Physiological paradigm for assessing reward prediction and extinction using cortical direct current potential responses in rats.

Anticipating positive outcomes is a core cognitive function in the process of reward prediction. However, no neurophysiological method objectively assesses reward prediction in basic medical research. In the present study, we established a physiological paradigm using cortical direct current (DC) potential responses in rats to assess reward prediction. This paradigm consisted of five daily 1-h sessions with two tones, wherein the rewarded tone was followed by electrical stimulation of the medial forebrain bundle (MFB) scheduled at 1000 ms later, whereas the unrewarded tone was not. On day 1, both tones induced a negative DC shift immediately after auditory responses, persisting up to MFB stimulation. This negative shift progressively increased and peaked on day 4. Starting from day 3, the negative shift from 600 to 1000 ms was significantly larger following the rewarded tone than that following the unrewarded tone. This negative DC shift was particularly prominent in the frontal cortex, suggesting its crucial role in discriminative reward prediction. During the extinction sessions, the shift diminished significantly on extinction day 1. These findings suggest that cortical DC potential is related to reward prediction and could be a valuable tool for evaluating animal models of depression, providing a testing system for anhedonia.

Chronic antidepressant treatment rescues abnormally reduced REM sleep theta power in socially defeated rats.

The effects of chronic antidepressant (AD) treatment on sleep disturbances in rodent chronic stress models have not been thoroughly investigated. Here, we show that chronic social defeat stress (SDS) in rats induces prolonged social avoidance, alterations in sleep architecture (increased total rapid eye movement [REM] sleep duration, bout, and shortened REM latency), and contextual but not cued fear memory deficits, even 1 month after the last SDS. These abnormalities were associated with changes in electroencephalography (EEG) spectral powers, including reduced REM sleep theta power during the light phase. Chronic treatment with two different classes of antidepressants (ADs), imipramine and fluoxetine, significantly ameliorated these behavioral, sleep, and EEG abnormalities. Interestingly, REM theta power was normalized by chronic (1 month) but not 1 week AD administration and solely correlated with the ratio (an objective indicator) of social interaction 1 month after the last SDS. These data suggest that reductions in REM sleep theta power, an EEG parameter that has never been directly investigated in humans, is a core sleep symptom in socially defeated rats, and, potentially, also in patients with stress-related psychiatric disorders, including major depressive and posttraumatic stress disorders.

Return-to-Work Screening by Linear Discriminant Analysis of Heart Rate Variability Indices in Depressed Subjects.

Using a linear discriminant analysis of heart rate variability (HRV) indices, the present study sought to verify the usefulness of autonomic measurement in major depressive disorder (MDD) patients by assessing the feasibility of their return to work after sick leave. When reinstatement was scheduled, patients' HRV was measured using a wearable electrocardiogram device. The outcome of the reinstatement was evaluated at one month after returning to work. HRV indices including high- and low-frequency components were calculated in three conditions within a session: initial rest, mental task, and rest after task. A linear discriminant function was made using the HRV indices of 30 MDD patients from our previous study to effectively discriminate the successful reinstatement from the unsuccessful reinstatement; this was then tested on 52 patients who participated in the present study. The discriminant function showed that the sensitivity and specificity in discriminating successful from unsuccessful returns were 95.8% and 35.7%, respectively. Sensitivity is high, indicating that normal HRV is required for a successful return, and that the discriminant analysis of HRV indices is useful for return-to-work screening in MDD patients. On the other hand, specificity is low, suggesting that other factors may also affect the outcome of reinstatement.

Essential roles of plexin-B3+ oligodendrocyte precursor cells in the pathogenesis of Alzheimer's disease.

