within 2–8 weeks after the initiation of antipsychotic treatment. For each participant, MSE was calculated on one continuous 60 second epoch for each experimental session. Schizophrenia subjects showed significantly higher complexity at higher time scales (lower frequencies), than that of healthy controls in fronto-centro-temporal, but not in parieto-occipital regions. Post-treatment, this higher complexity decreased to healthy control subject levels selectively in fronto-central regions, while the increased complexity in temporal sites remained higher. Comparative power analysis identified spectral slowing in frontal regions in pre-treatment schizophrenia subjects, consistent with previous findings, whereas no antipsychotic treatment effect was observed. In summary, multiscale entropy measures identified abnormal dynamical EEG signal complexity in anterior brain areas in schizophrenia that normalized selectively in fronto-central areas with antipsychotic treatment. These findings show that entropy-based analytic methods may serve as a novel approach for characterizing and understanding abnormal cortical dynamics in schizophrenia, and elucidating the therapeutic mechanisms of antipsychotics.

Goal-directed behavior requires cognitive control to effect online adjustments in response to ongoing processing demands. How signaling for these adjustments occurs has been a question of much interest. A basic question regarding the architecture of the cognitive control system is whether such signaling for control is specific to task context or generalizes across contexts. In this study, the authors explored this issue using a stimulus–response compatibility paradigm. They examined trial-to-trial adjustments, specifically, the findings that incompatible trials elicit improved performance on subsequent incompatible trials and that responses are slower after errors. The critical question was, Do such control effects—typically observed within a single task context—occur across task contexts? The paradigm involved 2 orthogonal, stimulus–response sets: Stimuli in the horizontal direction mapped only to responses in the horizontal direction, and likewise for the vertical direction. Cues indicated that either compatible (same direction as stimulus) or incompatible (opposite to stimulus) responses were required. The results showed that trial-to-trial adjustments exist for both direction-repeat and direction-switch trials, demonstrating that signaling for control adjustments can extend beyond the task context within which they arise.

A critical component of cognitive impairments in schizophrenia can be characterized as a disturbance in cognitive control, or the ability to guide and adjust cognitive processes and behavior flexibly in accordance with one's intentions and goals. Cognitive control impairments in schizophrenia are consistently linked to specific disturbances in prefrontal cortical functioning, but the underlying neurophysiologic mechanisms are not yet well characterized. Synchronous gamma-band oscillations have been associated with a wide range of perceptual and cognitive processes, raising the possibility that they may also help entrain prefrontal cortical circuits in the service of cognitive control processes. In the present study, we measured induced gamma-band activity during a task that reliably engages cognitive control processes in association with prefrontal cortical activations in imaging studies. We found that higher cognitive control demands were associated with increases in induced gamma-band activity in the prefrontal areas of healthy subjects but that control-related modulation of prefrontal gamma-band activity was absent in schizophrenia subjects. Disturbances in gamma-band activity in patients correlated with illness symptoms, and gamma-band activity correlated positively with performance in control subjects but not in schizophrenia patients. Our findings may provide a link between previously reported postmortem abnormalities in thalamofrontocortical circuitry and alterations in prefrontal activity observed in functional neuroimaging studies. They also suggest that deficits in frontal cortical gamma-band synchrony may contribute to the cognitive control impairments in schizophrenia.

The dorsolateral prefrontal cortex and the anterior cingulate cortex are critical components of the brain circuitry underlying executive control. The objective of this study was to investigate control-related dorsolateral prefrontal cortex functioning and conflict-related anterior cingulate cortex functioning in a group of never medicated first-episode schizophrenia patients to determine whether both regions show dysfunction at illness onset. A second objective was to assess short-term effects of atypical antipsychotic medication on dorsolateral prefrontal cortex and anterior cingulate cortex functioning.First-episode schizophrenia patients (N=23) and healthy comparison subjects (N=24) underwent event-related fMRI and performed a cognitive task designed to functionally dissociate the two regions. Four weeks after initiation of pharmacotherapy for patients, a subset of 11 patients and 16 comparison subjects underwent a repeat assessment.At baseline, patients exhibited hypoactivation in the dorsolateral prefrontal cortex and anterior cingulate cortex. After 4 weeks of antipsychotic treatment, the patients demonstrated improved functioning in the anterior cingulate cortex but not in the dorsolateral prefrontal cortex.These findings confirm the presence of dorsolateral prefrontal cortex dysfunction early in the course of schizophrenia and suggest that anterior cingulate cortex functioning may be altered at illness onset as well. Results also suggest that anterior cingulate cortex functioning may be especially sensitive to remedial antipsychotic treatment effects. These findings are consistent with an emerging literature documenting short-term benefits of atypical antipsychotic medication for the neural circuitry underlying cognitive deficits in schizophrenia.

"Measurement and Treatment Research to Improve Cognition in Schizophrenia" or MATRICS is a National Institute of Mental Health (NIMH)--sponsored research effort to drive novel drug development for the treatment of cognitive impairments in schizophrenia. On September 9-10, 2004, MATRICS convened representatives from NIMH, academia, and industry for the final of a series of consensus-oriented conferences, with this meeting entitled "New Approaches to Assessing and Improving Cognition in Schizophrenia." In this article, we present a summary of the discussions that focused on functional neuroimaging and electrophysiology biomarkers, outlining the research priorities, which included developing further consensus regarding the cognitive processes that are critical to examine in schizophrenia and the paradigms to examine them, resolving issues of test-retest reliability and discrepant findings in the literature, and additional basic research regarding the methods before fully implementing these paradigms in drug trials. Also summarized are the relative advantages and disadvantages of the different approaches and varying perspectives among the participants regarding these tools. Our hope is that this report will help guide and further stimulate coordinated efforts among researchers, industry, and funding agencies in meeting the urgent need for novel pharmacotherapeutics for cognitive impairments in schizophrenia and useful neurobiological indexes for tracking the resulting improvements in cognitive function.

