Characterization of the signature of peripheral innate immunity in women with later-life major depressive disorder.

The prevalence of depression in later life is higher in women than in men. However, the sex difference in the pathophysiology of depression in elderly patients is not fully understood. Here, we performed gene expression profiling in leukocytes of middle-aged and elderly patients with major depressive disorder, termed later-life depression (LLD) in this context, and we characterized the sex-dependent pathophysiology of LLD. A microarray dataset obtained from leukocytes of patients (aged ≥50 years) with LLD (32 males and 39 females) and age-matched healthy individuals (20 males and 24 females) was used. Differentially expressed probes were determined by comparing the expression levels between patients and healthy individuals, and then functional annotation analyses (Ingenuity Pathway Analysis, Reactome pathway analysis, and cell-type enrichment analysis) were performed. A total of 1656 probes were differentially expressed in LLD females, but only 3 genes were differentially expressed in LLD males. The differentially expressed genes in LLD females were relevant to leukocyte extravasation signaling, Tec kinase signaling and the innate immune response. The upregulated genes were relevant to myeloid lineage cells such as CD14+ monocytes. In contrast, the downregulated genes were relevant to CD4+ and CD8+ T cells. Remarkable innate immune signatures are present in the leukocytes of LLD females but not males. Because inflammation is involved in the pathophysiology of depression, the altered inflammatory activity may be involved in the pathophysiology of LLD in women. In contrast, abnormal inflammation may be an uncommon feature in LLD males.

Magnetoencephalography study of the effect of attention modulation on somatosensory processing in patients with major depressive disorder.

AIMS: Although affective and/or attention modulation of somatosensory processing has been well studied, the biological bases of somatic symptoms in patients with major depressive disorder (MDD) have rarely been examined. To elucidate changes in somatosensory processing underlying somatic symptoms in patients with MDD, we conducted a magnetoencephalography study of patients with MDD and healthy controls. METHODS: After median nerve stimulation, somatosensory evoked fields (SEF) were recorded in 10 patients with MDD and 10 sex-, age-, and height-matched healthy volunteers under somatosensory attending, visually attending, and non-attending conditions. The latencies and magnitudes of N20m and P60m SEF were examined. RESULTS: In the MDD group, P60m latency was significantly prolonged, irrespective of attention modulation, whereas N20m latency and root mean squares N20m and P60m amplitudes remained unchanged. Prolonged P60m latency negatively correlated with the somatosensory threshold, which was relatively high in the MDD group. Prolonged P60m latency also negatively correlated with a state of anxiety during the examination, but not with depressive symptoms or psychotropic medication. CONCLUSIONS: These results suggested that patients with MDD experience dysfunction in somatosensory information processing, approximately 60 ms after stimuli, irrespective of attentional conditions.

[The Report of the Survey to the Members of the Society about the Functional Dissociation of the Psychiatric Hospital beds].

In 2014, Japanese Ministry of Health, Labour and Welfare published the guideline on the policy of the psychiatric hospitals. We executed a survey to the members of "The Japanese Society of Psychiatry and Neurology" about the impression of this guideline, especially about "The functional differentiation of psychiatric hospital beds". Nine questions were notified on the home page of the society. 862 answers (5.3% of the members) were corrected by website from 1st to 30th of May in 2015. Attribution of the answers : doctors working at the psychiatric hospitals (70.9%), the psychiatric clinics (20%), the others (9.1%). The questions which more than 80% of the answers agreed were "The reduction of the psychiatric beds should be stepwise under the rule of check & balance in the improvement of the psychiatric community treatment", "Improve the function of the recovery phase treatment" and "The adequate treat- ment for the patients of the severe and chronic phases". The questions more than 55% of the answers agreed were "The reduction of the chronic phase beds for the improvement of the function of the acute phase beds". The questions which opposites exceeded (almost 47%) were "The assessment of the psychiatric symptoms in the patients of the chronic phase should be done by the third party" and "The facility for social skill treatment should be placed in the community". We could know the mind of the members about the revolution of the psychiatric.

