Role In Mental Disorders Research Articles

Altered cortical synaptic lipid signaling leads to intermediate phenotypes of mental disorders.

Excitation/inhibition (E/I) balance plays important roles in mental disorders. Bioactive phospholipids like lysophosphatidic acid (LPA) are synthesized by the enzyme autotaxin (ATX) at cortical synapses and modulate glutamatergic transmission, and eventually alter E/I balance of cortical networks. Here, we analyzed functional consequences of altered E/I balance in 25 human subjects induced by genetic disruption of the synaptic lipid signaling modifier PRG-1, which were compared to 25 age and sex matched control subjects. Furthermore, we tested therapeutic options targeting ATX in a related mouse line. Using EEG combined with TMS in an instructed fear paradigm, neuropsychological analysis and an fMRI based episodic memory task, we found intermediate phenotypes of mental disorders in human carriers of a loss-of-function single nucleotide polymorphism of PRG-1 (PRG-1R345T/WT). Prg-1R346T/WT animals phenocopied human carriers showing increased anxiety, a depressive phenotype and lower stress resilience. Network analysis revealed that coherence and phase-amplitude coupling were altered by PRG-1 deficiency in memory related circuits in humans and mice alike. Brain oscillation phenotypes were restored by inhibtion of ATX in Prg-1 deficient mice indicating an interventional potential for mental disorders.

Comparing pregnancy and pregnancy outcome rates between adolescents with and without pre-existing mental disorders.

There are limited population-based data on the role of mental disorders in adolescent pregnancy, despite the presence of mental disorders that may affect adolescents' desires and decisions to become pregnant. This study aimed to examine the relationship between specific types of mental disorders and pregnancy rates and outcome types among adolescents aged 13-19 years, using single-year age groups. We conducted a retrospective cohort study using data from the Merative™ MarketScan Research Databases. The study population consisted of females aged 13-19 years with continuous insurance enrollment for three consecutive calendar years between 2005 and 2015. Pregnancy incidence rates were calculated both overall and within the different categories of mental disorders. The presence of mental disorders, identified through diagnosis codes, was classified into 15 categories. Pregnancy and pregnancy outcome types were determined using diagnosis and procedure codes indicating the pregnancy status or outcome. To address potential over- or underestimations of mental disorder-specific pregnancy rates resulting from variations in age distribution across different mental disorder types, we applied age standardization using 2010 U.S. Census data. Finally, multivariable logistic regression models were used to examine the relationships between 15 specific types of mental disorders and pregnancy incidence rates, stratified by age. The age-standardized pregnancy rate among adolescents diagnosed with at least one mental disorder was 15.4 per 1,000 person-years, compared to 8.5 per 1,000 person-years among adolescents without a mental disorder diagnosis. Compared to pregnant adolescents without a mental disorder diagnosis, those with a mental disorder diagnosis had a slightly but significantly higher abortion rate (26.7% vs 23.8%, P-value < 0.001). Multivariable logistic regression models showed that substance use-related disorders had the highest odds ratios (ORs) for pregnancy incidence, ranging from 2.4 [95% confidence interval (CI): 2.1-2.7] to 4.5 [95% CI:2.1-9.5] across different age groups. Overall, bipolar disorders (OR range: 1.6 [95% CI:1.4-1.9]- 1.8 [95% CI: 1.7-2.0]), depressive disorders (OR range: 1.4 [95% CI: 1.3-1.5]- 2.7 [95% CI: 2.3-3.1]), alcohol-related disorders (OR range: 1.2 [95% CI: 1.1-1.4]- 14.5 [95% CI: 1.2-178.6]), and attention-deficit/conduct/disruptive behavior disorders (OR range: 1.1 [95% CI: 1.0-1.1]- 1.8 [95% CI: 1.1-3.0]) were also significantly associated with adolescent pregnancy, compared to adolescents without diagnosed mental disorders of the same age. This study emphasizes the elevated rates of pregnancy and pregnancy ending in abortion among adolescents diagnosed with mental disorders, and identifies the particular mental disorders associated with higher pregnancy rates.

