Software for non-parametric image registration of 2-photon imaging data.

Functional 2-photon microscopy is a key technology for imaging neuronal activity. The recorded image sequences, however, can contain non-rigid movement artifacts which requires high-accuracy movement correction. Variational optical flow (OF) estimation is a group of methods for motion analysis with established performance in many computer vision areas. However, it has yet to be adapted to the statistics of 2-photon neuroimaging data. In this work, we present the motion compensation method Flow-Registration that outperforms previous alignment tools and allows to align and reconstruct even low signal-to-noise ratio 2-photon imaging data and is able to compensate high-divergence displacements during local drug injections. The method is based on statistics of such data and integrates previous advances in variational OF estimation. Our method is available as an easy-to-use ImageJ/FIJI plugin as well as a MATLAB toolbox with modular, object oriented file IO, native multi-channel support and compatibility with existing 2-photon imaging suites.

Combined Optogenetic Approaches Reveal Quantitative Dynamics of Endogenous Noradrenergic Transmission in the Brain.

Little is known about the real-time cellular dynamics triggered by endogenous catecholamine release despite their importance in brain functions. To address this issue, we expressed channelrhodopsin in locus coeruleus neurons and protein kinase-A activity biosensors in cortical pyramidal neurons and combined two-photon imaging of biosensors with photostimulation of locus coeruleus cortical axons, in acute slices and in vivo. Burst photostimulation of axons for 5-10 s elicited robust, minutes-lasting kinase-A activation in individual neurons, indicating that a single burst firing episode of synchronized locus coeruleus neurons has rapid and lasting effects on cortical network. Responses were mediated by ß1 adrenoceptors, dampened by co-activation of α2 adrenoceptors, and dramatically increased upon inhibition of noradrenaline reuptake transporter. Dopamine receptors were not involved, showing that kinase-A activation was due to noradrenaline release. Our study shows that noradrenergic transmission can be characterized with high spatiotemporal resolution in brain slices and in vivo using optogenetic tools.

Reliability and validity of the Multidimensional Measure of Leader-Member Exchange Japanese version for staff nurses.

AIM: To verify the reliability and validity of Multidimensional Measure of Leader-Member Exchange Japanese version (LMX-MDM-J) for staff nurses. BACKGROUND: Staff nurses who have a high-quality relationship with nurse managers tend to have low turnover intention. However, the validity and reliability of LMX-MDM Japanese version have not been confirmed. METHODS: Staff nurses (n = 870) working in wards of four Japanese hospitals were surveyed using self-administered questionnaires. Reliability was tested by internal consistency. Validity was tested by the confirmatory factor analysis for construct validity and relationships with external criteria for criterion-related validity. RESULTS: There were 450 valid responses. Cronbach's α coefficients of the overall scale and each dimension were 0.97 and 0.86-0.95, respectively. The goodness-of-fit indices of the confirmatory factor analysis showed CFI = 0.981 and RMSEA = 0.076. Correlation coefficients with external criteria were 0.57 for job satisfaction, 0.80 for relationship satisfaction with the nurse manager and -0.36 for turnover intention (all p < .001). CONCLUSION: The reliability and validity of LMX-MDM-J were determined to be adequate for staff nurses. IMPLICATIONS FOR NURSING MANAGEMENT: LMX-MDM-J can accurately measure the quality of the dyadic relationship between nurse managers and staff nurses. This measurement indicates whether nurse managers are providing leadership.

Seasonality in mood and behaviours of Japanese residents in high-latitude regions: transnational cross-sectional study.

