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Working memory engages multiple distributed brain networks to support goal-directed behavior and higher order cognition. Dysfunction in working memory has been associated with cognitive impairment in neuropsychiatric disorders. It is important to characterize the interactions among cortical networks that are sensitive to working memory load since such interactions can also hint at the impaired dynamics in patients with poor working memory performance. Functional connectivity is a powerful tool used to investigate coordinated activity among local and distant brain regions. Here, we identified connectivity footprints that differentiate task states representing distinct working memory load levels. We employed linear support vector machines to decode working memory load from task-based functional connectivity matrices in 177 healthy adults. Using neighborhood component analysis, we also identified the most important connectivity pairs in classifying high and low working memory loads. We found that between-network coupling among frontoparietal, ventral attention and default mode networks, and within-network connectivity in ventral attention network are the most important factors in classifying low vs. high working memory load. Task-based within-network connectivity profiles at high working memory load in ventral attention and default mode networks were the most predictive of load-related increases in response times. Our findings reveal the large-scale impact of working memory load on the cerebral cortex and highlight the complex dynamics of intrinsic brain networks during active task states.

Since 1998, the U.S. has mandated folic acid (FA) fortification of certain grain products to reduce the risk of neural tube defects. Folate intake and red blood cell (RBC) folate concentrations increased substantially post-intervention, although recent studies raise concerns about the level of ongoing benefit. This study investigated blood folate level determinants in healthy young adults, including intake of naturally occurring food folate, synthetic FA, and the interaction of naturally occurring food folate with a common missense variant in the FOLH1 gene thought to affect absorption. Participants (n = 265) completed the Diet History Questionnaire II, RBC folate testing, and were genotyped for the 484T>C FOLH1 variant. Men reported significantly greater intake of all folate sources except for supplemental FA, but RBC folate levels did not significantly differ by sex. Synthetic FA was a stronger predictor of RBC folate than naturally occurring food folate. In the largest racial group, synthetic FA and the interaction of FOLH1 genotype with naturally occurring food folate significantly predicted RBC folate, with the overall model accounting for 13.8% of the variance in RBC folate levels. Blood folate levels rely on a complex interaction of natural and synthetic folate intake as well as FOLH1 genotype.

Folic acid supplementation confers modest benefit in schizophrenia, but its effectiveness is influenced by common genetic variants in the folate pathway that hinder conversion to its active form. We examined physiological and clinical effects of l-methylfolate, the fully reduced and bioactive form of folate, in schizophrenia. In this randomized, double-blind trial, outpatients with schizophrenia (n=55) received l-methylfolate 15 mg or placebo for 12 weeks. Patients were maintained on stable doses of antipsychotic medications. The pre-defined primary outcome was change in plasma methylfolate at 12 weeks. Secondary outcomes included change in symptoms (Positive and Negative Syndrome Scale (PANSS), Scale for Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia), cognition (Measurement and Treatment Research to Improve Cognition in Schizophrenia composite) and three complementary magnetic resonance imaging measures (working memory-related activation, resting connectivity, cortical thickness). Primary, mixed model, intent-to-treat analyses covaried for six genetic variants in the folate pathway previously associated with symptom severity and/or response to folate supplementation. Analyses were repeated without covariates to evaluate dependence on genotype. Compared with placebo, l-methylfolate increased plasma methylfolate levels (d=1.00, P=0.0009) and improved PANSS Total (d=0.61, P=0.03) as well as PANSS Negative and General Psychopathology subscales. Although PANSS Total and General Psychopathology changes were influenced by genotype, significant PANSS Negative changes occurred regardless of genotype. No treatment differences were seen in other symptom rating scales or cognitive composite scores. Patients receiving l-methylfolate exhibited convergent changes in ventromedial prefrontal physiology, including increased task-induced deactivation, altered limbic connectivity and increased cortical thickness. In conclusion, l-methylfolate supplementation was associated with salutary physiological changes and selective symptomatic improvement in this study of schizophrenia patients, warranting larger clinical trials. ClinicalTrials.gov, NCT01091506.