The truth is in there: Belief processes in the human brain.

Belief, defined by William James as the mental state or function of cognizing reality, is a core psychological function with strong influence on emotion and behavior. Furthermore, strong and aberrant beliefs about the world and oneself play important roles in mental disorders. The underlying processes of belief have been the matter of a long debate in philosophy and psychology, and modern neuroimaging techniques can provide insight into the underlying neural processes. Here, we conducted a functional magnetic resonance imaging study with N = 30 healthy participants in which we presented statements about facts, politics, religion, conspiracy theories, and superstition. Participants judged whether they considered them as true (belief) or not (disbelief) and reported their certainty in the decision. We found belief-associated activations in bilateral dorsolateral prefrontal cortex, left superior parietal cortex, and left lateral frontopolar cortex. Disbelief-associated activations were found in an anterior temporal cluster extending into the amygdala. We found a larger deactivation for disbelief than belief in the ventromedial prefrontal cortex that was most pronounced during decisions, suggesting a role of the vmPFC in belief-related decision-making. As a category-specific effect, we found disbelief-associated activation in retrosplenial cortex and parahippocampal gyrus for conspiracy theory statements. Exploratory analyses identified networks centered at anterior cingulate cortex for certainty, and dorsomedial prefrontal cortex for uncertainty. The uncertainty effect identifies a neural substrate for Alexander Bain's notion from 1859 of uncertainty as the real opposite of belief. Taken together, our results suggest a two-factor neural process model of belief with falsehood/veracity and uncertainty/certainty factors.

Diagnostic value and role of serum miR-15a-5p in patients with schizophrenia

BackgroundMore and more studies have confirmed that the heredity plays an important role in mental disorders, especially microRNA. The objective of this research was to explore the level of miR-15a-5p in patients with schizophrenia (SZ), and to evaluate the feasibility of this miRNA as a diagnostic marker of SZ.MethodsThe serum level of miR-15a-5p in patients with SZ and healthy people was detected by RT-qPCR. ROC curve was established to evaluate the clinical diagnostic significance of miR-15a-5p in SZ. Pearson correlation coefficient was used to evaluate the correlation between miR-15a-5p level and PANSS score. Logistic regression was used to assess the risk factors of SZ. A rat model of SZ was established, and the effects of miR-15a-5p on the behavior of SZ rats were observed through water maze test and open field test.ResultsThe serum level of miR-15a-5p in patients with SZ was significantly increased, and ROC analysis revealed that miR-15a-5p had clinical diagnostic value in SZ. High level of miR-15a-5p was positively correlated with the positive symptom, negative symptom and general psychopathology subscore of patients. Logistic regression results showed that miR-15a-5p was a risk factor affecting the occurrence of SZ. Animal studies showed that the serum level of miR-15a-5p was elevated in the SZ rats, and inhibiting the expression of miR-15a-5p has a positive effect on improving the cognitive function and anxiety behavior of SZ rats.ConclusionsSerum miR-15a-5p is a risk factor for SZ, which is of great significance for the diagnosis of SZ.

A conceptual framework on body representations and their relevance for mental disorders.

Many mental disorders are accompanied by distortions in the way the own body is perceived and represented (e.g., eating disorders, body dysmorphic disorder including muscle dysmorphia, or body integrity dysphoria). We are interested in the way these distortions develop and aim at better understanding their role in mental health across the lifespan. For this purpose, we first propose a conceptual framework of body representation that defines this construct and integrates different perspectives (e.g., cognitive neuroscience, clinical psychology) on body representations. The framework consists of a structural and a process model of body representation emphasizing different goals: the structural model aims to support researchers from different disciplines to structure results from studies and help collectively accumulate knowledge about body representations and their role in mental disorders. The process model is reflecting the dynamics during the information processing of body-related stimuli. It aims to serve as a motor for (experimental) study development on how distorted body representations emerge and might be changed. Second, we use this framework to review the normative development of body representations as well as the development of mental disorders that relate to body representations with the aim to further clarify the potential transdiagnostic role of body representations.