BACKGROUND: Daylight hours in high-latitude regions tend to be longer than those in Japan in summer, and shorter than those in Japan in winter. For example, daylight hours in London in winter are one-third those of Tokyo. Therefore, this study investigated and compared seasonal changes in mood and behaviours of Japanese individuals living in and outside Japan. METHODS: Surveys were conducted with Japanese residents in summer and winter in the UK (n = 106), Nordic countries (n = 40), Southeast Asia (n = 50), and Japan (n = 96). First, summer and winter General Health Questionnaire-28 (GHQ28) scores of each regional group were analysed. Subsequently, month-wise differences in mood and behaviours were compared across the four geographical regions. RESULTS: Summer and winter GHQ28 scores of participants living in the UK and Nordic countries differed significantly, while no seasonal differences were observed for residents in Japan and Southeast Asia. Further, in the UK and Nordic countries, summer was associated with better mood and more activity, while winter was linked to lowered mood and reduced activity. CONCLUSION: The results indicate that Japanese living in the UK and Nordic countries (high-latitude regions) experience seasonal fluctuations in depressive symptoms that may be linked to drastic seasonal environmental changes. Observed over a 12-month period, their mood and behaviour declined in winter and improved in summer. Therefore, considering the prevalence of overseas stressors that differ from those in their home country, it is necessary to investigate the effectiveness of support systems that help migrants adapt to seasonal changes in high-latitude regions.

Development and future perspectives of behavioral medicine in Japan.

Development and Future Perspectives of Behavioral Medicine in Japan The study of the "Type A behavior pattern and myocardial infarction" was one of the main themes in the early stage of Behavioral Medicine. After that, behavior modification came to be widely applied to the treatment of various kinds of chronic diseases, and a general concept of Behavioral Medicine was subsequently formed. The Japanese Society of Behavioral Medicine was established in 1992 and is comprised of researchers in the fields of clinical medicine, social medicine, and psycho-behavioral science. Recently, we devised a core curriculum for behavioral science and behavioral medicine and have published a Japanese version of the "Textbook of Behavioral Medicine" in conformity with it. It is a primer that includes all of the basics and clinical applications of Behavioral Medicine and is edited as a manual that can be utilized in clinical practice. We hope this book will contribute to the development of Behavioral Medicine in Japan, to a more healthy life for our people, and to the improvement of the QOL of our patients. In this paper, I discuss the future perspectives from my personal opinion while looking back on the history of Behavioral Medicine in Japan.

Differential reactivity of attention biases in patients with social anxiety disorder

Information-processing biases based on cognitive and cognitive behavioral models have been reported in social anxiety disorder (SAD). One such bias is the attention bias, or selectively attending to threat stimuli. This bias has been associated in anxiety with maintenance and worsening of SAD symptoms. The objective of the present study was to examine, compare, and clarify differences in attention biases to language stimuli between SAD patients and healthy people. Results indicated, no differences between the two groups, but differences were seen in the attention bias score among SAD patients. This suggests that there is an increased threat effect among SAD patients triggered by their attention bias toward social threat stimuli (AU)

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Anger tendency may be associated with duration of illness in panic disorder.

BACKGROUND: Several studies have reported an increased tendency towards anger in patients with panic disorder (PD). If this propensity for anger arises from the pathological process of PD, it may be associated with the duration of the illness. The present study therefore examined the relationship between duration of PD and the personality tendency to experience anger in PD patients. METHODS: Participants were 413 patients (132 men and 281 women; age = 38.7 years) with PD. Diagnoses were confirmed using the Mini-International Neuropsychiatric Interview. Illness duration ranged from less than a year to 51 years. After participants completed the Revised NEO Personality Inventory, we examined the association between illness duration and the Angry Hostility and Impulsiveness subscale scores. In the analysis, participants were divided into two groups by duration of illness (long group, n = 186 and short group, n = 200) using the median value (9 years) as a cut-off because of the skewed distribution of the duration. Patients with an illness duration of 9 years (n = 27) were excluded from the comparison. RESULTS: The duration of illness was significantly correlated with the Angry Hostility score (p = 0.002) after controlling for age. Scores were significantly higher in the long group than in the short group (p = 0.04). No significant association was observed between Impulsiveness scores and duration of illness. CONCLUSION: The present study suggests that longer PD duration is related to a stronger tendency to experience anger.

Effect of prolonged stress on the adrenal hormones of individuals with irritable bowel syndrome.

