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Neuroimaging plays a crucial role in understanding brain structure and function, but the lack of transparency, reproducibility, and reliability of findings is a significant obstacle for the field. To address these challenges, there are ongoing efforts to develop reporting checklists for neuroimaging studies to improve the reporting of fundamental aspects of study design and execution. In this review, we first define what we mean by a neuroimaging reporting checklist and then discuss how a reporting checklist can be developed and implemented. We consider the core values that should inform checklist design, including transparency, repeatability, data sharing, diversity, and supporting innovations. We then share experiences with currently available neuroimaging checklists. We review the motivation for creating checklists and whether checklists achieve their intended objectives, before proposing a development cycle for neuroimaging reporting checklists and describing each implementation step. We emphasize the importance of reporting checklists in enhancing the quality of data repositories and consortia, how they can support education and best practices, and how emerging computational methods, like artificial intelligence, can help checklist development and adherence. We also highlight the role that funding agencies and global collaborations can play in supporting the adoption of neuroimaging reporting checklists. We hope this review will encourage better adherence to available checklists and promote the development of new ones, and ultimately increase the quality, transparency, and reproducibility of neuroimaging research.

A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 205 demographically diverse cases with a psychotic disorder who underwent comprehensive psychiatric and neurological phenotyping and 115 matched controls. Following genotyping, we calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if overall genetic risk can be partitioned into affected neurotransmitter pathways, we calculated pathway PGSs (pPGSs) for SZ risk affecting each of four major neurotransmitter systems: glutamate, GABA, dopamine, and serotonin. Psychosis subjects had elevated SZ PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association within psychosis cases between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were moderately associated with specific endophenotypes; notably, glutamate was associated with SZ diagnosis and with deficits in cognitive control during task-based fMRI, while dopamine was associated with global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. All clusters showed strong genome-wide risk. Cluster 2, characterized by deficits in cognitive control and negative symptoms, additionally showed specific risk concentrated in glutamatergic and GABAergic pathways. Due to the intensive characterization of our subjects, the present study was limited to a relatively small cohort. As such, results should be followed up with additional research at the population and mechanism level. Our study suggests pathway-based PGS analysis may be a powerful path forward to study genetic mechanisms driving psychiatric endophenotypes.

Maternal infection has emerged as an important environmental risk factor for neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Animal model systems of maternal immune activation (MIA) suggest that the maternal immune response plays a significant role in the offspring’s neurodevelopment and behavioral outcomes. Extracellular free water is a measure of freely diffusing water in the brain that may be associated with neuroinflammation and impacted by MIA. The present study evaluates the brain diffusion characteristics of male rhesus monkeys (Macaca mulatta) born to MIA-exposed dams (n= 14) treated with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the end of the first trimester (n= 10) or were untreated (n= 4). Offspring underwent diffusion MRI scans at 6, 12, 24, 36, and 45 months. Offspring born to MIA-exposed dams showed significantly increased extracellular free water in cingulate cortex gray matter starting as early as 6 months of age and persisting through 45 months. In addition, offspring gray matter free water in this region was significantly correlated with the magnitude of the maternal IL-6 response in the MIA-exposed dams. Significant correlations between brain volume and extracellular free water in the MIA-exposed offspring also indicate converging, multimodal evidence of the impact of MIA on brain development. These findings provide strong evidence for the construct validity of the nonhuman primate MIA model as a system of relevance for investigating the pathophysiology of human neurodevelopmental psychiatric disorders. Elevated free water in individuals exposed to immune activation in utero could represent an early marker of a perturbed or vulnerable neurodevelopmental trajectory.

Objective: 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 (GABAA) receptors containing [[alpha].sub.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.sub.A] receptors containing [[alpha].sub.2] subunits would improve cognitive function and gamma band oscillations in individuals with schizophrenia. Method: 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.sub.A] receptors containing [[alpha].sub.2] or [[alpha].sub.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. Results: 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. Conclusions: These findings provide preliminary support for the hypothesis that enhanced GABA activity at [alpha]2 subunit containing GABAA receptors improves behavioral and electrophysiological measures of prefrontal function in individuals with schizophrenia.

Objective: Although deficits in cognitive control are thought to contribute to the diverse cognitive and behavioral abnormalities in individuals with schizophrenia, the neural mechanisms underlying these deficits remain unclear. In this event-related functional magnetic resonance imaging (fMRI) study, the authors tested the hypothesis that during cognitive control tasks, impaired activation of the dorsolateral prefrontal cortex in schizophrenia patients is associated with disrupted coordinated activity between this prefrontal region and a distributed brain network that supports cognitive control. Method: Through the use of an event-related design, 25 patients with first-episode schizophrenia and 24 healthy comparison subjects, matched on demographic characteristics, were assessed while performing a version of the AX continuous performance task. Functional neuroimaging data were analyzed using 1) univariate (region-of-interest blood-oxygen-level-dependent [BOLD] time series and whole brain voxel-wise regression) analysis to confirm the presence of dorsolateral prefrontal cortex dysfunction and 2) multivariate analysis to examine dorsolateral prefrontal cortex functional connectivity. In addition, correlations between dorsolateral prefrontal cortex functional connectivity and the following variables were investigated: clinical symptoms, task performance, and coordinated brain activity associated with cognitive control. Results: Schizophrenia patients exhibited a specific deficit in cognitive control, with significantly reduced accuracy in the BX condition relative to any other condition. Univariate fMRI revealed dorsolateral prefrontal cortex dysfunction during the high cognitive control condition. Multivariate analysis revealed significant impairment in functional connectivity between the dorsolateral prefrontal cortex and task-relevant brain regions. Significant correlations were also found between dorsolateral prefrontal cortex functional connectivity and cognitive performance, behavioral disorganization, and global functioning. Conclusions: These findings suggest that there is an association between decreased dorsolateral prefrontal cortex activity and connectivity and a task-related neural network. This deficit in coordinated brain activity may result in the disabling disorganization symptoms related to impaired cognition in individuals with schizophrenia.