The role of oligodendrocyte lineage cells, the largest glial population in the adult central nervous system (CNS), in the pathogenesis of Alzheimer's disease (AD) remains elusive. Here, we developed a culture method for adult oligodendrocyte progenitor cells (aOPCs). Fibroblast growth factor 2 (FGF2) promotes survival and proliferation of NG2+ aOPCs in a serum-free defined medium; a subpopulation (~5%) of plexin-B3+ aOPCs was also found. FGF2 withdrawal decreased NG2+, but increased plexin-B3+ aOPCs and Aß1-42 secretion. Plexin-B3+ aOPCs were distributed throughout the adult rat brain, although less densely than NG2+ aOPCs. Spreading depolarization induced delayed cortical plexin-B3+ aOPC gliosis in the ipsilateral remote cortex. Furthermore, extracellular Aß1-42 accumulation was occasionally found around plexin-B3+ aOPCs near the lesions. In AD brains, virtually all cortical SPs were immunostained for plexin-B3, and plexin-B3 levels increased significantly in the Sarkosyl-soluble fractions. These findings suggest that plexin-B3+ aOPCs may play essential roles in AD pathogenesis, as natural Aß-secreting cells.

Usefulness of heart rate variability indices in assessing the risk of an unsuccessful return to work after sick leave in depressed patients.

AIM: The present study aimed to examine whether heart rate variability (HRV) indices in depressed patients measured at return to work after sick leave are related to the outcome of reinstatement. METHODS: This study included 30 workers who took a leave of absence due to major depressive disorder. HRV was measured twice, once when participants left work and another when they returned to work. One month after returning to work, 19 participants continued their original work (successful return group), while 11 failed to perform their original work (unsuccessful return group). HRV indices including high- and low-frequency components (HF and LF) were calculated in three conditions within a session lasting for about 5 minutes, initial rest (Rest), mental task (Task), and rest after task (After), and were compared between the two participant groups. Psychological states were evaluated using Self-rating Depression Scale and State-Trait Anxiety Inventory. RESULTS: No significant differences were observed in the HRV indices on leaving work between groups. On returning to work, the "unsuccessful return group" exhibited lower HF Rest score, higher HF Task/Rest ratio, and higher LF/HF Rest score than the "successful return group." Psychological scores improved in both groups. CONCLUSION: These results indicate that autonomic dysregulations revealed by HRV measurement at return to work after a leave of absence in MDD patients were related to the outcome of reinstatement and can serve as useful information for the assessment of the risk of unsuccessful return.

Human Herpesvirus 6B Greatly Increases Risk of Depression by Activating Hypothalamic-Pituitary -Adrenal Axis during Latent Phase of Infection.

Little is known about the effect of latent-phase herpesviruses on their host. Human herpesvirus 6B (HHV-6B) is one of the most ubiquitous herpesviruses, and olfactory astrocytes are one of the most important sites of its latency. Here, we identified SITH-1, an HHV-6B latent protein specifically expressed in astrocytes. Mice induced to produce SITH-1 in their olfactory astrocytes exhibited olfactory bulb apoptosis, a hyper-activated hypothalamic-pituitary-adrenal (HPA) axis and depressive symptoms. The binding of SITH-1 to the host protein calcium-modulating ligand (CAML) to form an activated complex promoted the influx of extracellular calcium. The serum antibody titers for depressive patients with respect to this activated complex were significantly higher than for normal controls (p = 1.78 × 10-15), when the antibody positive rates were 79.8% and 24.4%, respectively, and the odds ratio was 12.2. These results suggest that, in the latent phase, HHV-6B may be involved in the onset of depression.

Ergothioneine, a metabolite of the gut bacterium Lactobacillus reuteri, protects against stress-induced sleep disturbances.