BACKGROUND: The purpose of this study was to investigate the effect of prolonged stress on the salivary adrenal hormones (cortisol, dehydroepiandrosterone [DHEA], DHEA-sulfate [DHEA-S]) of individuals with irritable bowel syndrome (IBS). METHODS: The participants were female college students, including 10 with IBS and 16 without IBS (control group), who were scheduled for a 2-week teaching practice at a kindergarten. Participants were asked to collect saliva for determining adrenal hormones immediately and 30 min after awakening and before sleep, 2 weeks before the practice, the first week of the practice, the second week of the practice, and a few days after the practice. RESULTS: Regarding cortisol/DHEA ratio, significantly increased levels were found during the first week of the practice, and a significant interaction between group and time was found; the ratio at 30 min after awakening in the IBS group was higher than that in the control group. For the other adrenal hormone indexes, no significant differences due to the presence of IBS were found. CONCLUSIONS: Individuals with IBS showed an elevated cortisol/DHEA ratio after awakening compared with individuals without IBS, and the elevated ratio peaked under the prolonged stress. The present study suggests that the cortisol effect is dominant in individuals with IBS under prolonged stress.

Salivary 3-methoxy-4-hydroxyphenylglycol increases after awakening in healthy young adults.

Levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) may reflect central noradrenergic activity. In this study, we investigated salivary MHPG changes after awakening, and explored their relationships with cortisol and peripheral autonomic activity. The participants were 25 college students. Saliva samples were collected on awakening and 30 min after awakening to determine MHPG and cortisol. Ambulatory electrocardiograms were obtained to assess heart rate, cardiac sympathetic index (CSI), and cardiac vagal index (CVI) before and after awakening. MHPG levels increased significantly during the first 30 min after awakening. Similarly, cortisol, heart rate, and CSI increased during the 30 min after awakening, but changes in MHPG did not correlate with changes in cortisol, heart rate, CSI, and CVI during that period. This study demonstrated that salivary MHPG levels increase after awakening, in common with cortisol, heart rate, and cardiac sympathetic activity.

Glutamate receptors of the delta family are widely expressed in the adult brain.

Recent reports point to critical roles of glutamate receptor subunit delta2 (GluD2) at excitatory synapses and link GluD1 gene alteration to schizophrenia but the expression patterns of these subunits in the brain remain almost uncharacterized. We examined the distribution of GluD1-2 mRNAs and proteins in the adult rodent brain, focusing mainly on GluD1. In situ hybridization revealed widespread neuronal expression of the GluD1 mRNA, with higher levels occurring in several forebrain regions and lower levels in cerebellum. Quantitative RT-PCR assessed differential GluD1 expression in cortex and cerebellum, and revealed GluD2 expression in cortex, albeit at markedly lower level than in cerebellum. Likewise, a high GluD1/GluD2 mRNA ratio was observed in cortex and a low ratio in cerebellum. GluD1 and GluD2 mRNAs were co-expressed in single cortical and hippocampal neurons, with a large predominance of GluD1. Western blots using GluD1- and GluD2-specific antibodies showed expression of both subunits in various brain structures, but not in non-nervous tissues examined. Both delta subunits were upregulated during postnatal development. Widespread neuronal expression of the GluD1 protein was confirmed using immunohistochemistry. Examination at the electron microscopic level in the hippocampus revealed that GluD1 was mainly localized at postsynaptic density of excitatory synapses on pyramidal cells. Control experiments performed using mice carrying deletion of the GluD1- or the GluD2-encoding gene confirmed the specificity of the present mRNA and protein analyses. Our results support a role for the delta family of glutamate receptors at excitatory synapses in neuronal networks throughout the adult brain.

Noradrenalin and dopamine receptors both control cAMP-PKA signaling throughout the cerebral cortex.