Objective: In controlled treatment trials, 40%-60% of unmedicated depressed individuals respond to cognitive behavior therapy (CBT). The authors examined whether pretreatment neural reactivity to emotional stimuli accounted for this variation Method: Unmedicated depressed individuals (N=14) and never depressed comparison subjects (N=21) underwent fMRI during performance of a task sensitive to sustained emotional information processing. Afterward, depressed participants completed 16 sessions of CBT. Results: Participants whose sustained reactivity to emotional stimuli was low in the subgenual cingulate cortex (Brodmann's area 25) and high in the amygdala displayed the strongest improvement with CBT. Conclusions: The presence of emotion regulation disruptions, which are targeted in CBT, may be the key to recovery with this intervention.

Objective: 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. Method: 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. Results: 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. Conclusions: 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.

Objective: People with schizophrenia have exhibited reduced functional activity in the anterior cingulate cortex during the performance of many types of cognitive tasks and during the commission of errors. According to conflict theory, the anterior cingulate cortex is involved in the monitoring of response conflict, acting as a signal for a need for greater cognitive control. This study examined whether impaired conflict monitoring in people with schizophrenia could underlie reduced anterior cingulate activity during both correct task performance and error-related activity. Method: Functional activity in the anterior cingulate of 13 schizophrenia patients and 13 healthy comparison subjects was investigated by using event-related fMRI and a Stroop task that allowed simultaneous examination of activity during both conflict (incongruent trials) and error (commission of error trials). Results: In the presence of comparable reaction time measures for conflict as well as comparable error rates, the schizophrenia subjects showed both decreased conflict-and error-related activity in the same region of the anterior cingulate cortex. Moreover, those with schizophrenia did not exhibit significant post-conflict or post-error behavioral adjustments. Conclusions: Concurrently reduced conflict-and error-related activity in the anterior cingulate cortex along with reduced trial-to-trial adjustments in performance has not previously been reported in schizophrenia. The current results suggest that impaired conflict monitoring by the anterior cingulate cortex might play an important role in contributing to cognitive control deficits in patients with schizophrenia.

Objective: Context processing is a cognitive construct associated with activity in the middle frontal gyrus. Schizophrenia-related deficits in context processing tasks have been associated with prefrontal cortical dysfunction. This study evaluated whether prefrontal cortical dysfunction related to context processing occurred in first-episode, never-medicated schizophrenia patients, whether this dysfunction also occurred in patients with nonschizophrenia psychosis, and whether this dysfunction was related to psychotic symptom expression. Method: A modified version of the AX continuous performance task was conducted during event-related functional magnetic resonance imaging in 18 never-medicated, first-episode schizophrenia patients, 12 never-medicated patients with first-episode nonschizophrenia psychosis, and 28 comparison participants without psychiatric disorder. Results: In-scanner measures of errors and interference reaction time showed that the schizophrenia patients had a specific deficit in context processing. Trials with greater context processing demands corresponded to activity in the middle frontal gyrus (Brodmann's area 9) in the comparison subjects and in the patients with nonschizophrenia psychosis, but not in the schizophrenia patients. Individual differences in prefrontal cortical dysfunction were associated with context processing measures and disorganization symptoms. The schizophrenia patients also showed increased activity in the anterior (Brodmann's area 10) and inferior prefrontal cortices (Brodmann's area 45/46) when they were maintaining context over a delay. Conclusions: Prefrontal dysfunctions related to context processing were found only in schizophrenia patients early in the course of the illness, and these dysfunctions were related to disorganization symptoms. Instead of using context processing during a continuous performance task, schizophrenia patients may use an inefficient encoding and retrieval strategy.

