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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cogpsych.2006.06.003 Byline: John R. Anderson (a), Yulin Qin (a), Kwan-Jin Jung (b), Cameron S. Carter (c) Keywords: Cognitive architecture; fMRI Abstract: This research uses fMRI to understand the role of eight cortical regions in a relatively complex information-processing task. Modality of input (visual versus auditory) and modality of output (manual versus vocal) are manipulated. Two perceptual regions (auditory cortex and fusiform gyrus) only reflected perceptual encoding. Two motor regions were involved in information rehearsal as well as programming of overt actions. Two cortical regions (parietal and prefrontal) performed processing (retrieval and representational change) independent of input and output modality. The final two regions (anterior cingulate and caudate) were involved in control of cognition independent of modality of input or output and content of the material. An information-processing model, based on the ACT-R theory, is described that predicts the BOLD response in these regions. Different modules in the theory vary in the degree to which they are modality-specific and the degree to which they are involved in central versus peripheral cognitive processes. Author Affiliation: (a) Psychology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA (b) Brain Imaging Research Center, University of Pittsburgh and Carnegie Mellon University, Pittsburgh, PA 15203, USA (c) Departments of Psychiatry and Psychology, University of California at Davis, Sacramento, CA 95817, USA Article History: Accepted 25 June 2006

Magnetic resonance spectroscopy studies measuring brain glutamate separately from glutamine are helping elucidate schizophrenia pathophysiology. An expanded literature and improved methodologies motivate an updated meta-analysis examining effects of measurement quality and other moderating factors in characterizing abnormal glutamate levels in schizophrenia. Searching previous meta-analyses and the MEDLINE database identified 83 proton magnetic resonance spectroscopy datasets published through March 25, 2020. Three quality metrics were extracted—Cramér–Rao lower bound (CRLB), line width, and coefficient of variation. Pooled effect sizes (Hedges' g) were calculated with random-effects, inverse variance-weighted models. Moderator analyses were conducted using quality metrics, field strength, echo time, medication, age, and stage of illness. Across 36 datasets (2086 participants), medial prefrontal cortex glutamate was significantly reduced in patients (g = −0.19, confidence interval [CI] = −0.07 to −0.32). CRLB and coefficient of variation quality subgroups significantly moderated this effect. Glutamate was significantly more reduced in studies with lower CRLB or coefficient of variation (g = −0.44, CI = −0.29 to −0.60, and g = −0.43, CI = −0.29 to −0.57, respectively). Studies using echo time ≤20 ms also showed significantly greater reduction in glutamate (g = −0.41, CI = −0.26 to −0.55). Across 11 hippocampal datasets, group differences and moderator effects were nonsignificant. Group effects in thalamus and dorsolateral prefrontal cortex were also nonsignificant. High-quality measurements reveal consistently reduced medial prefrontal cortex glutamate in schizophrenia. Stricter CRLB criteria and reduced nuisance variance may increase the sensitivity of future studies examining additional regions and the pathophysiological significance of abnormal glutamate levels in schizophrenia. [ABSTRACT FROM AUTHOR]

Imaging genomics is a new field of investigation that seeks to gain insights into the impact of human genetic variation on the structure, chemistry, and function of neural systems in health and disease. Because publications in this field have increased over the past decade, increasing concerns have been raised about false-positive results entering the literature. Here, we provide an overview of the field of imaging genomic and genetic approaches and discuss factors related to research design and analysis that can enhance the informativeness and replicability of these studies. We conclude that imaging genetic studies can provide important insights into the role of human genetic variation on neural systems and circuits, both in the context of normal quantitative variation and in relation to neuropsychiatric disease. We also argue that demonstrating genetic association to imaging-derived traits is subject to the same constraints as any other genetic study, including stringent type I error control. Adequately powered studies are necessary; however, there are currently limited data available to allow precise estimates of effect sizes for candidate gene studies. Independent replication is necessary before a result can be considered definitive, and for studies with small sample sizes it is necessary before publication. Increased transparency of methods and enhanced data sharing will further enhance replicability. [ABSTRACT FROM AUTHOR]