The Association between Nonsuicidal Self-Injury and Perfectionism in Adolescence: The Role of Mental Disorders.

Previous evidence has drawn attention to the fact that maladaptive perfectionism is a risk factor for engagement in nonsuicidal self-injury (NSSI). Until now, few studies have examined this topic, especially among community adolescents. The aim of this study was to explore the relationship between perfectionism dimensions and NSSI functions to examine the potential mediating effect of mental disorders. Altogether, 146 Hungarian community adolescents (ages 13-18 years) were involved. All participants completed the Hungarian adaptation of the Inventory of Statements about Self-Injury (ISAS), the Frost Multidimensional Perfectionism Scale (FMPS), and the Mini International Neuropsychiatric Interview Kid. To analyse the interrelationships among NSSI, perfectionism, and mental disorders, we conducted regression and network analysis. Of the 146 adolescents, 90 (61.64%, girls: 71.11%) engaged in NSSI. The Concern over Mistakes and Doubts about Action scales of the FMPS significantly and positively predicted both NSSI intrapersonal and interpersonal motivation, with comparable effect sizes, and this association was fully mediated by anxiety disorders. There was a significant direct negative relationship between the FMPS Organisation dimension and both main NSSI functions. This study draws attention to an increasing trend and the extremely high NSSI prevalence rate among community adolescents. Adolescents with perfectionistic concerns are at heightened risk for anxiety disorders, which can increase their vulnerability to NSSI engagement.

To What Extent Do Sleep and Psychological Treatment of Lucid Dream Therapy Play an Effective Role in Mental Disorders?

Sleep is such a complex and dynamic process and dream that it still is a scientific enigma. Over more than a century of research has established a wide range of dream-relevant theories, whereas, no one has yet reached an accurate conclusion about the function and meaning of dreams. So, in this project, I desire to review the relationship between sleep and dream and illustrate what is the function of sleep and dream. Firstly, is to state the specific processes of sleep. Humans undergo REM (Rapid Eye Movement) and NREM (non-rapid-eye-movement) during sleep. Additionally, there are various functions of REM, NREM sleep, and dreams which remain controversial. The third ambition of this project is to discuss whether dreams can act as a kind of therapy for mental disorders. And evaluate the effectiveness of lucid dreaming therapy (LDT) in patients suffering from mental disorders.

Downregulation of FTO in the hippocampus is associated with mental disorders induced by fear stress during pregnancy

Mental disorders (MD), such as anxiety, depression, and cognitive impairment, are very common during pregnancy and predispose to adverse pregnancy outcomes; however, the underlying mechanisms are still under intense investigation. Although the most common RNA modification in epigenetics, N6-methyladenosine (m6A) has been widely studied, its role in MD has not been investigated. Here, we observed that fat mass and obesity-associated protein (FTO) are downregulated in the hippocampus of pregnant rats with MD induced by fear stress and demonstrated that FTO participates in and regulates MD induced by fear stress. In addition, we identified four genes with anomalous modifications and expression (double aberrant genes) that were directly regulated by FTO, namely Angpt2, Fgf10, Rpl21, and Adcy7. Furthermore, we found that these genes might induce MD by regulating the PI3K/Akt and Rap1 signaling pathways. It appears that FTO-mediated m6A modification is a key regulatory mechanism in MD caused by fear stress during pregnancy.

The critical role of gut-brain axis microbiome in mental disorders.