Kraepelin, in his early descriptions of schizophrenia (SZ), characterized the illness as having “an orchestra without a conductor.” Kraepelin further speculated that this “conductor” was situated in the frontal lobes. Findings from multiple studies over the following decades have clearly implicated pathology of the dorsolateral prefrontal cortex (DLPFC) as playing a central role in the pathophysiology of SZ, particularly with regard to key cognitive features such as deficits in working memory and cognitive control. Following an overview of the cognitive mechanisms associated with DLPFC function and how they are altered in SZ, we review evidence from an array of neuroscientific approaches addressing how these cognitive impairments may reflect the underlying pathophysiology of the illness. Specifically, we present evidence suggesting that alterations of the DLPFC in SZ are evident across a range of spatial and temporal resolutions: from its cellular and molecular architecture, to its gross structural and functional integrity, and from millisecond to longer timescales. We then present an integrative model based upon how microscale changes in neuronal signaling in the DLPFC can influence synchronized patterns of neural activity to produce macrocircuit-level alterations in DLPFC activation that ultimately influence cognition and behavior. We conclude with a discussion of initial efforts aimed at targeting DLPFC function in SZ, the clinical implications of those efforts, and potential avenues for future development.

Objective: The authors examined brain activity associated with the internal monitoring of performance to test the hypothesis that error-related activity in the anterior cingulate cortex is impaired in patients with schizophrenia. Method: Seventeen patients with schizophrenia and 16 healthy comparison subjects underwent event-related functional magnetic resonance imaging during a continuous performance task; stimulus degradation was used to increase error rates. Results: Comparison subjects, but not schizophrenic patients, showed error-related activity in the anterior cingulate cortex, and this difference in brain activity was significantly different across the two groups. Patients also showed less slowing of reaction time after error commission. Conclusions: Lower error-related activity in the anterior cingulate cortex and less performance adjustment after error commission are consistent with the hypothesis that disturbances in anterior cingulate cortex function are related to a specific alteration in an evaluative component of executive functioning--the internal monitoring of performance. (Am J Psychiatry 2001; 158:1423-1428)

People with schizophrenia (SZ) exhibit impaired episodic memory when relating objects to each other in time and space. Empirical studies and computational models suggest that low-frequency neural oscillations may be a mechanism by which the brain keeps track of temporal relationships during encoding and retrieval, with modulation of oscillatory power as sequences are learned. It is unclear whether sequence memory deficits in SZ are associated with altered neural oscillations.

Noncardiac chest pain poses a common diagnostic challenge that contributes substantially to morbidity and health care costs. A careful evaluation is required to make an accurate, cost-effective diagnosis. Noncardiac chest [...]

Objective: Attentional deficits are a prominent aspect of cognitive dysfunction in schizophrenia. The anterior cingulate gyrus is proposed to be an important component of frontal attentional control systems. Structural and functional abnormalities have been reported in this region in schizophrenia, but their relationship to attentional deficits is unknown. The authors investigated the function of the anterior cingulate gyrus and the related neural systems that are associated with selective attention in patients with schizophrenia. Method: While subjects performed multiple blocks of a single-trial Stroop task, [15O]H2O positron emission tomography scans were obtained. Fourteen patients with schizophrenia were compared with 15 normal subjects matched for age, gender, and parental education. Results: The patients with schizophrenia responded at the same rate but made more errors in color naming during the color-incongruent condition. Consistent with the authors' hypothesis, patients with schizophrenia showed significantly less anterior cingulate gyrus activation while naming the color of color-incongruent stimuli. Conclusions: Patients with schizophrenia fail to activate the anterior cingulate gyrus during selective attention performance. This finding adds to the understanding of the functional significance of the structural and metabolic abnormalities in schizophrenia that have been previously reported in this region of the brain.

Objective: This study was designed to clarify the nature of the reduced function of the peripheral Beta adrenoreceptor system observed in panic disorder with agoraphobia. The authors hypothesized that this phenomenon reflected a regulatory and adaptive process. Method: Lymphocyte Beta adrenoreceptor density and affinity, basal lymphocyte cAMP level, and isoproterenol-stimulated cAMP generation were measured in 27 untreated outpatients with panic disorder with agoraphobia and 24 healthy comparison subjects. Lymphocyte Beta receptor attributes were again assessed in patients after 4 weeks of double-blind treatment with adinazolam (slow-release form) or placebo. Panic frequency, agoraphobic symptoms, overall anxiety, and improvement with treatment were assessed with standard rating instruments. Results: Multivariate statistics revealed significantly lower Beta receptor density and isoproterenol-stimulated cAMP generation in patients than in comparison subjects. Beta receptor density tended to normalize after adinazolam but not after placebo. Pretreatment Beta receptor density was lower in treatment responders than nonresponders. Patients with mild agoraphobia had lower cAMP responsivity than patients with moderate or severe agoraphobia. Conclusions: Decreased function of lymphocyte Beta receptors in panic disorder with agoraphobia is expressed as both decreased density and decreased cAMP responsivity. This pattern of changes, and the tendency for receptor density to normalize with treatment, is consistent with an active, regulatory process rather than a structural deficit in the Beta receptor system. Preliminary clinical findings suggest that these changes may reflect adaptive processes associated with a favorable clinical course in panic disorder with agoraphobia.