Transplanted microvascular endothelial cells promote oligodendrocyte precursor cell survival in ischemic demyelinating lesions.

We previously showed that transplantation of brain microvascular endothelial cells (MVECs) greatly stimulated remyelination in the white matter infarct of the internal capsule (IC) induced by endothelin-1 injection and improved the behavioral outcome. In the present study, we examined the effect of MVEC transplantation on the infarct volume using intermittent magnetic resonance image and on the behavior of oligodendrocyte lineage cells histochemically. Our results in vivo show that MVEC transplantation reduced the infarct volume in IC and apoptotic death of oligodendrocyte precursor cells (OPCs). These results indicate that MVECs have a survival effect on OPCs, and this effect might contribute to the recovery of the white matter infarct. The conditioned-medium from cultured MVECs reduced apoptosis of cultured OPCs, while the conditioned medium from cultured fibroblasts did not show such effect. These results suggest a possibility that transplanted MVECs increased the number of OPCs through the release of humoral factors that prevent their apoptotic death. Identification of such humoral factors may lead to the new therapeutic strategy against ischemic demyelinating diseases.

[Toward the Introduction of Repetitive Transcranial Magnetic Stimulation in Japan to Treat Antidepressant-resistant Depression].

Treatment of major depressive disorder (MDD) can include a variety of biopsychosocial approaches. In medical practice, antidepressant drugs are the most common treatment for moderate to severe depressive episodes; however, their efficacy is limited. Many depressed patients are considered treatment-resistant, with 33% failing to achieve remission after ≥ 3 treatment trials. A systemic review and meta-analysis revealed that repetitive transcranial magnetic stimulation (rTMS) may be reasonably considered for patients with MDD and ≥ 2 prior failures of antidepressant treatment. No rTMS devices have been approved by the Japanese Pharmaceuticals and Medical Devices Agency, which has resulted in its off-label use; therefore, to offer better care for cases of treatment-resistant MDD, we should continue efforts to seek the introduction of rTMS to Japan.

[Implementation of Guidelines on Conflict of Interest in Clinical Research of the Japanese Society of Psychiatry and Neurology: actual status and future perspectives].

In May 2011, the Japanese Society of Psychiatry and Neurology released their Guidelines on Conflict of Interest (COI) in Clinical Research and detailed regulations. These guidelines cover clinical research, although each committee of the society may have a policy to cover basic research as well as clinical research. The COI Committee implemented the guidelines, including a one-year trial period. According to the guidelines, members of the society have to disclose their COIs at the time of presentations, manuscript submissions, and publications; the board and committees members have to submit their COIs to the president of the society. During the trial period, the latter was limited to the four committees involved in the development of the guidelines: Conflict of Interest; Pharmaceutical Affairs; Research Ethics; and Editorial Committees. The COI Committee reviewed the COIs submitted by the board and committee members. The COI Committee found that, among the 382 board and committee members, 298 were without COI; 31 COIs were regarded by one committee member as not necessary to be circulated to all the attending members (total of these 2 categories: 329, 87%); 31 COIs (8%) were regarded as necessary to be circulated; and 18 cases (4.7%) were problematic: not submitted or explicit rejection of submission. Considering the seriousness of scientific misconduct by a researcher in another disease area who resigned his professorship and is now under investigation, we should further discuss the implementation of our COI guidelines.

[Adverse drug reactions of psychotropic agents: adverse drug reactions and safety monitoring of psychotropic agents].

Pharmacological treatments of psychiatric illness have been developed and many psychotropic drugs are now on the market. The body of safety information regarding psychotropic agents is so large that it is difficult for clinicians to consider all the details of possible adverse drug reactions(ADRs) in daily clinical practice. Although it is impossible to predict and prevent all occurrences of ADRs, many of them may be preventable. In this context, there is a strong need for compact manuals of diagnosis and treatment for ADRs arising from psychotropic agents that are likely to be used in daily practice. Under the auspices of the Japanese Society of Psychiatry and Neurology, a task force was convened to answer this need. This review focuses on the general considerations of ADRs with psychotropic agents, based on discussions of the task force. We also discuss the guidelines for drug safety monitoring, targeted towards specific psychiatric disorders or patients taking specific classes of drugs. Finally, we introduce the Adverse Drug Reactions Relief System in Japan.