Individuals with schizophrenia exhibit problems in language comprehension that are most evident during discourse processing. We hypothesized that deficits in cognitive control contribute to these comprehension deficits during discourse processing, and investigated the underlying cognitive-neural mechanisms using EEG (alpha power) and ERPs (N400). N400 amplitudes to globally supported or unsupported target words near the end of stories were used to index sensitivity to previous context. ERPs showed reduced sensitivity to context in patients versus controls. EEG alpha-band activity was used to index attentional engagement while participants listened to the stories. We found that context effects varied with attentional engagement in both groups, as well as with negative symptom severity in patients. Both groups demonstrated trial-to-trial fluctuations in alpha. Relatively high alpha power was associated with compromised discourse processing in participants with schizophrenia when it occurred during any early portion of the story. In contrast, discourse processing was only compromised in controls when alpha was relatively high for longer segments of the stories. Our results indicate that shifts in attention from the story context may be more detrimental to discourse processing for participants with schizophrenia than for controls, most likely due to an impaired ability to benefit from global context. [ABSTRACT FROM AUTHOR]

Abstract: Exaggerated reactivity to food cues involving calorically-dense foods may significantly contribute to food consumption beyond caloric need. Chronic stress, which can induce palatable “comfort” food consumption, may trigger or reinforce neural pathways leading to stronger reactions to highly rewarding foods. We implemented functional magnetic resonance imaging (fMRI) to assess whether chronic stress influences activation in reward, motivation and executive brain regions in response to pictures of high calorie and low calorie foods in thirty women. On separate lab visits, we also assessed food intake from a snack food buffet and circulating cortisol. In women reporting higher chronic stress (HCS), pictures of high calorie foods elicited exaggerated activity in regions of the brain involving reward, motivation, and habitual decision-making. In response to pictures of high calorie food, higher chronic stress was also associated with significant deactivation in frontal regions (BA10; BA46) linked to strategic planning and emotional control. In functional connectivity analysis, HCS strengthened connectivity between amygdala and the putamen, while LCS enhanced connectivity between amygdala and the anterior cingulate and anterior prefrontal cortex (BA10). A hypocortisolemic signature and more consumption of high calorie foods from the snack buffet were observed in the HCS group. These results suggest that persistent stress exposure may alter the brain's response to food in ways that predispose individuals to poor eating habits which, if sustained, may increase risk for obesity. [Copyright &y& Elsevier]

Abstract: In classic Stroop paradigms, increasing the proportion of control-demanding incongruent trials results in strategic adjustments in behavior and implementation of cognitive control processes. We manipulated expectancy for incongruent trials in an emotional facial Stroop task to investigate the behavioral and neural effects of proportion manipulation in a cognitively demanding task with emotional stimuli. Subjects performed a high expectancy (HE) task (65% incongruent trials) and a low expectancy (LE) task (35% incongruent trials) during functional magnetic resonance imaging (fMRI). As in standard Stroop tasks, behavioral interference was reduced in the emotional facial Stroop HE task compared to the LE task. Functional MRI data revealed a switch in cognitive control strategy, from a reactive, event-related activation of a medial and lateral cognitive control network and right amygdala in the LE task to a proactive, sustained activation of right dorsolateral prefrontal cortex (DLPFC) in the HE task. Higher trait anxiety was associated with impairment (slower response time and decreased accuracy) as well as reduced activity in left ventrolateral prefrontal cortex, anterior insula, and orbitofrontal cortex in the HE task on high conflict trials with task-irrelevant emotional information, suggesting that individual differences in anxiety may be associated with expectancy-related strategic control adjustments, particularly when emotional stimuli must be ignored. [Copyright &y& Elsevier]

Schizophrenia is one of the most debilitating of all common brain disorders, exacting a heavy toll on the afflicted and having a tremendous public health impact. Clinical outcome is more strongly predicted by cognitive deficits than psychotic symptoms, with no established treatment for these deficits. In this review, we discuss the status of treatment development for impaired cognition in schizophrenia. These treatments include a range of pharmacological targets within diverse neurotransmitter systems. New technologies, including transcranial magnetic stimulation and transcranial direct current stimulation, and psychological therapies, such as computer-based cognitive training, may also benefit cognition in schizophrenia. Each of these approaches shows promise and their integration may optimize benefits for patients in the future. [ABSTRACT FROM AUTHOR]

The Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative, funded by an R13 from the National Institute of Mental Health, seeks to enhance translational research in treatment development for impaired cognition in schizophrenia by developing tools from cognitive neuroscience into useful measures of treatment effects on behavior and brain function. An initial series of meetings focused on the selection of a new set of tasks from cognitive neuroscience for the measurement of treatment effects on specific cognitive and neural systems. Subsequent validation and optimization studies are underway and a subset of validated measures with well-characterized psychometric properties will be generally available in 2011. This article describes results of the first meeting of the second phase of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia, which seeks to develop imaging biomarkers and improved animal models to enhance translational research. In this meeting, we considered issues related to the use of methods such as functional magnetic resonance imaging, electroencephalography, magnetoencephalography, and transcranial magnetic simulation as biomarkers for treatment development. We explored the biological nature of the signals measured by each method, their validity and reliability as measures of cognition-related neural activity, potential confounds related to drug effects on the signal of interest, and conceptual, methodological, and pragmatic issues related to their use in preclinical, first into human, and multicenter phase II and III studies. This overview article describes the background and goals of the meeting together with a summary of the major issues discussed in more detail in the accompanying articles appearing in this issue of Biological Psychiatry. [Copyright &y& Elsevier]

Abstract: Orbitofrontal cortical (OFC) dysfunction has been repeatedly involved in obsessive-compulsive disorder, but the precise significance of this abnormality is still unclear. Current neurocognitive models propose that specific areas of the OFC contribute to behavioral regulation by representing the anticipated affective value of future events. This leads to the hypothesis that these OFC areas are hyperactive in patients, reflecting ruminative preoccupation with future aversive events. In experimental situations, such hyperactivity should be triggered by negative affect in response to high likelihood of events such as the conflict between simultaneously active incompatible responses, which can potentially lead to poor task performance. We tested this hypothesis by examining fMRI indices of brain activity of 15 OCD patients and 15 matched controls. Subjects were scanned while performing a cognitive task which involved responding to cues and subsequent probes, and some of the probes elicited response conflict. Relative to controls, the lateral OFC of patients was specifically hyperactive to cues associated with high proportion of subsequent high-conflict probes. The level of OFC hyperactivity correlated directly with the severity of anxiety symptoms. These results support the hypothesis that OCD is characterized by exaggerated OFC representations of anticipated aversive events. [Copyright &y& Elsevier]

• Dorsolateral prefrontal cortex dysfunction is evident in recent onset schizophrenia. • Elevated choline-containing metabolites were observed in DLPFC in such patients. • Similar elevation of the 1H-MRS choline signal was observed in the visual cortex. • Increased choline may reflect membrane remodeling associated with neuroinflammation. A complete characterization of neurometabolite profiles in the dorsolateral prefrontal cortex (DLPFC) in recent onset schizophrenia (SZ) remains elusive. Filling in this knowledge gap is essential in order to better understand how the neurochemistry of this region contributes to SZ pathology. To that end, DLPFC N-acetyl aspartate (NAA), myo-inositol, glutamate, choline, and creatine levels were examined by 3 T magnetic resonance spectroscopy (MRS) in recent onset individuals with SZ (n = 40) and healthy controls (HC) (n = 47). Metabolite levels were also examined in the visual cortex (VC) as a control region. People with SZ showed significantly higher choline in both the DLPFC and VC, but no differences in NAA, myo-inositol, glutamate, or creatine in either region. A trend-level negative correlation was also observed between DLPFC NAA and negative symptoms in SZ. Our results suggest that choline is increased in both the prefrontal and occipital cortices in recent onset SZ, and that DLPFC NAA levels may be inversely related to negative symptoms in the illness. The observed increase in choline-containing compounds in both DLPFC and VC in recent onset SZ could reflect increased membrane remodeling such as occurs in activated microglia and astrocytes in response to neuroinflammation. [ABSTRACT FROM AUTHOR]