Blunted and exaggerated neuronal response to rewards are hypothesized to be core features of schizophrenia spectrum disorders (SZ) and bipolar disorder (BD), respectively. Nonetheless, direct tests of this hypothesis, in which response between SZ and BD is compared in the same study, are lacking. Here we examined the functional correlates of reward processing during the Incentivized Control Engagement Task (ICE-T) using 3T fMRI. Reward-associated activation was examined in 49 healthy controls (HCs), 52 recent-onset individuals with SZ, and 22 recent-onset individuals with Type I BD using anterior cingulate (ACC), anterior insula, and ventral striatal regions of interest. Significant group X reward condition (neutral vs. reward) interactions were observed during reward anticipation in the dorsal ACC (F(2,120) = 4.21, P= 0.017) and right insula (F(2,120) = 4.77, P= 0.010). The ACC interaction was driven by relatively higher activation in the BD group vs. HCs (P= 0.007) and vs. individuals with SZ (P= 0.010). The insula interaction was driven by reduced activation in the SZ group relative to HCs (P= 0.018) and vs. people with BD (P= 0.008). A composite of reward anticipation-associated response across all associated ROIs also differed significantly by diagnosis (F(1,120) = 5.59, P= 0.02), BD > HC > SZ. No effects of group or group X reward interactions were observed during reward feedback. These results suggest that people with SZ and BD have opposite patterns of activation associated with reward anticipation but not reward receipt. Implications of these findings in regard to Research Domain Criteria-based classification of illness and the neurobiology of reward in psychosis are discussed.

People with psychosis and mood disorders experience disruptions in working memory; however, the underlying mechanism remains unknown. We focused on 2 potential mechanisms: first, poor attentional engagement should be associated with elevated levels of prestimulus alpha-band activity within the electroencephalogram (EEG), whereas impaired working memory encoding should be associated with reduced poststimulus alpha suppression.

Evidence has been accumulating for an immune-based component to the etiology of psychotic disorders. Advancements in diffusion magnetic resonance imaging (MRI) have enabled estimation of extracellular free water (FW), a putative biomarker of neuroinflammation. Furthermore, inflammatory processes may be associated with altered brain levels of metabolites, such as glutathione (GSH). Consequently, we sought to test the hypotheses that FW is increased and associated with decreased GSH in patients with first-episode schizophrenia (SZ) compared with healthy controls (HC). SZ (n= 36) and HC (n= 40) subjects underwent a multi-shell diffusion MRI scan on a Siemens 3T scanner. 1H-MR spectroscopy data were acquired using a GSH-optimized MEGA-PRESS editing sequence and GSH/creatine ratios were calculated for DLPFC (SZ: n= 33, HC: n= 37) and visual cortex (SZ: n= 29, HC: n= 35) voxels. Symptoms and functioning were measured using the SANS, SAPS, BPRS, and GSF/GRF. SZ demonstrated significantly elevated FW in whole-brain gray (p= .001) but not white matter (p= .060). There was no significant difference between groups in GSH in either voxel. However, there was a significant negative correlation between DLPFC GSH and both whole-brain and DLPFC-specific gray matter FW in SZ (r = –.48 and –.47, respectively; both p< .05), while this relationship was nonsignificant in HC and in both groups in the visual cortex. These data illustrate an important relationship between a metabolite known to be important for immune function—GSH—and the diffusion extracellular FW measure, which provides additional support for these measures as neuroinflammatory biomarkers that could potentially provide tractable treatment targets to guide pharmacological intervention.

The goal of this study was to use transcranial direct current stimulation (tDCS) to examine the role of the prefrontal cortex (PFC) in neural oscillatory activity associated with proactive cognitive control in schizophrenia. To do so, we tested the impact of PFC-targeted tDCS on behavioral and electrophysiological markers of proactive cognitive control engagement in individuals with schizophrenia. Using a within-participants, double-blinded, sham-controlled crossover design, we recorded EEG while participants with schizophrenia completed a proactive cognitive control task (the Dot Pattern Expectancy (DPX) Task), after receiving 20 min of active prefrontal stimulation at 2 mA or sham stimulation. We hypothesized that active stimulation would enhance proactive cognitive control, leading to changes in behavioral performance on the DPX task and in activity in the gamma frequency band during key periods of the task designed to tax proactive cognitive control. The results showed significant changes in the pattern of error rates and increases in EEG gamma power as a function of tDCS condition (active or sham), that were indicative of enhanced proactive cognitive control. These findings, considered alongside our previous work in healthy adults, provides novel support for the role gamma oscillations in proactive cognitive control and they suggest that frontal tDCS may be a promising approach to enhance proactive cognitive control in schizophrenia.

Objective: Hypofrontality is a common but not invariable finding in schizophrenia. Inconsistencies in the literature may reflect, in part, the fact that abnormal physiological responses in the prefrontal cortex are best identified under conditions that place well-specified functional demands on this region. Method: The authors studied eight patients with schizophrenia and eight matched comparison subjects using [[15.sub.O]][H.sub.2]O positron emission tomography and the 'N-back' task, which activates the prefrontal cortex as a function of working memory load in normal subjects. Results: Under low-working-memory-load conditions, the accuracy of both groups in the N-back task was equal, but when the memory load increased, the patients' performance deteriorated more than did that of the comparison subjects. The regional cerebral blood flow response to increased working memory load was significantly reduced in the patients' right dorsolateral prefrontal cortex. Conclusions: These results confirm the importance of using tasks that tap specific cognitive functions, linked to specific neural systems, in studies of brain-behavior relationships in schizophrenia. Hypofrontality is reliably demonstrated in schizophrenia during tasks that engage working memory functions of the prefrontal cortex.