Dopamine orchestrates changes in cortical network synchrony that underlie working memory, as revealed with simultaneous PET-MRI., Local prefrontal dopamine signaling supports working memory by tuning pyramidal neurons to task-relevant stimuli. Enabled by simultaneous positron emission tomography–magnetic resonance imaging (PET-MRI), we determined whether neuromodulatory effects of dopamine scale to the level of cortical networks and coordinate their interplay during working memory. Among network territories, mean cortical D1 receptor densities differed substantially but were strongly interrelated, suggesting cross-network regulation. Indeed, mean cortical D1 density predicted working memory–emergent decoupling of the frontoparietal and default networks, which respectively manage task-related and internal stimuli. In contrast, striatal D1 predicted opposing effects within these two networks but no between-network effects. These findings specifically link cortical dopamine signaling to network crosstalk that redirects cognitive resources to working memory, echoing neuromodulatory effects of D1 signaling on the level of cortical microcircuits.

Working memory (WM) impairment, a core feature of schizophrenia, is often associated with aberrant dorsolateral prefrontal cortex (dlPFC) activation. Reduced resting-state connectivity within the frontoparietal control network (FPCN) has also been reported in schizophrenia. However, interpretation of WM-related dlPFC dysfunction has been limited by performance differences between patients and controls, and by uncertainty over the relevance of resting-state connectivity to network engagement during task. We contrasted brain activation in 40 schizophrenia patients and 40 controls during verbal WM performance, and evaluated underlying functional connectivity during rest and task. During correct trials, patients demonstrated normal FPCN activation, despite an inverse relationship between positive symptoms and activation. FPCN activation differed between the groups only during error trials (controls>patients). In contrast, controls demonstrated stronger deactivation of the ventromedial prefrontal cortex (vmPFC) during correct and error trials. Functional connectivity analysis indicated impaired resting-state FPCN connectivity in patients, but normal connectivity during task. However, patients showed abnormal connectivity among regions such as vmPFC, lateral orbitofrontal cortex, and parahippocampal gyrus (PHG) during both rest and task. During task, patients also exhibited altered thalamic connectivity to PHG and FPCN. Activation and connectivity patterns that were more characteristic of controls generally correlated with better performance. In summary, patients demonstrated normal FPCN activation when they remained on-task, and exhibited normal FPCN connectivity during WM, whereas vmPFC deactivation differences persisted regardless of WM performance. Our findings suggest that altered FPCN activation in patients reflects performance difference, and that limbic and thalamic dysfunction is critically involved in WM deficits in schizophrenia.

Background: Psychodynamic psychotherapy has been used to treat depression for more than a century. However, not all patients respond equally well, and there are few reliable predictors of treatment outcome. Methods: We used resting 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) scans immediately before and after a structured, open trial of brief psychodynamic psychotherapy (n = 16) in conjunction with therapy process ratings and clinical outcome measures to identify neural correlates of treatment response. Results: Pretreatment glucose metabolism within the right posterior insula correlated with depression severity. Reductions in depression scores correlated with a pre- to posttreatment reduction in right insular metabolism, which in turn correlated with higher objective measures of patient insight obtained from videotaped therapy sessions. Pretreatment metabolism in the right precuneus was significantly higher in patients who completed treatment and correlated with psychological mindedness. Conclusions: Resting brain metabolism predicted both clinical course and relevant psychotherapeutic process during short-term psychodynamic psychotherapy for depression.

patients treated with stable doses of antipsychotics were randomly assigned to two groups that received an infusion of either sodium nitroprusside or placebo for four hours. Psychiatric symptoms were assessed at baseline and every hour during the infusion with the Brief Psychiatric Rating Scale (BPRS) and the negative subscale of the Positive and Negative Syndromes Scale (PANNS-n). Additional assessments were made 12 hours after the infusion, daily for seven days, and weekly for four weeks. Cognitive tests (Stroop Color Word Test, N-back, and FAS) were administered at baseline and 12 hours after the end of the infusion. No side effects were reported by the participants. All the clinical and demographic characteristics of the sample including age, education, duration of disease, gender, diagnostic subtype, and type of antipsychotic in use were matched across groups. Symptom ratings were significantly reduced in the group treated with sodium nitroprusside, but not in the placebo group. Cognitive performance was also significantly improved in the nitroprusside group compared to placebo. There were no significant differences between the two groups regarding the physiological parameters analyzed (systolic and diastolic blood pressure, cardiac rhythm, and oxygen saturation). The strategy of treating schizophrenia patients for four hours with 0,5 mcg/kg/min sodium nitroprusside improved psychopathology and cognitive function. Our findings support the hypothesis that the NMDA-NO-GMPc pathway is affected in schizophrenia and that nitric oxide donors such as sodium nitroprusside could thus be a promising approach in the management of the disorder. Although exciting, these results are preliminary and must be replicated by future studies.