Conflict monitoring by the anterior cingulate cortex (ACC) has been posited to signal a need for greater cognitive control, producing neural and behavioral adjustments. However, the very occurrence of behavioral adjustments after conflict has been questioned, along with suggestions that there is no direct evidence of ACC conflict-related activity predicting subsequent neural or behavioral adjustments in control. Using the Stroop color-naming task and controlling for repetition effects, we demonstrate that ACC conflict-related activity predicts both greater prefrontal cortex activity and adjustments in behavior, supporting a role of ACC conflict monitoring in the engagement of cognitive control.

There has been accumulating evidence that cognitive control can be adaptively regulated by monitoring for processing conflict as an index of online control demands. However, it is not yet known whether top-down control mechanisms respond to processing conflict in a manner specific to the operative task context or confer a more generalized benefit. While previous studies have examined the taskset-specificity of conflict adaptation effects, yielding inconsistent results, control-related performance adjustments following errors have been largely overlooked. This gap in the literature underscores recent debate as to whether post-error performance represents a strategic, control-mediated mechanism or a nonstrategic consequence of attentional orienting. In the present study, evidence of generalized control following both high conflict correct trials and errors was explored in a task-switching paradigm. Conflict adaptation effects were not found to generalize across tasksets, despite a shared response set. In contrast, post-error slowing effects were found to extend to the inactive taskset and were predictive of enhanced post-error accuracy. In addition, post-error performance adjustments were found to persist for several trials and across multiple task switches, a finding inconsistent with attentional orienting accounts of post-error slowing. These findings indicate that error-related control adjustments confer a generalized performance benefit and suggest dissociable mechanisms of post-conflict and post-error control.

We extended perceptual studies of the Brodatz set of textured materials. In the experiments, texture perception for different texture sets, viewing distances, or lighting intensities was examined. Subjects compared one pair of textures at a time. The main task was to rapidly rate all of the texture pairs on a number scale for their overall dissimilarities first and then for their dissimilarities according to six specified attributes (e.g., texture contrast). The implied dimensionality of perceptual texture space was usually at least four, rather than three. All six attributes proved to be useful predictors of overall dissimilarity, especially coarseness and regularity. The novel attribute texture lightness, an assessment of mean surface reflectance, was important when viewing conditions were wide-ranging. We were impressed by the general validity of texture judgments across subject, texture set, and comfortable viewing distances or lighting intensities. The attributes are nonorthogonal directions in four-dimensional perceptual space and are probably not narrow linear axes. In a supplementary experiment, we studied a completely different task: identifying textures from a distance. The dimensionality for this more refined task is similar to that for rating judgments, so our findings may have general application.

Background: All currently available atypical antipsychotics have, at clinically relevant doses: i) high serotonin (5-HT) 2 occupancy; ii) greater 5-HT 2 than dopamine (D) 2 occupancy; and iii) a higher incidence of extrapyramidal side effects when their D 2 occupancy exceeds 80%. A review of pharmacologic and behavioral data suggested that amoxapine should also conform to this profile; therefore, we undertook a positron-emission tomography (PET) study of its 5-HT 2 and D 2 occupancy. Methods: Seven healthy volunteers received 50–250 mg/day of amoxapine for 5 days and then had [ 11 C]-raclopride and [ 18 F]-setoperone PET scans. Results: 5-HT 2 receptors showed near saturation at doses of 100 mg/day and above. The D 2 receptor occupancies showed a dose-dependent increase, never exceeding 80%; at all doses 5-HT 2 occupancy exceeded D 2 occupancy. Conclusions: PET data show that amoxapine's profile is very similar to that of the established atypical antipsychotics. These data, together with amoxapine's in vitro pharmacologic profile, effectiveness in animal models, and efficacy in psychotic depression raise the possibility of amoxapine as an "atypical" antipsychotic agent in the treatment of schizophrenia.

5-HT 2A receptors on platelet membranes are often measured as indirect markers of the central 5-HT 2A receptors. However, the 5-HT 2A receptors on the platelets and those in the brain have never been assessed simultaneously in humans. The purpose of this study was to evaluate the relationship between platelet membrane and neocortical 5-HT 2A receptors measured simultaneously in normal healthy volunteers. Twelve healthy volunteers had the 5-HT 2A receptors on their platelet membranes assessed in vitro using [ 3 H]lysergic acid diethylamide ([ 3 H]LSD) and their central 5-HT 2A receptors measured in vivo using [ 18 F]setoperone and positron emission tomography (PET) imaging. We find no significant correlation between the binding potential ( B max / K d ) of 5-HT 2A receptors on platelets and in brain in the same individual ( F 1,10 =0.7, P =0.42). The study was limited by a small sample and the fact the two different ligands were used (i.e. LSD for platelets and setoperone for brain); nonetheless, the findings suggest that changes in platelet 5-HT 2A receptors may not indicate similar changes in central 5-HT 2A receptors.