Associations among parenting experiences during childhood and adolescence, hypothalamus-pituitary-adrenal axis hypoactivity, and hippocampal gray matter volume reduction in young adults.

Recent human studies have indicated that adverse parenting experiences during childhood and adolescence are associated with adulthood hypothalamus-pituitary-adrenal (HPA) axis hypoactivity. Chronic HPA axis hypoactivity inhibits hippocampal gray matter (GM) development, as shown by animal studies. However, associations among adverse parenting experiences during childhood and adolescence, HPA axis activity, and brain development, particularly hippocampal development, are insufficiently investigated in humans. In this voxel-based structural magnetic resonance imaging study, using a cross-sectional design, we examined the associations among the scores of parental bonding instrument (PBI; a self-report scale to rate the attitudes of parents during the first 16 years), cortisol response determined by the dexamethasone/corticotropin-releasing hormone test, and regional or total hippocampal GM volume in forty healthy young adults with the following features: aged between 18 and 35 years, no cortisol hypersecretion in response to the dexamethasone test, no history of traumatic events, or no past or current conditions of significant medical illness or neuropsychiatric disorders. As a result, parental overprotection scores significantly negatively correlated with cortisol response. Additionally, a significant positive association was found between cortisol response and total or regional hippocampal GM volume. No significant association was observed between PBI scores and total or regional hippocampal GM volume. In conclusion, statistical associations were found between parental overprotection during childhood and adolescence and adulthood HPA axis hypoactivity, and between HPA axis hypoactivity and hippocampal GM volume reduction in healthy young adults, but no significant relationship was observed between any PBI scores and adulthood hippocampal GM volume.

Micropolygyria in an infant born to a patient with severe anorexia nervosa: a case report.

We report the case of an anorexia nervosa (AN) patient with extremely low body weight who became pregnant following ovulation induction and subsequently delivered an infant with micropolygyria. To the best of our knowledge, no previous report has described live birth for a patient with such low body weight. The patient underwent hMG-hCG therapy for ovulation induction. Despite becoming pregnant, weight loss continued with extreme anemia occurring during the pregnancy. However, blood transfusion therapy was used for successful treatment. Despite the therapeutic and protective measures instituted, the child was born with micropolygyria. Pregnancy in an AN patient with extremely low body weight needs therapeutic intervention during early pregnancy with aggressive precautionary measures, particularly against anemia. On the basis of our experience, we consider that ovulation induction therapy should not be administered without sufficient caution for an AN patient with low body weight.

Differential relationships between personality and brain function in monetary and goal-oriented subjective motivation: multichannel near-infrared spectroscopy of healthy subjects.

AIM: To examine relationships between personality traits and cerebral cortex reactivity under different motivating conditions. METHODS: Relationships between personality traits assessed using the NEO Personality Inventory-Revised (NEO-PI-R) and cerebral cortex reactivity during a verbal fluency task monitored using multichannel near-infrared spectroscopy (NIRS) were examined under three different motivational conditions: control, monetary reward, and goal-oriented, in healthy young male volunteers. RESULTS: Significant correlations between cerebral cortex reactivity and personality traits were found in the frontopolar region: a positive correlation with agreeableness and a negative correlation with the neuroticism and conscientiousness scores of the NEO-PI-R under the three motivational conditions. Higher scores for agreeableness were more strongly associated with a greater increase in total hemoglobin concentration ([total-Hb]) under the goal-oriented and control conditions than under the monetary reward condition. In addition, higher scores for neuroticism were more strongly associated with a greater increase in deoxygenated hemoglobin concentration ([deoxy-Hb]) under the monetary reward condition than the goal-oriented condition, and higher scores for conscientiousness were more strongly associated with a greater increase in [deoxy-Hb] under control conditions than under the goal-oriented condition. CONCLUSION: Using multichannel NIRS, certain personality traits of the big-five model are related to frontopolar reactivity. These relationships vary depending on the motivational condition when brain functions are monitored: agreeableness, neuroticism, and conscientiousness are all related to frontopolar reactivity depending on the motivational condition.

