GPCR-mediated calcium and cAMP signaling determines psychosocial stress susceptibility and resiliency.

Chronic stress increases the risk of developing psychiatric disorders, including mood and anxiety disorders. Although behavioral responses to repeated stress vary across individuals, the underlying mechanisms remain unclear. Here, we perform a genome-wide transcriptome analysis of an animal model of depression and patients with clinical depression and report that dysfunction of the Fos-mediated transcription network in the anterior cingulate cortex (ACC) confers a stress-induced social interaction deficit. Critically, CRISPR-Cas9-mediated ACC Fos knockdown causes social interaction deficits under stressful situation. Moreover, two classical second messenger pathways, calcium and cyclic AMP, in the ACC during stress differentially modulate Fos expression and regulate stress-induced changes in social behaviors. Our findings highlight a behaviorally relevant mechanism for the regulation of calcium- and cAMP-mediated Fos expression that has potential as a therapeutic target for psychiatric disorders related to stressful environments.

Neuroimaging at 7 Tesla: a pictorial narrative review.

Neuroimaging using the 7-Tesla (7T) human magnetic resonance (MR) system is rapidly gaining popularity after being approved for clinical use in the European Union and the USA. This trend is the same for functional MR imaging (MRI). The primary advantages of 7T over lower magnetic fields are its higher signal-to-noise and contrast-to-noise ratios, which provide high-resolution acquisitions and better contrast, making it easier to detect lesions and structural changes in brain disorders. Another advantage is the capability to measure a greater number of neurochemicals by virtue of the increased spectral resolution. Many structural and functional studies using 7T have been conducted to visualize details in the white matter and layers of the cortex and hippocampus, the subnucleus or regions of the putamen, the globus pallidus, thalamus and substantia nigra, and in small structures, such as the subthalamic nucleus, habenula, perforating arteries, and the perivascular space, that are difficult to observe at lower magnetic field strengths. The target disorders for 7T neuroimaging range from tumoral diseases to vascular, neurodegenerative, and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, major depressive disorder, and schizophrenia. MR spectroscopy has also been used for research because of its increased chemical shift that separates overlapping peaks and resolves neurochemicals more effectively at 7T than a lower magnetic field. This paper presents a narrative review of these topics and an illustrative presentation of images obtained at 7T. We expect 7T neuroimaging to provide a new imaging biomarker of various brain disorders.

Epigenetic clock analysis and increased plasminogen activator inhibitor-1 in high-functioning autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by impaired social communication and behavioral problems. An increased risk of premature mortality has been observed in individuals with ASD. Therefore, we hypothesized that biological aging is accelerated in individuals with ASD. Recently, several studies have established genome-wide DNA methylation (DNAm) profiles as 'epigenetic clocks' that can estimate biological aging. In addition, ASD has been associated with differential DNAm patterns. METHODS: We used two independent datasets from blood samples consisting of adult patients with high-functioning ASD and controls: the 1st cohort (38 ASD cases and 31 controls) and the 2nd cohort (6 ASD cases and 10 controls). We explored well-studied epigenetic clocks such as HorvathAge, HannumAge, SkinBloodAge, PhenoAge, GrimAge, and DNAm-based telomere length (DNAmTL). In addition, we investigated seven DNAm-based age-related plasma proteins, including plasminogen activator inhibitor-1 (PAI-1), and smoking status, which are the components of GrimAge. RESULTS: Compared to controls, individuals with ASD in the 1st cohort, but not in the 2nd cohort, exhibited a trend for increased GrimAge acceleration and a significant increase of PAI-1 levels. A meta-analysis showed significantly increased PAI-1 levels in individuals with ASD compared to controls. CONCLUSION: Our findings suggest there is no epigenetic age acceleration in the blood of individuals with ASD. However, this study provides novel evidence regarding increased plasma PAI-1 levels in individuals with high-functioning ASD. These findings suggest PAI-1 may be a biomarker for high-functioning ASD, however, larger studies based on epigenetic clocks and PAI-1 will be necessary to confirm these findings.

A Call for a Rational Polypharmacy Policy: International Insights From Psychiatrists.