The Gut-brain axis is a bidirectional neural and humoral signaling that plays an important role in mental disorders and intestinal health and connects them as well. Over the past decades, the gut microbiota has been explored as an important part of the gastrointestinal tract that plays a crucial role in the regulation of most functions of various human organs. The evidence shows several mediators such as short-chain fatty acids, peptides, and neurotransmitters that are produced by the gut may affect the brain's function directly or indirectly. Thus, dysregulation in this microbiome community can give rise to several diseases such as Parkinson's disease, depression, irritable bowel syndrome, and Alzheimer's disease. So, the interactions between the gut and the brain are significantly considered, and also it provides a prominent subject to investigate the causes of some diseases. In this article, we reviewed and focused on the role of the largest and most repetitive bacterial community and their relevance with some diseases that they have mentioned previously.

Human neural network activity reacts to gravity changes in vitro.

During spaceflight, humans experience a variety of physiological changes due to deviations from familiar earth conditions. Specifically, the lack of gravity is responsible for many effects observed in returning astronauts. These impairments can include structural as well as functional changes of the brain and a decline in cognitive performance. However, the underlying physiological mechanisms remain elusive. Alterations in neuronal activity play a central role in mental disorders and altered neuronal transmission may also lead to diminished human performance in space. Thus, understanding the influence of altered gravity at the cellular and network level is of high importance. Previous electrophysiological experiments using patch clamp techniques and calcium indicators have shown that neuronal activity is influenced by altered gravity. By using multi-electrode array (MEA) technology, we advanced the electrophysiological investigation covering single-cell to network level responses during exposure to decreased (micro-) or increased (hyper-) gravity conditions. We continuously recorded in real-time the spontaneous activity of human induced pluripotent stem cell (hiPSC)-derived neural networks in vitro. The MEA device was integrated into a custom-built environmental chamber to expose the system with neuronal cultures to up to 6 g of hypergravity on the Short-Arm Human Centrifuge at the DLR Cologne, Germany. The flexibility of the experimental hardware set-up facilitated additional MEA electrophysiology experiments under 4.7 s of high-quality microgravity (10-6 to 10-5 g) in the Bremen drop tower, Germany. Hypergravity led to significant changes in activity. During the microgravity phase, the mean action potential frequency across the neural networks was significantly enhanced, whereas different subgroups of neurons showed distinct behaviors, such as increased or decreased firing activity. Our data clearly demonstrate that gravity as an environmental stimulus triggers changes in neuronal activity. Neuronal networks especially reacted to acute changes in mechanical loading (hypergravity) or de-loading (microgravity). The current study clearly shows the gravity-dependent response of neuronal networks endorsing the importance of further investigations of neuronal activity and its adaptive responses to micro- and hypergravity. Our approach provided the basis for the identification of responsible mechanisms and the development of countermeasures with potential implications on manned space missions.

Approach-Bias Retraining and Other Training Interventions as Add-On in the Treatment of AUD Patients.

In the past two decades, a variety of cognitive training interventions have been developed to help people overcome their addictive behaviors. Conceptually, it is important to distinguish between programs in which reactions to addiction-relevant cues are trained (varieties of cognitive bias modification, CBM) and programs in which general abilities are trained such as working memory or mindfulness. CBM was first developed to study the hypothesized causal role in mental disorders: by directly manipulating the bias, it was investigated to what extent this influenced disorder-relevant behavior. In these proof-of-principle studies, the bias was temporarily modified in volunteers, either temporarily increased or decreased, with corresponding effects on behavior (e.g., beer consumption), in case the bias was successfully manipulated. In subsequent clinical randomized controlled trials (RCTs), training (away from the substance vs. sham training) was added to clinical treatment. These studies have demonstrated that CBM, as added to treatment, reduces relapse with a small effect of about 10% (similar effect size as for medication, with the strongest evidence for approach-bias modification). This has not been found for general ability training (e.g., working memory training), although effects on other psychological functions have been found (e.g., impulsivity). Mindfulness also has been found to help people overcome addictions, and different from CBM, also as stand-alone intervention. Research on (neuro-)cognitive mechanisms underlying approach-bias modification has pointed to a new perspective in which automatic inferences rather than associations are influenced by training, which has led to the development of a new variety of training: ABC training.