[Clinical application of near-infrared spectroscopy (NIRS) in psychiatry: the advanced medical technology for differential diagnosis of depressive state].

Near-infrared spectroscopy (NIRS) is a functional neuroimaging technique that has been increasingly employed in psychology and psychiatry. Because NIRS can detect only cerebral cortex reactivities with low spatial resolution and may suffer from contaminating signals from skin and skull, its data should be interpreted as a global index of cerebral cortex reactivities. Within these limitations, the advantages of NIRS over fMRI such as complete non-invasiveness, small measurement apparatus, high time resolution, and natural examination setting makes it the preferred method in studies of brain substrates of subjective feeling of sleepiness and fatigue, personality, conversation, and psychiatric disorders. Two-thirds of the original articles on NIRS application in psychiatry have been published by Japanese researchers. NIRS examination of psychiatric disorders using a verbal fluency task of only three minutes demonstrated their characteristics of frontal lobe function: depression was characterized by smaller activation, bipolar depression by comparable but delayed activation, and schizophrenia by reduced activation followed by re-activation during the post-task period. These characteristics can also be identified in individual NIRS data using two automatically calculated parameters. Based on these results, NIRS application in psychiatry has been approved as one of the Advanced Medical Technologies in 2009 as an aid for differential diagnosis of depressive symptoms. A lack of clinical laboratory tests for diagnosis and treatment has been one of the major difficulties for reliable diagnosis, quantitative treatment assessment, and prevention of psychiatric disorders; NIRS may be the first step toward such clinical laboratory tests in psychiatry.

[Augmentation therapy with cilostazol for the intractable geriatric major depressive disorder patients with deep white matter hyperintensities on T2-weighted brain MRI].

Several studies report that vascular lesions contribute to depression in late life, but whether vascular lesions contribute to depression or indeed result from depression is debatable. To address this question, we segregated mood disorder patients into late- and early-onset mood disorder groups (LOM and EOM, respectively) and compared the areas of high intensity on the subcortical MRI scans of the 2 groups. We found that the LOM group exhibited higher ratings than the EOM group; significant between-group differences were detected in the bilateral frontal areas and in the left parieto-occipital area. Our results suggest that vascular lesions in these areas are crucial for the development of late-onset mood disorders. Furthermore, treatment is often difficult in depressed patients with cerebrovascular lesions. Therefore, a new therapeutic approach that takes into account cerebrovascular factors is necessary. We concomitantly administered cilostazol with conventional antidepressants to patients with intractable geriatric major depressive disorder; of these patients, 2 showed improvements of their depressive symptoms. These findings suggest a potential efficacy of cilostazol as a novel drug for use in augmentation therapy for depressed patients with silent cerebrovascular disorder. Evidence that vascular disease is the underlying link between depression and dementia is strong. Therefore, further studies that include follow-up of such cases are necessary.

Distinct epigenetic signatures between adult-onset and late-onset depression.

The heterogeneity of major depressive disorder (MDD) is attributed to the fact that diagnostic criteria (e.g., DSM-5) are only based on clinical symptoms. The discovery of blood biomarkers has the potential to change the diagnosis of MDD. The purpose of this study was to identify blood biomarkers of DNA methylation by strategically subtyping patients with MDD by onset age. We analyzed genome-wide DNA methylation of patients with adult-onset depression (AOD; age ≥ 50 years, age at depression onset < 50 years; N = 10) and late-onset depression (LOD; age ≥ 50 years, age at depression onset ≥ 50 years; N = 25) in comparison to that of 30 healthy subjects. The methylation profile of the AOD group was not only different from that of the LOD group but also more homogenous. Six identified methylation CpG sites were validated by pyrosequencing and amplicon bisulfite sequencing as potential markers for AOD in a second set of independent patients with AOD and healthy control subjects (N = 11). The combination of three specific methylation markers achieved the highest accuracy (sensitivity, 64%; specificity, 91%; accuracy, 77%). Taken together, our findings suggest that DNA methylation markers are more suitable for AOD than for LOD patients.