The relationships between depression and gut microbiota, particularly those involving the immune system, have become a major focus of recent research. Here, we analyzed changes in gut microbiota and their sulfur metabolites in the feces of a depression rat model using the modified 14-day social defeat stress (SDS) paradigm. Our results showed that SDS increased fecal Lactobacillus reuteri in correlation with ergothioneine levels at around day 11, which continued for at least 1 month following SDS administration. In vitro study further revealed that L. reuteri is capable of producing ergothioneine. Although the known anti-inflammatory and anti-oxidative actions of ergothioneine suggested that the increased fecal ergothioneine levels may be related to intestinal anti-inflammatory defense mechanisms, no change was observed in the plasma ergothioneine levels during the same observation period, indicating that the defense mechanisms may not be sufficiently reflected in the body. As ergothioneine is a natural ingredient that is absorbed mainly from the upper gastrointestinal tract, we hypothesized that oral ergothioneine may exert antidepressant effects. As expected, oral administration of ergothioneine prior to and during the SDS paradigm had a preventative effect on SDS-induced depressive behaviors, such as social avoidance and depression-like sleep abnormalities, particularly those of rapid eye movement sleep. These findings indicate that ergothioneine, a metabolite of L. reuteri, may be a common substance in the microbiota-gut-brain axis that prevents stress-induced sleep disturbances, especially those associated with depression.

Therapy-refractory schizophrenia in a patient who previously suffered from Meige's syndrome.

The main symptoms of Meige's syndrome are involuntary eye blinking with muddled speech and uncontrollable contraction of the platysma muscle characterized by segmental, primarily oromandibular, dystonia (hyperkinesia). It can also develop after long-term medication of first- and second-generation antipsychotics. Here, we report the case of a Japanese female schizophrenic patient comorbid with Meige's syndrome and hyperthyroidism. We discuss the relationship between the three diseases, that is, schizophrenia, Meige's syndrome, and hyperthyroidism. Our intention is to consider the important role of the cerebral basal ganglia, where little attention has been given in regard to schizophrenia and Meige's syndrome. A part of this article was presented in a poster section at the joint congress of the 28th Annual Meeting of the Japanese Society of Clinical Neuropsychopharmacology and the 48th Annual Meeting of the Japanese Society of Neuropsychopharmacology held in 2018.

Motivation factors for suicidal behavior and their clinical relevance in admitted psychiatric patients.

BACKGROUND: Suicidal behavior (SB) is a major, worldwide health concern. To date there is limited understanding of the associated motivational aspects which accompany this self-initiated conduct. AIMS: To develop a method for identifying motivational features associated with SB by studying admitted psychiatric patients, and to examine their clinical relevance. METHODS: By performing a factor analytic study using data obtained from a patient sample exhibiting high suicidality and a variety of SB methods, Motivations for SB Scale (MSBS) was constructed to measure the features. Data included assessments of DSM-IV psychiatric and personality disorders, suicide intent, depressive symptomatology, overt aggression, recent life events (RLEs) and methods of SB, collated from structured interviews. Association of identified features with clinical variables was examined by correlation analyses and MANCOVA. RESULTS: Factor analyses elicited a 4-factor solution composed of Interpersonal-testing (IT), Interpersonal-change (IC), Self-renunciation (SR) and Self-sustenance (SS). These factors were classified according to two distinctions, namely interpersonal vs. intra-personal directedness, and the level of assumed influence by SB or the relationship to prevailing emotions. Analyses revealed meaningful links between patient features and clinical variables. Interpersonal-motivations (IT and IC) were associated with overt aggression, low suicidality and RLE discord or conflict, while SR was associated with depression, high suicidality and RLE separation or death. Borderline personality disorder showed association with IC and SS. When self-strangulation was set as a reference SB method, self-cutting and overdose-taking were linked to IT and SS, respectively. CONCLUSIONS: The factors extracted in this study largely corresponded to factors from previous studies, implying that they may be useful in a wider clinical context. The association of these features with SB-related factors suggests that they constitute an integral part of the process leading to SB. These results provide a base for further research into clinical strategies for patient management and therapy.

The regulation of soluble receptor for AGEs contributes to carbonyl stress in schizophrenia.