ADRA2B and HTR1A: An Updated Study of the Biogenic Amine Receptors Reveals Novel Conserved Motifs Which Play Key Role in Mental Disorders.

Mental disorders are strongly connected with several psychiatric conditions including depression, bipolar disorder, schizophrenia, eating disorder, and suicides. There are many biological conditions and pathways that define these complicated illnesses. For example, eating disorders are complex mental health conditions that require the intervention of geneticists, psychiatrists, and medical experts in order to alleviate their symptoms. A patient with suicidal ideation should first be identified and consequently monitored by a similar team of specialists. Both genetics and epigenetics can shed light on eating disorders and suicides as they are found in the main core of such investigations. In the present study, an analysis has been performed on two specific members of the GPCR family toward drawing conclusions regarding their functionality and implementation in mental disorders. Specifically, evolutionary and structural studies on the adrenoceptor alpha 2b (ADRA2B) and the 5-hydroxytryptamine receptor 1A (HTR1A) have been carried out. Both receptors are classified in the biogenic amine receptors sub-cluster of the GPCRs and have been connected in many studies with mental diseases and malnutrition conditions. The major goal of this study is the investigation of conserved motifs among biogenic amine receptors that play an important role in this family signaling pathway, through an updated evolutionary analysis and the correlation of this information with the structural features of the HTR1A and ADRA2B. Furthermore, the structural comparison of ADRA2B, HTR1A, and other members of GPCRs related to mental disorders is performed.

Prevalence of Depression in Patients with Oral Lichen Planus Referred to Isfahan Dental School

Introduction: Oral lichen planus is a relatively common chronic autoimmune and inflammatory disease in which altered cellular mediated immune response plays a major role in its pathogenesis. Among the possible factors influencing development of oral lichen planus, the role of mental disorders, especially depression and anxiety, has been discussed in pathogenesis of this disease. Therefore, the aim of this study was to investigate the prevalence of depression in patients with oral lichen planus referred to the dental clinic of Isfahan University in year 2018-2019.&#x0D; Materials &amp; Methods: In the present case-control study, 40 patients with oral lichen planus referred to the dental clinic of Isfahan University in 2018-2019 (case group) and 40 subjects without oral lichen planus (control group) were investigated. Next, the Beck Depression Inventory (BDI) was completed by all subjects. Finally, the obtained data were analyzed using statistical software.&#x0D; Results: The obtained results indicated that the average age in case group (43.53 years) was lower than the control group (44.68 years). In addition, the mean for depression in case group (12.78) was higher than control group (9.5), however, this difference was not statistically significant (p value &gt; 0.05).&#x0D; Conclusion: In general, this study indicated the role of depression in the pathogenesis of oral lichen planus. It was noted that high levels of depression can be an initiation point for various autoimmune reactions and oral lichen planus.

Does contemporary Western culture play a role in mental disorders?

Does contemporary Western culture play a role in mental disorders?

Mental disorders as an indication for surgical treatment of drug-resistant temporal lobe epilepsy.

This study recruited 82 patients with temporal lobe epilepsy (TLE): 41 men and 41 women, who underwent an open epilepsy surgery to remove the epileptic focus from 1963 to 1970. The patients before surgery were divided into two groups: group I included 49 patients with minor mental disorders and group II included 33 patients with major mental disorders. Features of mental disorders in patients with monotemporal lobe epilepsy were identified. The significance of mental disorders for topical diagnosis of the epileptic focus has been emphasized. The course of mental disorders in patients with TLE after open surgery for epileptic focus removal was carefully monitored. The role of mental disorders as an indication for surgical treatment of TLE has been shown. The patients were followed up for 14±6years.