Similar activation patterns in the prefrontal cortex for Chinese and Japanese verbal fluency tests with syllable cues as revealed by near-infrared spectroscopy.

The verbal fluency test (VFT) is utilized in neuropsychology to evaluate the cognitive function of the prefrontal cortex (PFC) in the human brain. We present a novel Chinese VFT similar to the established Japanese VFT; both tests prompt a syllable to the subject. However, it was uncertain whether the Chinese VFT can activate the PFC and whether PFC activation patterns are similar between the two tests. Here we administered the Chinese VFT to 30 native Chinese speakers and the Japanese VFT to 30 native Japanese speakers. We used near-infrared spectroscopy (NIRS) to observe PFC activation. Then we compared the similarities between the Chinese VFT and the Japanese VFT. The subjects generated an average of 12.8 ± 4.7 words during the Chinese VFT. NIRS indicates that the concentration of oxygenated hemoglobin during the test was significantly higher than those before and after the test. It exhibited similar PFC activation patterns with the Japanese VFT. The novel Chinese VFT can activate the PFC in the human brain effectively in Chinese speakers. Our work thus provides the first validated phonetically cued Chinese VFT, unique from other not strictly phonemic Chinese VFTs, and facilitates the diagnosis of various PFC-related cognitive impairments.

Stimulus intensity dependence of cerebral blood volume changes in left frontal lobe by low-frequency rTMS to right frontal lobe: A near-infrared spectroscopy study.

Repetitive transcranial magnetic stimulation (rTMS) has recently been widely employed for the investigation of brain function and treatment of psychiatric and neurological disorders. Although high and low stimulation frequencies are assumed to activate and deactivate brain function, respectively, the optimal parameters of rTMS for treatment of depression have been determined only on the basis of their clinical efficacy. In this study, we administered a 60-s low-frequency rTMS of three grades low intensities over the right dorsolateral prefrontal cortex (DLPFC) in 10 healthy volunteers, and monitored functional changes of the contralateral DLPFC by near-infrared spectroscopy (NIRS) during and immediately after rTMS. Obtained results demonstrated significant [oxy-Hb] decreases during rTMS, and significant differences in the time courses of [oxy-Hb] changes among three stimulus intensities, that is, [oxy-Hb] decreases were most prominent during the latter half of the stimulation and the first 30s of poststimulation only at 15mm condition (58% intensity). These results suggest that monitoring of brain functional changes due to rTMS using NIRS is useful for elucidating the brain mechanisms underlying the clinical effects of rTMS, and the effects of rTMS over contralateral DLPFC are obtained if the stimulus intensities are more than one-half of the motor thresholds.

Large-scale analysis of glucocorticoid target genes in rat hypothalamus.

Insufficient glucocorticoid (GC) signaling is frequently observed in major depressive disorder (MDD). Since emotional and behavioral symptoms are often accompanied by disturbances in hypothalamic systems, GC insufficiency in this region is regarded as important in the pathogenesis of MDD. In this study, 22 early GC-responsive genes comprising 15 up-regulated and 7 down-regulated genes in rat hypothalamus were identified as being regulated at least two-fold by dexamethasone using microarray with 22 599 unique transcripts. Among these 22 genes, five of which are novel GC-responsive genes, the expression patterns of sgk, bcl6, pdk4, and plekhf1 were examined in vitro in detail, and GC-responsive regions were identified only within the promoter of sgk. This suggests that glucocorticoid response element-independent pathways also play a critical role in early GC-response in hypothalamus. Considering that a number of these GC-responsive genes are candidate neuronal regulators, this gene list should be useful in clarifying the relationship between GC insufficiency and the pathogenesis of MDD.