Objective: To characterize the functional neuroanatomy of late-life depression (LLD) by probing for both episodic and persistent alterations in the executive-control circuit of elderly adults. Design: Event-related functional magnetic resonance imaging (fMRI) data were collected while participants performed an executive-control task. Setting: Participants were recruited through a depression-treatment study within the Pittsburgh, PA, Intervention Research Center for Late-Life Mood Disorders. Participants: Thirteen nondepressed elderly comparison participants and 13 LLD patients. Intervention: The depressed patients underwent imaging before initiating and after completing 12 weeks of paroxetine. Measurements: Regional fMRI activity was assessed in the dorsolateral prefrontal cortex (dLPFC: BA9 and BA46 bilaterally) and the dorsal anterior cingulate cortex (dACC). Functional connectivity was assessed by correlating the fMRI time-series in the dLPFC and dACC. Results: Both depressed and comparison participants performed the task as expected, with greater response latency during high versus low-load trials. The response-latency load-effect did not differ between groups. In contrast to the null findings for behavioral data, pretreatment, depressed patients showed diminished activity in the dLPFC (BA46 left, t(25) = 1.9, p = 0.035) and diminished functional connectivity between the dLPFC and dACC. Moreover, right dLPFC (BA46 right, t(25) = 2.17, p <0.02) showed increased activity after treatment. Conclusions: These results support a model of both episodic and persistent neurobiologic components of LLD. The altered functional connectivity, perhaps due to vascular damage to frontal white matter, appears to be persistent. Further, at least some of the prefrontal hypoactivity (in the right dLPFC) seems to be an episodic characteristic of acute depression amenable to treatment. [ABSTRACT FROM AUTHOR]

With the widespread availability of functional magnetic resonance imaging (fMRI), there has been rapid progress in identifying neural correlates of cognition and emotion in the human brain. In conjunction with basic research studies, fMRI has been increasingly applied in clinical disorders, making it a central research tool in human psychopathology, psychopharmacology, and genetics. In the present article, we discuss a number of conceptual and methodological challenges that confront the implementation of fMRI in clinical and translational research, and we offer a set of recommendations intended to enhance the interpretability and reproducibility of results in clinical fMRI. [Copyright &y& Elsevier]

Abstract: Task switching is an important aspect of cognitive control and understanding its underlying mechanisms is the focus of considerable research. In this paper, we contrast two different kinds of task switching paradigms and provide evidence that different cognitive mechanisms underlie switching behavior depending on whether the switch is between sets of rules (rule switch) or sets of features presented simultaneously (perceptual switch). In two experiments, we demonstrate that behavioral effects (Experiment 1) and neural recruitment (Experiment 2) vary with the type of switch performed. While perceptual switch costs occurred when the alternative feature set was physically present, rule switch costs were observed even in their absence. Rule switching was also characterized by larger target repetition effects and by greater engagement of the dorsolateral prefrontal cortex. In contrast, perceptual switching was associated with greater recruitment of the parietal cortex. These results provide strong evidence for multiple forms of switching and suggest the limitations of generalizing results across shift types. [Copyright &y& Elsevier]

This overview describes the generation and development of the ideas that led to the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative. It also describes the organization, process, and products of the first meeting. The CNTRICS initiative involves a series of three conferences that will systematically address barriers to translating paradigms developed in the basic animal and human cognitive neuroscience fields for use in translational research aimed at developing novel treatments for cognitive impairments in schizophrenia. The articles in this special section report on the results of the first conference, which used a criterion-based consensus-building process to develop a set of cognitive constructs to be targeted for translation efforts. [Copyright &y& Elsevier]