Noradrenergic fibers innervate the entire cerebral cortex, whereas the cortical distribution of dopaminergic fibers is more restricted. However, the relative functional impact of noradrenalin and dopamine receptors in various cortical regions is largely unknown. Using a specific genetic label, we first confirmed that noradrenergic fibers innervate the entire cortex whereas dopaminergic fibers were present in all layers of restricted medial and lateral areas but only in deep layers of other areas. Imaging of a genetically encoded sensor revealed that noradrenalin and dopamine widely activate PKA in cortical pyramidal neurons of frontal, parietal and occipital regions with scarce dopaminergic fibers. Responses to noradrenalin had higher amplitude, velocity and occurred at more than 10-fold lower dose than those elicited by dopamine, whose amplitude and velocity increased along the antero-posterior axis. The pharmacology of these responses was consistent with the involvement of Gs-coupled beta1 adrenergic and D1/D5 dopaminergic receptors, but the inhibition of both noradrenalin and dopamine responses by beta adrenergic antagonists was suggestive of the existence of beta1-D1/D5 heteromeric receptors. Responses also involved Gi-coupled alpha2 adrenergic and D2-like dopaminergic receptors that markedly reduced their amplitude and velocity and contributed to their cell-to-cell heterogeneity. Our results reveal that noradrenalin and dopamine receptors both control cAMP-PKA signaling throughout the cerebral cortex with moderate regional and laminar differences. These receptors can thus mediate widespread effects of both catecholamines, which are reportedly co-released by cortical noradrenergic fibers beyond the territory of dopaminergic fibers.

The preliminary study of individual cognitive behavior therapy for Japanese patients with social anxiety disorder.

Research has demonstrated the effectiveness of both individual and group cognitive behavior therapy (CBT) programs for social anxiety disorder (SAD) with patients in many countries. The present preliminary study reports the effectiveness of individual CBT for Japanese patients with SAD. Fifteen outpatients diagnosed with SAD completed an individual CBT program of six 50-min sessions with several components, including cognitive restructuring to modify cost and probability bias, repeated speech exposure, and homework about idiosyncratic anxiety-provoking situations. The results show that SAD symptoms improved after completion of the program. Large effect sizes were found for cognitive factors of SAD. In addition, repeated speech exposure was highly effective for improving the self-perception of subjective anxiety. The present findings suggest that an individual CBT program can be effective for reducing SAD symptoms with Japanese patients.

Analysis for distinctive activation patterns of pain and itchy in the human brain cortex measured using near infrared spectroscopy (NIRS).

Pain and itch are closely related sensations, yet qualitatively quite distinct. Despite recent advances in brain imaging techniques, identifying the differences between pain and itch signals in the brain cortex is difficult due to continuous temporal and spatial changes in the signals. The high spatial resolution of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) has substantially advanced research of pain and itch, but these are uncomfortable because of expensiveness, importability and the limited operation in the shielded room. Here, we used near infrared spectroscopy (NIRS), which has more conventional usability. NIRS can be used to visualize dynamic changes in oxygenated hemoglobin and deoxyhemoglobin concentrations in the capillary networks near activated neural circuits in real-time as well as fMRI. We observed distinct activation patterns in the frontal cortex for acute pain and histamine-induced itch. The prefrontal cortex exhibited a pain-related and itch-related activation pattern of blood flow in each subject. Although it looked as though that activation pattern for pain and itching was different in each subject, further cross correlation analysis of NIRS signals between each channels showed an overall agreement with regard to prefrontal area involvement. As a result, pain-related and itch-related blood flow responses (delayed responses in prefrontal area) were found to be clearly different between pain (τ = +18.7 sec) and itch (τ = +0.63 sec) stimulation. This is the first pilot study to demonstrate the temporal and spatial separation of a pain-induced blood flow and an itch-induced blood flow in human cortex during information processing.

An increase in salivary interleukin-6 level following acute psychosocial stress and its biological correlates in healthy young adults.

Although interleukin-6 (IL-6) has been investigated frequently in stress research, knowledge regarding the biological processes of IL-6 in association with psychosocial stress remains incomplete. This study focused on salivary IL-6 and reports its temporal variation and biological correlates following acute psychosocial stress. Fifty healthy young adults (39 male and 11 female students) were subjected to the psychosocial stress test 'Trier Social Stress Test' (TSST), wherein the participants were asked to deliver a speech and perform a mental arithmetic task in front of 2 audiences. Collection of saliva samples, measurement of heart rate, and assessment of negative moods by visual analogue scales were conducted before, during, and after TSST. Salivary IL-6 levels increased by approximately 50% in response to the TSST and remained elevated for 20 min after the stress tasks were completed. Cluster analyses revealed that individuals with sustained elevation of IL-6 levels following the TSST exhibited a lower cortisol response compared to individuals with lower IL-6 levels. In the correlation analyses, a greater IL-6 response was associated with a higher heart rate during the mental arithmetic task (r=.351, p<.05) and with a lower cortisol response (r=-.302, p<.05). This study demonstrates that salivary IL-6 levels are elevated for a relatively long period following acute psychosocial stress, and suggests that sympathetic activity and cortisol secretion are involved in elevation of salivary IL-6 levels.