Incomplete homicide-suicide in Hunan China from 2010 to 2019: characteristics of surviving perpetrators

BackgroundThe mental and psychological conditions of the individuals involved in homicide followed by suicide (H-S) are still unclear, especially in China. Information on these aspects cannot be accurately obtained due to the death of perpetrators. This study aims to demonstrate the characteristics of incomplete H-S with surviving perpetrators, which provide the possibility to obtain detailed mental and psychological information.MethodsThis study explores incomplete H-S events occurred in Hunan, China from 2010 to 2019, in which the surviving perpetrators received a forensic psychiatric assessment. Three aspects of information, i.e., the subject’s demographic, clinical and criminal information, were recorded and analysed.Results125 incomplete H-S incidents involved 166 victims were found in the current study. A total of 112 (89.6%) perpetrators were diagnosed with mental disorders, but only 56 of them had a history of consultation due to mental problems, and only one of them adhered to treatment. In most cases, the motivation is related to the psychopathological states, with the most common diagnosis being major depression, followed by schizophrenia. Gender difference was significant among the subjects: females were more likely to have a suicidal history, to be diagnosed as major depression and to be motivated by delirious altruism and family problems.ConclusionsThis study indicated that psychopathology might be a predisposing factor, which highlighted the importance of mental state assessment for the population involved in incomplete H-S. A clearer understanding of the role of mental disorders might be helpful for the intervention of H-S.

Oxidative Stress Markers and Antioxidant Enzymes in Children and Adolescents with Depressive Disorder and Impact of Omega-3 Fatty Acids in Randomised Clinical Trial.

Oxidative stress (OS) is thought to play a role in mental disorders. However, it is not clear whether the OS is the cause or consequence of the disorder. We investigated markers of oxidative stress (8-isoprostane (8-IsoP-U), lipoperoxides (LP), advanced oxidation protein products (AOPP) and nitrotyrosine (NT)) and antioxidant protection (Trolox equivalent antioxidant capacity (TEAC), activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) in 60 paediatric and adolescent patients with depressive disorder (DD) compared to healthy controls. The patients were divided into two groups (1:1). One group received an emulsion of omega-3 fatty acid (FA), and the other group an emulsion of sunflower oil with omega-6 FA for 12 weeks. The levels of 8-IsoP-U, AOPP and NT were increased, and GPx activity was decreased in patients compared to the controls. We found a significant positive correlation of the Children’s Depression Inventory score with NT and a negative correlation with TEAC, SOD and GPx. NT correlated positively with the baseline omega-6/omega-3 FA ratio and a negatively with SOD. A supplementation with omega-3 FA, but not with omega-6 FA, decreased 8-IsoP-U, AOPP, NT levels and increased TEAC and SOD activity. Our results suggest that NT may play a role in the pathophysiology of DD, while elevated isoprostane is likely caused by the high omega-6/omega-3 FA ratio. Omega-3 FA supplementation reduces oxidative stress in patients with DD. This study was registered with the ISRCTN registry (ISRCTN81655012).

Bioinformatics Analysis of circRNA Expression and Construction of "circRNA-miRNA-mRNA" Competing Endogenous RNAs Networks in Bipolar Disorder Patients.

Bipolar disorder (BD) is a severe mood disorder disease in China, and its underlying pathogenesis remains unknown. Circular RNAs (circRNAs) have been reported to play a key role in mental disorders and can be used as competitive endogenous RNAs (ceRNAs). However, little is known about the correlation of circRNAs with BD. In this study, Deep RNA sequencing was used to identify differentially expressed circRNAs (DE-circRNAs) and differentially expressed mRNAs (DE-mRNAs) between BD patients and a control group. Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to validate the differentially expressed RNAs (DE-RNAs). In all 9,593 circRNAs and 20,030 mRNAs were found in the two groups of specimens, among which 50 DE-circRNAs and 244 DE-mRNAs were significantly upregulated, and 44 DE-circRNAs and 294 DE-mRNAs were significantly downregulated. Based on the regulatory mechanism of ceRNAs, circRNAs can directly bind microRNAs (miRNAs) to affect mRNA expression, and the expression trends of circRNAs and mRNAs are consistent. According to this mechanism, we constructed two ceRNA networks by using the RNA sequencing data. The function of these DE-circRNAs was further elucidated by enrichment analysis. In summary, the present study showed that the circRNA expression profile of BD patients is altered, and a ceRNA regulatory network was constructed, which provided a hypothesis about the pathogenesis of BD.