Our previous study showed that enhanced carbonyl stress is closely related to schizophrenia. The endogenous secretory receptor for advanced glycation end-products (esRAGE) is a splice variant of the AGER gene and is one of the soluble forms of RAGE. esRAGE is considered to be a key molecule for alleviating the burden of carbonyl stress by entrapping advanced glycation end-products (AGEs). In the current study, we conducted genetic association analyses focusing on AGER, in which we compared 212 schizophrenic patients to 214 control subjects. We also compared esRAGE levels among a subgroup of 104 patients and 89 controls and further carried out measurements of total circulating soluble RAGE (sRAGE) in 25 patients and 49 healthy subjects. Although the genetic association study yielded inconclusive results, multiple regression analysis indicated that a specific haplotype composed of rs17846798, rs2071288, and a 63 bp deletion, which were in perfect linkage disequilibrium (r2 = 1), and rs2070600 (Gly82Ser) were significantly associated with a marked decrease in serum esRAGE levels. Furthermore, compared to healthy subjects, schizophrenia showed significantly lower esRAGE (p = 0.007) and sRAGE (p = 0.03) levels, respectively. This is the first study to show that serum esRAGE levels are regulated by a newly identified specific haplotype in AGER and that a subpopulation of schizophrenic patients are more vulnerable to carbonyl stress.

Neural stem cells and neuro/gliogenesis in the central nervous system: understanding the structural and functional plasticity of the developing, mature, and diseased brain.

Neurons and glia in the central nervous system (CNS) originate from neural stem cells (NSCs). Knowledge of the mechanisms of neuro/gliogenesis from NSCs is fundamental to our understanding of how complex brain architecture and function develop. NSCs are present not only in the developing brain but also in the mature brain in adults. Adult neurogenesis likely provides remarkable plasticity to the mature brain. In addition, recent progress in basic research in mental disorders suggests an etiological link with impaired neuro/gliogenesis in particular brain regions. Here, we review the recent progress and discuss future directions in stem cell and neuro/gliogenesis biology by introducing several topics presented at a joint meeting of the Japanese Association of Anatomists and the Physiological Society of Japan in 2015. Collectively, these topics indicated that neuro/gliogenesis from NSCs is a common event occurring in many brain regions at various ages in animals. Given that significant structural and functional changes in cells and neural networks are accompanied by neuro/gliogenesis from NSCs and the integration of newly generated cells into the network, stem cell and neuro/gliogenesis biology provides a good platform from which to develop an integrated understanding of the structural and functional plasticity that underlies the development of the CNS, its remodeling in adulthood, and the recovery from diseases that affect it.

Pathways from life-historical events and borderline personality disorder to symptomatic disorders among suicidal psychiatric patients: A study of structural equation modeling.

AIMS: Suicidal behavior (SB) is a major mental health problem. The research has identified many factors related to SB, such as problems in the developmental period and psychiatric and personality disorders. However, the interrelation of these factors has not been clearly delineated. METHODS: The subjects were 155 patients consecutively admitted with SB to a psychiatric center in Tokyo. Structured interviews, including the Structured Clinical Interview for DSM-IV (SCID)-I and SCID-II, were conducted to determine characteristics of the SB-related factors. To illustrate their interrelation, this study applied the technique of structural equation modeling. The latent constructs of life-historical events, borderline personality disorder (BPD) features and three symptomatic disorders (depression, anxiety disorders and substance dependence) were aligned in the chronological order of their manifestation, and connected one another within the model. Indicator variables of life-historical events were maltreatment in the developmental period and early onset of problematic behaviors. Indicators of BPD features and symptomatic disorders included the scales composed of the items in the SCID-I and II. RESULTS: The constructed model with favorable goodness-of-fit indices confirmed that BPD features had a mediating role in which they were influenced by life-historical events, and exerted an influence on the symptomatic disorders. Outside the BPD-mediating paths, the model suggested three clinically interpretable links between life-historical events and symptomatic disorders. CONCLUSIONS: The model of this study demonstrated the pathways from life-historical events and BPD to symptomatic disorders, and indicated a generating process of psychiatric comorbidity among suicidal patients. The wide-range view this study portrayed has important clinical implications, and deserves further substantiation by future studies.

Depression and Alzheimer's disease: novel postmortem brain studies reveal a possible common mechanism.