Transcranial direct current stimulation (tDCS) is a promising method for altering the function of neural systems, cognition, and behavior. Evidence is emerging that it can also influence psychiatric symptomatology, including major depression and schizophrenia. However, there are many open questions regarding how the method might have such an effect, and uncertainties surrounding its influence on neural activity, and human cognition and functioning. In the present critical review, we identify key priorities for future research into major depression and schizophrenia, including studies of the mechanism(s) of action of tDCS at the neuronal and systems levels, the establishment of the cognitive impact of tDCS, as well as investigations of the potential clinical efficacy of tDCS. We highlight areas of progress in each of these domains, including data that appear to favor an effect of tDCS on neural oscillations rather than spiking, and findings that tDCS administration to the prefrontal cortex during task training may be an effective way to enhance behavioral performance. Finally, we provide suggestions for further empirical study that will elucidate the impact of tDCS on brain and behavior, and may pave the way for efficacious clinical treatments for psychiatric disorders.

The National Institutes of Health has established the PhenX Toolkit as a web-based resource containing consensus measures freely available to the research community. The National Institute of Mental Health (NIMH) has introduced the Mental Health Research Core Collection as part of the PhenX Toolkit and recently convened the PhenX Early Psychosis Working Group to generate the PhenX Early Psychosis Specialty Collection. The Working Group consisted of two complementary panels for clinical and translational research. We review the process, deliberations, and products of the translational research panel. The Early Psychosis Specialty Collection rationale for measure selection as well as additional information and protocols for obtaining each measure are available on the PhenX website (https://www.phenxtoolkit.org). The NIMH strongly encourages investigators to use instruments from the PhenX Mental Health Research Collections in NIMH-funded studies and discourages use of alternative measures to collect similar data without justification. We also discuss some of the potential advances that can be achieved by collecting common data elements across large-scale longitudinal studies of early psychosis.

ABSTRACTThis study examined the effects of stimulation targeting dorsolateral prefrontal cortex (DLPFC) on behavioral and neural oscillatory markers of proactive cognitive control in healthy adults. We hypothesized that active stimulation targeting the DLPFC would enhance proactive control compared to sham, leading to changes in the pattern of error rates and gamma-band power on the Dot Pattern Expectancy (DPX) task. We recorded EEG while participants completed the DPX, after receiving either 20 minutes of active DLPFC stimulation at 2 mA or sham stimulation in a counterbalanced within-participants design. The results showed significant tDCS-induced changes in the pattern of error rates on the DPX task indicative of enhanced proactive control, as well as predicted increases in gamma power associated with the engagement of proactive control. These results provide support for the role of DLPFC-mediated gamma activity in proactive cognitive control, and further, indicate that proactive control can be enhanced with non-invasive neurostimulation.

Objective: The dorsolateral prefrontal cortex has been implicated in both working memory and the pathophysiology of schizophrenia. A relationship among dorsolateral prefrontal cortex activity, working memory dysfunction, and symptoms in schizophrenia has not been firmly established, partly because of generalized cognitive impairments in patients and task complexity. Using tasks that parametrically manipulated working memory load, the authors tested three hypotheses: 1) patients with schizophrenia differ in prefrontal activity only when behavioral performance differentiates them from healthy comparison subjects, 2) dorsolateral prefrontal cortex dysfunction is associated with poorer task performance, and 3) dorsolateral prefrontal cortex dysfunction is associated with cognitive disorganization but not negative or positive symptoms. Method: Seventeen conventionally medicated patients with schizophrenia and 16 healthy comparison subjects underwent functional magnetic resonance imaging while performing multiple levels of the 'n-back' sequential-letter working memory task. Results: Patients with schizophrenia showed a deficit in physiological activation of the right dorsolateral prefrontal cortex (Brodmann's area 46/9) in the context of normal task-dependent activity in other regions, but only under the condition that distinguished them from comparison subjects on task performance. Patients with greater dorsolateral prefrontal cortex dysfunction performed more poorly. Dorsolateral prefrontal cortex dysfunction was selectively associated with disorganization symptoms. Conclusions: These results are consistent with the hypotheses that working memory dysfunction in patients with schizophrenia is caused by a disturbance of the dorsolateral prefrontal cortex and that this disturbance is selectively associated with cognitive disorganization. Further, the pattern of behavioral performance suggests that dorsolateral prefrontal cortex dysfunction does not reflect a deficit in the maintenance of stimulus representations per se but points to deficits in more associative components of working memory. (Am J Psychiatry 2001; 158:1105-1113)