The gut microbiome is associated with brain structure and function in schizophrenia

The effect of the gut microbiome on the central nervous system and its possible role in mental disorders have received increasing attention. However, knowledge about the relationship between the gut microbiome and brain structure and function is still very limited. Here, we used 16S rRNA sequencing with structural magnetic resonance imaging (sMRI) and resting-state functional (rs-fMRI) to investigate differences in fecal microbiota between 38 patients with schizophrenia (SZ) and 38 demographically matched normal controls (NCs) and explored whether such differences were associated with brain structure and function. At the genus level, we found that the relative abundance of Ruminococcus and Roseburia was significantly lower, whereas the abundance of Veillonella was significantly higher in SZ patients than in NCs. Additionally, the analysis of MRI data revealed that several brain regions showed significantly lower gray matter volume (GMV) and regional homogeneity (ReHo) but significantly higher amplitude of low-frequency fluctuation in SZ patients than in NCs. Moreover, the alpha diversity of the gut microbiota showed a strong linear relationship with the values of both GMV and ReHo. In SZ patients, the ReHo indexes in the right STC (r = − 0.35, p = 0.031, FDR corrected p = 0.039), the left cuneus (r = − 0.33, p = 0.044, FDR corrected p = 0.053) and the right MTC (r = − 0.34, p = 0.03, FDR corrected p = 0.052) were negatively correlated with the abundance of the genus Roseburia. Our results suggest that the potential role of the gut microbiome in SZ is related to alterations in brain structure and function. This study provides insights into the underlying neuropathology of SZ.

NMDAR Neurotransmission Needed for Persistent Neuronal Firing: Potential Roles in Mental Disorders.

The dorsolateral prefrontal cortex (dlPFC) generates the mental representations that are the foundation of abstract thought, and provides top-down regulation of emotion through projections to the medial PFC and cingulate cortices. Physiological recordings from dlPFC Delay cells have shown that the generation of mental representations during working memory relies on NMDAR neurotransmission, with surprisingly little contribution from AMPAR. Systemic administration of low “antidepressant” doses of the NMDAR antagonist, ketamine, erodes these representations and reduces dlPFC Delay cell firing. In contrast to the dlPFC, V1 neuronal firing to visual stimuli depends on AMPAR, with much less contribution from NMDAR. Similarly, neurons in the dlPFC that respond to sensory events (cue cells, response feedback cells) rely on AMPAR, and systemic ketamine increases their firing. Insults to NMDAR transmission, and the impaired ability for dlPFC to generate mental representations, may contribute to cognitive deficits in schizophrenia, e.g., from genetic insults that weaken NMDAR transmission, or from blockade of NMDAR by kynurenic acid. Elevated levels of kynurenic acid in dlPFC may also contribute to cognitive deficits in other disorders with pronounced neuroinflammation (e.g., Alzheimer's disease), or peripheral infections where kynurenine can enter brain (e.g., delirium from sepsis, “brain fog” in COVID19). Much less is known about NMDAR actions in the primate cingulate cortices. However, NMDAR neurotransmission appears to process the affective and visceral responses to pain and other aversive experiences mediated by the cingulate cortices, which may contribute to sustained alterations in mood state. We hypothesize that the very rapid, antidepressant effects of intranasal ketamine may involve the disruption of NMDAR-generated aversive mood states by the anterior and subgenual cingulate cortices, providing a “foot in the door” to allow the subsequent return of top-down regulation by higher PFC areas. Thus, the detrimental vs. therapeutic effects of NMDAR blockade may be circuit dependent.