The relationship between depression and Alzheimer's disease (AD) has always been relevant and controversial. Here, we briefly review epidemiological and biological studies that have investigated these disorders and then introduce our recent research about postmortem brains from patients with major depressive disorder (MDD). Our novel methodological approaches have revealed that MDD may be associated with an unknown type of myelin/myelination abnormalities in the frontopolar cortex. Based mainly on our findings, as well as on neuropathological observations by Braak and Braak (Acta Neuropathol 9, 197-201, 1996), we discuss the possible existence of an as yet unknown common mechanism linking the pathophysiologies underlying both depression and AD.

Increase in the IgG avidity index due to herpes simplex virus type 1 reactivation and its relationship with cognitive function in amnestic mild cognitive impairment and Alzheimer's disease.

After infection with herpes simplex virus type 1 (HSV-1), latent infection persists for life in the trigeminal ganglion and reactivation results in an outbreak of cold sores around the mouth. Many previous studies have reported HSV-1 reactivation to be a risk factor for Alzheimer's disease (AD). This study enrolled subjects with AD (n=85), subjects with amnestic mild cognitive impairment (aMCI; a prodromal stage of AD) (n=34), and healthy controls (n=28). The avidity index of anti-HSV-1 IgG antibodies--a known indicator of HSV-1 reactivation--was measured in order to clarify the relationship between HSV-1 reactivation and symptoms of cognitive function in AD. Cognitive function in AD and aMCI were evaluated using scores from the mini-mental state examination (MMSE) and frontal assessment battery (FAB). The results showed that the subjects with aMCI, for which cerebral function is better preserved than subjects with AD, had a higher anti-HSV-1 IgG antibody avidity index than the AD subjects or healthy controls. Furthermore, the anti-HSV-1 IgG antibody avidity index was even higher in the subjects with high MMSE scores on orientation to time and three-step command subscores. We observed a negative correlation between the anti-HSV-1 IgG antibody avidity index and plasma BDNF concentration, which is an indicator of encephalitis. This suggests that HSV-1 reactivation, as observed through an increase in the anti-HSV-1 IgG avidity index, does not progress to encephalitis. These results suggest that HSV-1 reactivation occurs from the stage of aMCI, which is prodromal to AD, and can affect AD symptoms without an intermediary stage of severe encephalitis. The study demonstrates that the anti-HSV-1 IgG antibody avidity index could be a useful biomarker for the early diagnosis of aMCI as well as AD, and suggests that antiviral medication to treat HSV-1 could play a role in preventing the onset of AD.

Post-hospitalization course and predictive signs of suicidal behavior of suicidal patients admitted to a psychiatric hospital: a 2-year prospective follow-up study.

BACKGROUND: Suicidal patients admitted to a psychiatric hospital are considered to be at risk of suicidal behavior (SB) and suicide. The present study aimed to seek predictors of SB recurrence of the high-risk patients by examining their post-hospitalization course. METHOD: The design was 2-year prospective follow-up study of patients consecutively admitted with SB to a psychiatric center in Tokyo. The DSM-IV diagnoses and SB-related features of subjects were determined in structured interviews. Subsequently, the subjects underwent a series of follow-up assessments at 6-month intervals. The assessment included inquiries into SB recurrence, its accompanying suicidal intent (SI) and SF-8 health survey. Analyses of serial change over time in the follow-up data and Cox proportional hazards regression analyses of SB recurrence were performed. RESULTS: 106 patients participated in this study. The dropout rate during the follow-up was 9%. Within 2 years, incidences of SB as a whole, SB with certain SI (suicide attempt) and suicide were 67% (95% CI 58 - 75%), 38% (95% CI 29 - 47%) and 6% (95% CI 3 - 12%), respectively. Younger age, number of lifetime SBs and maltreatment in the developmental period were predictive of SB as a whole, and younger age and hopelessness prior to index admission were predictive of suicide attempt. Regarding diagnostic variables, anxiety disorders and personality disorders appeared to have predictive value for SB. Additionally, poor physical health assessed during the follow-up was indicated as a possible short-term predictor of SB recurrence. CONCLUSIONS: This study demonstrated a high incidence of SB and suicide and possible predictors of SB recurrence in the post-hospitalization period of psychiatric suicidal patients. Specialized interventions should be developed to reduce the suicide risk of this patient population.