OBJECTIVE: Recently, rational polypharmacy approaches have been proposed, regardless of the lower risk and cost of monotherapy. Considering monotherapy as first-line treatment and polypharmacy as rational treatment, a balanced attitude toward polypharmacy is recommended. However, the high prevalence of polypharmacy led the Japanese government to establish a polypharmacy reduction policy. Based on this, the association between the policy and psychiatrists' attitude toward polypharmacy has been under debate. METHODS: We developed an original questionnaire about Psychiatrists' attitudes toward polypharmacy (PAP). We compared the PAP scores with the treatment decision-making in clinical case vignettes. Multiple regression analyses were performed to quantify associations of explanatory variables including policy factors and PAP scores. The anonymous questionnaires were administered to psychiatrists worldwide. RESULTS: The study included 347 psychiatrists from 34 countries. Decision-making toward polypharmacy was associated with high PAP scores. Multiple regression analysis revealed that low PAP scores were associated with the policy factor (ß=-0.20, p=0.004). The culture in Korea was associated with high PAP scores (ß=0.34, p<0.001), whereas the culture in India and Nepal were associated with low scores (ß=-0.15, p=0.01, and ß=-0.17, p=0.006, respectively). CONCLUSION: Policy on polypharmacy may influence psychiatrists' decision-making. Thus, policies considering rational polypharmacy should be established.

Treatment-resistant schizophrenia characterised by dopamine supersensitivity psychosis and efficacy of asenapine.

Dopamine supersensitivity psychosis (DSP) frequently arises with long-term antipsychotic treatment and accounts for a significant proportion of treatment-resistant schizophrenia. The mechanism underlying DSP is thought to be a compensatory increase in dopamine receptor density in the striatum caused by long-term antipsychotic treatment. Previous animal studies have reported that antipsychotics increase serotonin 5-HT2A receptor density in the striatum and that 5-HT2A receptor blockers suppress dopamine-sensitive psychomotor activity, which may be linked to the pathophysiology of DSP. In this paper, we describe a patient who was hospitalised with treatment-resistant schizophrenia. Following treatment with high-dose antipsychotic polypharmacy for 10 weeks, the patient experienced worsening of psychotic and extrapyramidal symptoms. The patient was then started on second-generation antipsychotic asenapine while other antipsychotics were tapered off, resulting in improvement of these symptoms. Retrospectively, we presumed that the high-dose antipsychotic polypharmacy caused DSP, which was effectively treated by the potent 5-HT2A receptor antagonism of asenapine.

Martial Arts "Kendo" and the Motivation Network During Attention Processing: An fMRI Study.

Japanese martial arts, Budo, have been reported to improve cognitive function, especially attention. However, the underlying neural mechanisms of the effect of Budo on attention processing has not yet been investigated. Kendo, a type of fencing using bamboo swords, is one of the most popular forms of Budo worldwide. We investigated the difference in functional connectivity (FC) between Kendo players (KPs) and non-KPs (NKPs) during an attention-related auditory oddball paradigm and during rest. The analyses focused on the brain network related to "motivation." Resting-state functional magnetic resonance imaging (rs-fMRI) and task-based fMRI using the oddball paradigm were performed in healthy male volunteers (14 KPs and 11 NKPs). Group differences in FC were tested using CONN-software within the motivation network, which consisted of 22 brain regions defined by a previous response-conflict task-based fMRI study with a reward cue. Daily general physical activities were assessed using the International Physical Activity Questionnaire (IPAQ). We also investigated the impact of major confounders, namely, smoking habits, alcohol consumption, IPAQ score, body mass index (BMI), and reaction time (RT) in the oddball paradigm. Resting-state fMRI revealed that KPs had a significantly lower FC than NKPs between the right nucleus accumbens and right frontal eye field (FEF) within the motivation network. Conversely, KPs exhibited a significantly higher FC than NKPs between the left intraparietal sulcus (IPS) and the left precentral gyrus (PCG) within the network during the auditory oddball paradigm [statistical thresholds, False Discovery Rate (FDR) < 0.05]. These results remained significant after controlling for major covariates. Our results suggest that attenuated motivation network integrity at rest together with enhanced motivation network integrity during attentional demands might underlie the instantaneous concentration abilities of KPs.

Self-efficacy modulates the neural correlates of craving in male smokers and ex-smokers: an fMRI study.