Irritable bowel syndrome, its cognition, anxiety sensitivity, and anticipatory anxiety in panic disorder patients.

AIM: The present study examined the effect of irritable bowel syndrome (IBS), cognitive appraisal of IBS, and anxiety sensitivity on anticipatory anxiety (AA) and agoraphobia (AG) in patients with panic disorder (PD). METHODS: We examined 244 PD patients who completed a set of questionnaires that included the Rome II Modular Questionnaire to assess the presence of IBS, the Anxiety Sensitivity Index (ASI), the Cognitive Appraisal Rating Scale (CARS; assessing the cognitive appraisal of abdominal symptoms in four dimensions: commitment, appraisal of effect, appraisal of threat, and controllability), and items about the severity of AA and AG. The Mini International Neuropsychiatric Interview was used to diagnose AG and PD. RESULTS: After excluding individuals with possible organic gastrointestinal diseases by using 'red flag items,' valid data were obtained from 174 participants, including 110 PD patients without IBS (PD/IBS[-]) and 64 with IBS (PD/IBS[+]). The PD/IBS[+] group had higher AA and higher comorbidity with AG than the PD/IBS[-] group. In the PD/IBS[+] group, the controllability score of CARS was significantly correlated with AA and ASI. Multiple regression analysis showed a significant effect of ASI but not of controllability on AA in PD/IBS[+] subjects. CONCLUSION: This study suggested that the presence of IBS may be related to agoraphobia and anticipatory anxiety in PD patients. Cognitive appraisal could be partly related to anticipatory anxiety in PD patients with IBS with anxiety sensitivity mediating this correlation.

Prevalence of bipolar disorder in panic disorder patients in the Japanese population.

BACKGROUND: We examined the rate of bipolar I (BPD-I) and bipolar II disorders (BPD-II) in panic disorder (PD) patients, and compared clinical and psychological variables between PD patients with and without bipolar disorders (BPD). METHODS: Participants were 649 Japanese patients with PD (215 men and 434 women, 38.49 ± 10.40 years) at outpatient clinics for anxiety disorders. Constructive interviews using the Mini-International Neuropsychiatric Interview (MINI) were conducted to confirm the diagnosis of PD, agoraphobia, and BPD, as well as the presence and severity of suicide risk in each subject. Clinical records were also reviewed to confirm the diagnosis of PD and BPD. Participants then completed several questionnaires, including the State Trait Anxiety Inventory-Trait scale, the Anxiety Sensitivity Index, and the Revised Neuroticism-Extraversion- Openness Personality Inventory (NEO-PI-R). RESULTS: We found that 22.34% of the PD patients had BPD (BPD-I: 5.24%, BPD-II: 17.10%). PD patients with BPD-I showed higher prevalence and severity of suicide risk, trait anxiety, anxiety sensitivity, and neuroticism, and lower agreeableness (subscales of the NEO-PI-R) than those with BPD-II and those without BPD. LIMITATION: First, we could not investigate the order of the onset of PD and BPD. Second, BPD patients without PD were not studied as another control group for PD patients with BPD. CONCLUSION: PD patients had high prevalence of BPD. Both PD patients with BPD-I and those with BPD-II had high severity of suicide risk, trait anxiety, anxiety sensitivity, neuroticism, and agreeableness, though these characteristics were more prominent in patients with BPD-I.

Psychological distress of the bereaved seeking medical counseling at a cancer center.