Abstract: Recent research suggests that the primate orbitofrontal cortex (OFC) is critical for representations of outcomes of actions and their subsequent impact on the control of behavior. In parallel, a recent theory of decision-making called decision affect theory (Mellers, Schwartz, and Ritov, Psychological Science, 1997) emphasizes the role of anticipated affective impact of outcomes in guiding choices, and the effects of comparisons with alternative outcomes (i.e., counterfactual effects). In the context of decision affect theory, we present results from two event-related functional MRI experiments consistent with two hypotheses regarding the role of the human OFC in guiding behavior through outcome representation: (1) counterfactual effects are manifested in the human OFC during expectation of outcomes, such that the anticipated affective impact of outcomes is modulated by the nature of the various possible alternative outcomes; (2) a regional specialization exists in the human prefrontal cortex, such that affective impact of potential negative outcomes of actions is represented mainly by the lateral areas of the OFC, while areas situated progressively more medial and dorsal on the ventral and medial PFC are specifically involved in representing the impact of positively valenced outcomes. We also discuss some of the implications that these hypotheses have for neuroimaging studies of reward processing and decision-making, and for studies of neuropsychiatric disorders in which these processes are thought to be disturbed. [Copyright &y& Elsevier]

We propose that the anterior cingulate cortex (ACC) contributes to cognition by detecting the presence of conflict during information processing, and to alert systems involved in top-down control to resolve this conflict. Here, we review several functional magnetic resonance imaging (fMRI) and event-related potential (ERP) studies that have used simple response interference tasks, and propose that ACC activity is activated prior to the response during correct conflict trials and reflected in the frontocentral N2, and immediately following error trials and reflected in the error-related negativity (ERN). Furthermore, we suggest that certain disturbances in cognition and behavior in common mental disorders such as schizophrenia and obsessive-compulsive disorder (OCD) can be understood as resulting from alteration in performance monitoring functions associated with this region of the brain. [Copyright &y& Elsevier]

Previous studies have suggested that schizophrenia patients do not utilize contextual information efficiently to modulate attentional performance. The goal of the current study was to compare the utilization of context in modulating responses to irrelevant information on the Stroop task between a group of schizophrenia outpatients and matched controls. A single-trial version of the Stroop task was used to investigate performance on the Stroop task under three expectancy conditions. Eleven schizophrenia outpatients (on and off antipsychotic medication) and sixteen matched controls were tested. The schizophrenia patients showed: (1) augmented facilitation; (2) interference comparable to normals; and (3) normal ability to reduce interference under certain experimental circumstances. Schizophrenia patients were able to utilize contextual information under certain conditions and could modulate the magnitude of irrelevant word interference, although they were not able to overcome the prepotent tendency to read the word during the Stroop task as effectively as normals, which was reflected in greater Stroop facilitation. This suggests that the integrity or impairment of cognitive control functions in schizophrenia is related to the complexity of the context representation required to support that function. [Copyright &y& Elsevier]

Theories of psychotic illness suggest that abnormal intrinsic functional connectivity may explain its characteristic positive and disorganization symptoms as well as lead to impaired general functioning. Here we used resting state functional magnetic resonance imaging (fMRI) to evaluate associations between these symptoms and the degree to which global connectivity is abnormal in early psychosis (EP). Eighty-six healthy controls (HCs) and 108 individuals with EP with resting state fMRI data were included in primary analyses. The EP group included 83 participants with schizophrenia-spectrum disorders and 25 with bipolar disorder type I with psychotic features. A global intrinsic connectivity "similarity index" for each EP individual was determined by calculating its correlation with the average HC connectivity matrix extracted using Schaefer atlases of multiple parcellations (100, 200, 300, and 400 region parcellations). As hypothesized, connectivity similarity with the average HC matrix was negatively associated with Brief Psychiatric Rating Scale total score, Scale for the Assessment of Positive Symptoms total score, and disorganization symptoms. Similarity was also positively associated with Global Assessment of Functioning score. Results were not driven by sex or diagnosis effects and were consistent across parcellation schemes. These results support the hypothesis that changes in whole-brain connectivity patterns are associated with psychosis symptoms and support the use of functional connectivity as a biomarker for these symptoms in EP. • Intrinsic connectivity similarity vs. controls predicts lower symptoms in psychosis • Intrinsic connectivity similarity vs. controls predicts functioning in psychosis • Results were similar across various brain parcellation schemes [ABSTRACT FROM AUTHOR]