The regulation of cue-induced craving for cigarettes is a key factor in smoking cessation. Outcomes of smoking cessation have been linked to self-efficacy, faith in one's own ability, in smokers. However, no study has examined the neural basis of self-efficacy during the control of craving. We examined whether self-efficacy can affect the neural response to smoking cues in smokers and ex-smokers using functional magnetic resonance imaging. During scanning, participants were instructed (1) to view smoking-related images passively, (2) to view the smoking-related images with a strategy focused on self-efficacy to control cue-induced craving or (3) to view neutral images. In smokers, the self-efficacy strategy significantly reduced self-reported craving. This strategy was related to increased activation in the rostral medial prefrontal cortex (rmPFC) and the pregenual anterior cingulate cortex in smokers compared with ex-smokers. Furthermore, smokers showed increased effective connectivity between rmPFC and hippocampus and between pregenual anterior cingulate cortex and parahippocampus gyrus when employing the self-efficacy strategy compared with ex-smokers. The magnitude of the rmPFC-hippocampus connectivity was positively correlated with self-reported self-efficacy. Our findings suggest that in smokers, self-efficacy is related to activation and connectivity in brain regions involved in regulating craving and self-assessment. The current study provides evidence for understanding the vunderlying cognitive and neurobiological mechanisms involved in the control of craving to smoke cigarettes.

Additive Effect of Cigarette Smoking on Gray Matter Abnormalities in Schizophrenia.

It is widely known that there is a high prevalence of cigarette smoking in schizophrenia. One of the explanations is the self-medication hypothesis. Based on this hypothesis, it has been suggested that nicotine has procognitive effect or even neuroprotective effect in schizophrenia. However, cigarettes contain numerous neurotoxic substances, making the net effect of cigarette smoking on brain function and structure complex. Indeed, recent studies have called into question the self-medication hypothesis. We aimed to test whether there is an interaction between diagnosis and smoking status in gray matter volume, ie, whether smoking has specific effects on gray matter or whether main effects of these 2 variables additively affect common brain regions. Magnetic resonance imaging (MRI) images were obtained from 4 groups: (1) normal controls with no smoking history, (2) normal controls currently smoking and/or with a past history of smoking, (3) schizophrenia patients with no smoking history, and (4) schizophrenia patients currently smoking and/or with a past history of smoking. We used voxel-based morphometry to compare gray matter volumes among the 4 groups. We did not find any interaction between diagnosis and smoking, but we did find negative additive effects of schizophrenia diagnosis and smoking status in the left prefrontal cortex. The decrease in left prefrontal volume was associated with greater numbers of cigarette pack years and severe positive and negative symptoms. The current findings do not support the neuroprotective effect of smoking on gross brain structure in schizophrenia, emphasizing the necessity of longitudinal studies to test causal relationships among these variables.

Paradise Lost: The relationships between neurological and psychological changes in nicotine-dependent patients.

The neural reward circuit and cognitive distortion play an important role in addiction; however, the relationship between the two has not yet been addressed. In this article, we review recent findings on nicotine dependence and propose a novel hypothesis. Previous research using functional magnetic resonance imaging (fMRI) has shown that while activation of the reward circuit (ventral striatum) appears in response to tobacco-related rewards in nicotine dependence, responses to rewards other than tobacco (e.g. food and money) are reduced. Moreover, this change is observed at the very early stages of smoking, even when a person has smoked fewer than 10 cigarettes in his/her lifetime. Thus, we propose the following hypothesis, called the Paradise Lost theory: given addicts' lower ventral striatal responses to non-tobacco rewards, nicotine addiction disables smokers from sensing the pleasures of ordinary life (the Paradise Lost state). However, since smokers do not notice this, they produce an overestimation of tobacco (cognitive distortion), such that they do not have many pastimes other than smoking or feel that quitting smoking would reduce the happiness and pleasure and increase the difficulty of life. Cognitive distortion thus makes it difficult for smokers to take the initiative to quit smoking and even causes relapse after smoking cessation. This theory furthers our understanding of addiction and could improve our approach to the prevention and treatment of addiction.

Emotion recognition from facial expressions in a temporal lobe epileptic patient with ictal fear.

Ictal fear (IF) is an affective aura observed in patients with temporal lobe epilepsy. It has been suggested that the amygdala, a region implicated in emotion processing, is involved in generating IF. Several studies have reported that the patients with IF have disturbances in emotional experience, but there has been no testing of the emotional recognition in those patients. In this report, emotion recognition from facial expressions was investigated in a patient with IF. The patient suffered from IF due to temporal lobe epilepsy, and underwent hippocampectomy surgery which completely suppressed IF. We examined the patient before and after surgery. Before surgery, the patient tended to attach enhanced fear, sadness, and anger to various facial expressions. After surgery, such biases disappeared. As an underlying mechanism of the pre-surgical skewed perception of emotional stimuli, the abnormal epileptogenic circuits involving a hypersensitive amygdala possibly due to the kindling mechanism were suggested.