In recent years, the boundaries of psychopathology as defined by diagnostic categories have been criticized as inadequately ‘carving nature at its joints’ with respect to the neurobiology of major mental disorders. In 2010 the NIMH launched the Research Domain Criteria (RDoC) framework for understanding mental illnesses as brain circuit disorders that extend beyond DSM-defined diagnoses. In the present study we focus on cognitive dysfunction, a core feature of schizophrenia (SZ) and bipolar disorder (BPD), and use functional magnetic resonance imaging (fMRI) during a cognitive control (CC) task in recent onset patients to test the hypothesis that at a behavioral and underlying neural circuitry level these deficits exist on a continuum (as opposed to showing categorical differences) across the two disorders. In total, 53 healthy controls, 24 recent (<1 y) onset patients with BPD Type I with psychotic features, and 70 recent onset patients with SZ performed the AX-Continuous Performance Task while undergoing event-related fMRI at 1.5 T. In addition to behavior task-associated response was examined in frontoparietal regions-of-interest. In an a priori contrast-based analysis, significant deficits across patient groups (vs controls) were observed on CC-associated performance as well as frontoparietal response. These analyses further revealed a continuum of deficits in which BPD showed intermediate levels of CC relative to controls and SZ. Poor CC was associated with poverty and disorganization symptoms across patient groups. These results support the hypothesis that CC dysfunction in BPD and SZ reflects a continuum of deficits that cuts across traditional, DSM-based classification. Implications for the neurobiology of these diseases are discussed.

Epidemiological studies suggest that maternal immune activation (MIA) is a significant risk factor for future neurodevelopmental disorders, including schizophrenia (SZ), in offspring. Consistent with findings in SZ research and work in rodent systems, preliminary cross-sectional findings in nonhuman primates suggest that MIA is associated with dopaminergic hyperfunction in young adult offspring.

The neurobiology of treatment-resistant schizophrenia (TRS) is poorly understood, and meta-analytic consensus regarding magnetic resonance spectroscopic profiles of glutamate, choline-containing compounds, myo-inositol, and other metabolites in the condition is lacking.

Dysfunctional cognitive control processes are now well understood to be core features of schizophrenia (SZ). A body of work suggests that the dorsolateral prefrontal cortex (DLPFC) plays a critical role in explaining cognitive control disruptions in SZ. Here, we examined relationships between DLPFC activation and drift rate (DR), a model-based performance measure that combines reaction time and accuracy, in people with SZ and healthy control (HC) participants.

Control-related cognitive processes such as rule selection and maintenance are associated with cortical oscillations in the gamma range, and modulated by catecholamine neurotransmission. Control-related gamma power is impaired in schizophrenia, and an understudied treatment target. It remains unknown whether pro-catecholamine pharmacological agents augment control-related gamma oscillations in schizophrenia. We tested the effects of 4-week fixed-dose daily adjunctive modafinil (MOD) 200 mg, in a randomized double-blind, placebo-controlled, parallel-groups design. Twenty-seven stable schizophrenia patients performed a cognitive control task during EEG, at baseline and after 4 weeks of treatment. EEG data underwent time-frequency decomposition with Morlet wavelets to determine power of 4–80 Hz oscillations. The modafinil group (n=14), relative to placebo group (n=13), exhibited enhanced oscillatory power associated with high-control rule selection in the gamma range after treatment, with additional effects during rule maintenance in gamma and sub-gamma ranges. MOD-treated patients who exhibited improved task performance with treatment also showed greater treatment-related delay period gamma compared with MOD-treated patients without improved performance. This is the first evidence in schizophrenia of augmentation of cognition-related gamma oscillations by an FDA-approved agent with therapeutic potential. Gamma oscillations represent a novel treatment target in this disorder, and modulation of catecholamine signaling may represent a viable strategy at this target.

Abstract.Background:Suicide is prevalent in schizophrenia (SZ), yet the neural system functions that confer suicide risk remain obscure. Circuits operated by the prefrontal cortex (PFC) are altered in SZ, including those that support reactive control, and PFC changes are observed in postmortem studies of heterogeneous suicide victims. Aims:We tested whether history of suicide attempt is associated with altered frontal motor cortex activity during reactive control processes. Method:We evaluated 17 patients with recent onset of DSM-IV-TR-defined SZ using the Columbia Suicide Severity Rating Scale and functional magnetic resonance imaging during Stroop task performance. Group-level regression models relating past suicidal behavior to frontal activation controlled for depression, psychosis, and impulsivity. Results:Past suicidal behavior was associated with relatively higher activation in the left-hemisphere supplementary motor area (SMA), pre-SMA, premotor cortex, and dorsolateral PFC, all ipsilateral to the active primary motor cortex. Conclusion:This study provides unique evidence that suicidal behavior in patients with recent-onset SZ directly relates to frontal motor cortex activity during reactive control, in a pattern reciprocal to the relationship with proactive control found previously. Further work should address how frontal-based control functions change with risk over time, and their potential utility as a biomarker for interventions to mitigate suicide risk in SZ.