[A flow cytometric postmortem brain study for major depressive disorders: implication for oligodendroglial differentiation and functions].

The neuropathology of psychiatric disorders has long been of interest in psychiatry. Several abnormalities in the prefrontal cortex have been demonstrated in major depressive disorders; however, only a small number of quantitative studies have been conducted, partly because the stereological techniques often used for such investigations are hampered by intrinsically low throughput, typically requiring long periods of time to complete. Recently, we developed a quantitative cell-counting method for frozen unfixed postmortem brains using a flow cytometer. Anisotropic frozen brain tissue was transformed into an isotropic suspension of nuclei; the numbers and fluorescent intensities of 7-AAD(+), a DNA marker, were quantified; and the nuclei were immunolabeled for the neuronal and oligodendroglial nuclear markers, NeuN and olig2, respectively. Using this method, the frontopolar and inferior temporal cortical gray matter of major depressive disorder patients, as well as that of normal controls, was analyzed. We found that the densities of 7-AAD(+) and olig2(+) nuclei in the gray matter tissue of the frontopolar cortex from major depressive disorder subjects were significantly reduced when compared to those from controls, but not in the inferior temporal cortex. Our findings suggest that the pathogenesis of major depressive disorders may involve some abnormalities in cortical myelination in the adult frontopolar cortex.

Neuropathological similarities and differences between schizophrenia and bipolar disorder: a flow cytometric postmortem brain study.

Recent studies suggest that schizophrenia (SCH) and bipolar disorder (BPD) may share a similar etiopathology. However, their precise neuropathological natures have rarely been characterized in a comprehensive and quantitative fashion. We have recently developed a rapid, quantitative cell-counting method for frozen unfixed postmortem brains using a flow cytometer. In the present study, we not only counted stained nuclei, but also measured their sizes in the gray matter of frontopolar cortices (FPCs) and inferior temporal cortices (ITCs) from patients with SCH or BPD, as well as in that from normal controls. In terms of NeuN(+) neuronal nuclei size, particularly in the reduced densities of small NeuN(+) nuclei, we found abnormal distributions present in the ITC gray matter of both patient groups. These same abnormalities were also found in the FPCs of SCH patients, whereas in the FPCs of BPD patients, a reduction in oligodendrocyte lineage (olig2(+)) cells was much more common. Surprisingly, in the SCH FPC, normal left-greater-than-right asymmetry in neural nuclei densities was almost completely reversed. In the BPD FPC, this asymmetry, though not obvious, differed significantly from that in the SCH FPC. These findings indicate that while similar neuropathological abnormalities are shared by patients with SCH or BPD, differences also exist, mainly in the FPC, which may at least partially explain the differences observed in many aspects in these disorders.

Reduced rate of neural differentiation in the dentate gyrus of adult dysbindin null (sandy) mouse.

Genetic variations in the gene encoding dysbindin has consistently been associated with schizophrenia and bipolar disorder, although little is known about the neural functions carried out by dysbindin. To gain some insight into this area, we took advantage of the readily available dysbindin-null mouse sandy (sdy-/-) and studied hippocampal neurogenesis using thymidine analogue bromodeoxuridine (BrdU). No significant differences were found in the proliferation (4 hours) or survival (1, 4 and 8 weeks after the last BrdU injection) of progenitors in the subgranular regions of the dentate gyrus between sdy-/- and sdy+/+ (control) mice. However, 4 weeks after the last BrdU injection, a significant reduction was observed in the ratio of neuronal differentiation in sdy-/- when compared to that of sdy+/+ (sdy+/+  = 87.0 ± 5.3% vs. sdy-/-  = 71.3 ± 8.3%, p = 0.01). These findings suggest that dysbindin plays a role during differentiation process in the adult hippocampal neurogenesis and that its deficit may negatively affect neurogenesis-related functions such as cognition and mood.