Decreased cortical reactivity underlies subjective daytime light sleepiness in healthy subjects: a multichannel near-infrared spectroscopy study.

Daytime sleepiness is considered to be one of the main problems in modern society. Of the four aspects of sleepiness, namely, subjective sleepiness, performance decrease, sleep propensity, and arousal decrease, subjective sleepiness is the most difficult to assess. Brain mechanisms underlying subjective light sleepiness in daytime were investigated in healthy subjects using multichannel near-infrared spectroscopy (NIRS), which enables the noninvasive measurement of regional cerebral blood volume (rCBV) changes under natural conditions. Forty right-handed healthy volunteers participated in this study. Relationships were investigated between subjective sleepiness and anxiety, assessed using the Stanford Sleepiness Scale (SSS) and State-Trait Anxiety Inventory (STAI), respectively, and cerebral cortex reactivities assessed as oxygenated and deoxygenated hemoglobin concentration ([oxy-Hb] and [deoxy-Hb], respectively) changes during a verbal fluency task using a 24-channel NIRS machine. SSS score correlated negatively with an [oxy-Hb] increase in the bilateral frontal channels mainly in the middle and last third of the verbal fluency task period. Subjective light daytime sleepiness in healthy subjects is considered to be related to decreased prefrontal reactivities in the later part of cognitive activation.

Time courses of brain activation and their implications for function: a multichannel near-infrared spectroscopy study during finger tapping.

The time courses of brain activation were monitored during a finger tapping task using multichannel near-infrared spectroscopy with a time resolution of 0.1s in 30 healthy volunteers. Task-induced brain activations were demonstrated as significant increases in oxygenated hemoglobin concentration ([oxy-Hb]) in a broad area around the motor cortex and significant decreases in deoxygenated hemoglobin concentration ([deoxy-Hb]) in a more restricted area, with a large degree of activation in the contralateral hemisphere. The time courses of the [oxy-Hb] changes varied depending on channel location: sustained activation across the task period in the motor cortex, transient activation during the initial segments of the task period in the somatosensory cortex, and accumulating activation along the task period in the frontal lobe. These characteristics are assumed to reflect the functional roles of the brain structures during the task period, that is, the execution, sensory monitoring, and maintenance of finger tapping.

The differential impact of executive attention dysfunction on episodic memory in obsessive-compulsive disorder patients with checking symptoms vs. those with washing symptoms.

Neuropsychological studies of obsessive-compulsive disorder (OCD) have pointed to memory and attention deficits among its sufferers, but these reports have largely ignored the possibility that cognitive disturbances may vary across OCD clinical subtypes, or that their interactions may differ between subtypes. The purpose of the present study was to determine whether "checkers" and "washers" demonstrate differences in their memory and executive attention function. Fifty-three outpatients with primary DSM-IV diagnosis of OCD with typical checking (n=27) or washing (n=26) rituals participated in the study. Patients were administered the Wechsler Memory Scale-Revised and a comprehensive neuropsychological battery to assess executive attention function. Various neuropsychological tests were then subjected to factor analysis. Neuropsychological test results and obtained factor scores were compared between "washers" and "checkers". Effects of these factor scores on memory by OCD subtypes were examined. No significant difference in terms of demographic and clinical variables was found between the two groups. Checkers displayed performance deficits on Stroop test, Trail Making Test, GO/NO GO test (commission errors) and category fluency. Three factors, inhibition, cognitive flexibility, and multi-tasking, were obtained. Statistically significant differences were observed between the two groups on the inhibition and the cognitive flexibility scores, but not on the general memory or the multi-tasking score. There was a statistically significant interaction between groups and the inhibition score. Only among "checkers", a significant correlation was noted between the inhibition factor and the general memory, while no such correlation was observed among "washers". Among "checkers", poor general memory was related to inhibition deficits.