Female coho salmon Oncorhynchus kisutchwere fed one of two broodstock diets during vitellogenesis to evaluate the contribution of dietary lipids to egg lipids and to assess any embryo or fry quality differences that were attributable to treatment. The diets contained lipids with different fatty acid profiles and carbon stable isotope signatures (d13C). Diets were formulated by top-dressing a low-fat salmon broodstock feed with either sardine oil (fish oil feed) or an algal oil–corn oil blend (algal oil feed). The added oils were balanced for total n-3 fatty acid content but contained markedly different levels of linoleic acid (LA), eicosapentaenoic acid, and docosahexaenoic acid (DHA). Analysis of d13C revealed that dietary lipids were significantly incorporated into egg lipids during vitellogenesis and that polar and neutral lipid fractions were equally affected. Eggs of fish in the algal oil treatment group had significantly higher levels of DHA and significantly lower protein content than the eggs of fish in the fish oil treatment group. Embryo survival and fry survival and growth were similar between the two treatment groups. Eggs from the algal oil treatment additionally had higher levels of LA, and there was evidence of direct elongation of LA to eicosadienoic acid (20:2[n-6]) and bioconversion of LA to arachidonic acid by the fish. Results from this experiment demonstrate the feasibility of increasing the DHA content of egg lipids in cultured salmonids without a concomitant decrease in egg or fry quality. The proposed enrichment would allow for the production of a value-added, high-DHA product for the cured roe market without reducing the value of eggs that are destined for the hatchery market.

Drug discovery and development in psychiatry is beset by many challenges, both those which are associated with the development process in general (and affecting all of medicine) and others, which are unique to psychiatry. Due to these factors, marginal progress has been achieved in the past as many features of serious mental illness remain untouched by existing treatments. Arguably, the most important of these drug targets is cognitive dysfunction, which strongly predicts clinical outcome in a number of major neuropsychiatric conditions. Therefore, a critical need exists for progress in the characterization of this and other targets for drug discovery and development. A key area, which is already showing promise, is the use of non-invasive functional neuroimaging to investigate both cognitive dysfunction and its remediation with novel agents. In this article, the authors describe the paradigmatic case of cognitive dysfunction in schizophrenia, and the prospects for using functional magnetic resonance imaging (fMRI) to investigate the effects of agents targeting cognition. The authors observe a number of advantages of this approach over other methodologies, as well as some significant issues to be resolved in the application of this technology. The authors propose that pharmaco-fMRI is emerging as a major tool to enhance the drug development process in order to bring truly novel treatments to patients with a range of neuropsychiatric disorders.

It has been hypothesized that the anterior cingulate cortex (ACC) contributes to cognition by detecting conflicts that might occur during information processing, to signal the need to engage top–down attentional processes. The present study was designed to investigate which levels of processing are being monitored by the ACC for the presence of conflict. Event-related fMRI was used to measure the response of the ACC during an interference task in which distracting information could be congruent, conflicting at the level of stimulus identification, or conflicting at the response level. Although both types of conflict caused reaction time interference, the fMRI data showed that the ACC is responsive only to response conflict, even when controlling for reaction times. These results suggest a highly specific contribution of the ACC to executive functions, through the detection of conflicts occurring at later or response-related levels of processing.

Using [O-15]-H2O PET Carter et al. (1997)reported that medicated patients with schizophrenia performing computerized single trial Stroop (1935)showed a reduction in the anterior cingulate activation response to the more attention demanding, incongruent Stroop condition. In that study, both patients and controls also showed a direct correlation between anterior cingulate activation and errors committed during incongruent trials of the task. In this study we follow up with an examination of paranoid schizophrenia outpatients and controls with very high resolution positron emission tomography (PET) and the longer half-life tracer [F-18]-fluorinated deoxyglucose (FDG) (Valk et al. 1990). All subjects (10 controls and 9 paranoid schizophrenia patients) were studied with FDG-PET while performing a computerized trial-by-trial version of the Stroop task during the uptake phase of the tracer (Carter et al. 1992). Results: As in previous studies using the single trial Stroop, patients were able to perform the task but made more color-naming errors during incongruent trials than controls. The patients in the present study showed a trend towards increased metabolic activity in the right anterior cingulate cortex. In the patient group, but not in controls, the anterior cingulate glucose metabolic rate correlated positively with the total incongruent trial errors. Conclusion: These results are consistent with the hypothesis that the anterior cingulate plays a performance-monitoring role during human cognition. This study does not rule out a reduction in error sensitivity in this region of the brain in schizophrenia, as other studies have suggested, however the data show that in unmedicated patients with the paranoid subtype this function is preserved to some extent.

This paper presents a pair of studies designed to empirically explore the severity of potential artifacts associated with overt verbal responding during fMRI scanning and to examine several different solutions to these artifacts. In Study One, we compared susceptibility artifacts, signal-to-noise ratios, and activation patterns when overt versus covert verbal responses were elicited during fMRI scanning, using both individual and group analyses. The results indicated that different patterns of brain activation were elicited during covert as compared to overt verbal responses. This suggests that covert responses cannot be used as a simple substitute for overt verbal responses. Further, the results suggested that the use of overt verbal responses during fMRI scanning can produce interpretable results if: (1) the primary comparison is between two conditions that both use overt verbal responses, and (2) analyses are conducted on pooled group data rather than individual participant data. In Study Two, we evaluated the feasibility and validity of a method for acquiring participants' overt responses during fMRI scanning. The results indicated that our method was very accurate in acquiring the content of participant's responses. Further, inspection of the responses demonstrated that participants do not always comply with task instructions and highlighted the importance of obtaining behavioral performance measures during fMRI scanning.

The success of the15O-water PET technique to localize statistically significant changes in regional cerebral blood flow is dependent on factors such as the activity level injected and the magnitude of the flow change. Undetectable changes may occur if insufficient activity is injected leading to high levels of statistical noise or the task performed results in only small changes in blood flow. To explore the relationship between injected activity and statistical significance, we performed a series of studies with the ECAT EXACT HR+, a high resolution PET tomograph. A parametric verbal working memory task (theN-back task) was selected to examine the relationship between regional cerebral blood flow and working memory load across a range of injected doses of15O-water. At each activity level the volunteers were required to perform four different levels of theN-back task, a task in which a letter displayed on a monitor is matched with the letter displayedNletters previously. With increasingN,this task places increased load on working memory. For this study, 5, 10, and 15 mCi of15O-water were injected into nine normal volunteers. The complete sequence of four tasks (N=0, 1, 2, and 3) at three activity levels was repeated twice, for a total of 24 injections of15O-water. We show that the peak count rate performance for the HR+ is approached at injected activity levels of15O-water around 15 mCi. For this particular choice ofN-back task, robust activation maps can nevertheless be obtained with as little as 5 mCi injected dose.

To investigate the functional anatomy of interference and facilitation during selective attention, we studied 15 normal subjects using the H₂¹⁵O positron emission tomography technique and a computer presented single-trial Stroop task for cognitive activation. Increases in regional cerebral blood flow (rCBF) were observed in a network of structures that have been previously associated with selective attention, including the anterior cingulate gyrus, the frontal polar cortex, the inferior parietal lobule, and the thalamus, as well as the lingual gyrus. Furthermore rCBF decreases (compared to control states) were observed in lateral extra-striate cortex. rCBF changes in prefrontal and extra-striate regions varied with differences in the need to modulate the influence of word and color information while subjects responded to either incongruent or congruent Stroop stimuli. These results indicate the utility of Stroop procedures for investigating the functional anatomy of selective attention. Given recent interest regarding the role of the anterior cingulate gyrus in the pathophysiology of neuropsychiatric disorders, our results also suggest that the Stroop task can serve as a reliable neurobehavioral probe for this region. The significance of these results for understanding processing mechanisms underlying selective attention is discussed within the framework of a parallel distributed processing model of Stroop task performance. Copyright 1995, 1999 Academic Press

Objectives: The objectives of the current study were to evaluate the prevalence of chest pain and related medical utilization in patients with generalized anxiety disorder and to investigate the possible relationship between the occurrence of chest pain in these patients and the episodes of excessive worry which characterize this disorder.Method: The presence of a history of chest pain in patients with generalized anxiety disorder was investigated in an outpatient psychiatric sample using a structured interview which also assessed related medical utilization and the relationship of chest pain to panic attacks and episodes of excessive worry.Results: Of fifty sequentially evaluated patients meeting DSM-IIIR criteria for G.A.D., twenty-four (48%) reported a history of chest pain. Seven of these patients also had a history of panic attacks, however, four of the seven reported that their pain occurred independently of their panic attacks. Sixteen patients with G.A.D. reported that their chest pain episodes were associated with episodes of excess worry. Eleven had sought medical evaluation for their pain. Patients with chest pain and normal coronary arteries are frequently found to have panic disorder. The pattern of utilization of medical care was comparable in this sample of patients with G.A.D. and a group of patients with panic disorder recruited in a similar manner.Conclusions: These results suggest that in addition to panic disorder, G.A.D. may also be a common diagnosis in chest pain patients with no demonstrable coronary disease. Future studies of coronary artery disease negative patients with chest pain should include assessments for the presence of G.A.D. Our results also suggest that chest pain may be a common symptom in G.A.D. The possibility that chest pain should be included in the diagnostic criteria for this disorder should be the subject of further investigation.

Background:A neural network computer model described in a companion paper predicted the effects of increased dopamine transmission on selective attention under two different hypotheses.

Background:Dopamine affects neural information processing, cognition, and behavior; however, the mechanisms through which these three levels of function are affected have remained unspecified. We present a parallel-distributed processing model of dopamine effects on neural ensembles that accounts for effects on human performance in a selective attention task.

Psychiatric diagnosis and treatment have historically taken a symptom-based approach, with less attention on identifying underlying symptom-producing mechanisms. Recent efforts have illuminated the extent to which different underlying circuitry can produce phenotypically similar symptomatology (e.g. psychosis in bipolar disorder vs schizophrenia). Computational modelling makes it possible to identify and mathematically differentiate behaviorally-unobservable, specific reinforcement-learning (RL) differences in schizophrenia (SZ) patients versus other disorders, likely due to a higher reliance on prediction-error(PE)-driven learning associated with basal ganglia, and under-reliance on explicit value representations associated with OFC.