OBJECTIVE: The death of a loved one is one of the most stressful events in life and is related to the physical and psychological wellbeing of the bereaved. Some bereaved individuals seek medical counseling to alleviate their distress. However, no studies have focused on the bereaved who have lost a loved one to cancer and have asked for medical help at a cancer center as a result. The aim of this study was to investigate the distress of the bereaved who sought consultation, as basic information for considering support. METHODS: We conducted a survey of people consulting outpatient services for bereaved families between April 2007 and September 2009. Data were obtained from medical records at initial consultation and qualitatively analyzed by content analysis using all statements related to their distress. RESULTS: Their statements were classified into 11 categories, which were further classified into six themes. The main categories of bereavement-related distress were as follows: (i) regret; (ii) anger; (iii) memories; (iv) loneliness; (v) anxiety; and (vi) hopelessness. 'Regret' was frequently recognized in their distress and it includes some points related to the cancer trajectory. CONCLUSIONS: Psychological distresses of the bereaved who have lost a loved one and have asked for medical counseling are revealed. Their distresses are strongly related to the cancer trajectory of a family member. Some of these distresses are related to medical misunderstanding about the course of cancer. These findings might provide basic information for considering their appropriate treatment.

Adrenal hormone response and psychophysiological correlates under psychosocial stress in individuals with irritable bowel syndrome.

OBJECTIVE: In this study, we investigated levels and relative ratios of adrenal hormones (including cortisol, dehydroepiandrosterone [DHEA], and DHEA-sulfate [DHEA-S]) and their psychophysiological correlates under acute psychosocial stress in individuals with irritable bowel syndrome (IBS). METHODS: Fifty-three college students participated in the study (male: 42, female: 11; mean age: 22.64years), including 13 individuals with IBS (IBS group) and 40 individuals without IBS (control group). The participants were exposed to a standardized laboratory stressor, which included delivering a speech and performing a mental arithmetic task. We measured subjective stress levels and salivary cortisol, DHEA, and DHEA-S levels at relevant time points before, during, and after the tasks. RESULTS: DHEA-S level and the DHEA-S/DHEA ratio in the IBS group were significantly lower than those in the control group, and the cortisol/DHEA-S ratio in the IBS group was higher than that in the control group throughout the experiment. In the IBS group, the appraisal of a threat was positively correlated with cortisol levels (r=0.61), and the appraisal of controllability was negatively correlated with cortisol levels (r=-0.64) and with the cortisol/DHEA ratio (r=-0.71). The control group showed a significant positive correlation between the appraisal of threat and cortisol levels (r=0.32). CONCLUSION: The present study indicates that individuals with IBS had lower DHEA-S levels, and that their stressful cognitive appraisals under acute psychosocial stress caused the effects of cortisol to dominate. This adrenal hormone response may be involved in exacerbating abdominal symptoms in individuals with IBS.

Relationship between cognitive factors and anxiety in individuals with irritable bowel syndrome.

BACKGROUND: Individuals with irritable bowel syndrome (IBS) have high anxiety. There is insufficient information about the relationships between concrete cognitive contents and anxiety in IBS. PURPOSE: The present study investigated the relationship between cognitive factors and anxiety in individuals with IBS. METHOD: The participants were 1,087 college students (male, 506; female, 576; unidentified, 5; age, 19.72 ± 1.76 years) who completed a set of questionnaires that included the Rome II Modular Questionnaire (based on diagnostic criteria for IBS), Anxiety Sensitivity Index (ASI), Cognitive Appraisal Rating Scale (CARS; subscales: commitment, appraisal of effect, appraisal of threat, and controllability) for measuring symptom-related cognition, an item about attention to abdominal symptoms, the Hospital Anxiety and Depression Scale-Anxiety Scale (HADS-A), and an item regarding the presence of avoidant behavior due to anxiety of IBS symptoms. RESULTS: The participants included 881 individuals without IBS and 206 individuals with IBS. Individuals with IBS had higher ASI and HADS-A scores than those of the individuals belonging to the control group (p < 0.001). Subscale scores of CARS (except those of controllability and attention to IBS symptoms) significantly correlated with the ASI and HADS-A scores (p < 0.01). Individuals with IBS and avoidant behavior had higher subscale scores of CARS (except those of controllability and attention to IBS symptoms) and higher HADS-A scores (p < 0.05). The hypothetical models containing ASI scores, subscale scores of CARS (except those of controllability), and HADS-A scores with and without attention to IBS symptoms exhibited a good fit. CONCLUSION: Severe anxiety sensitivity in individuals with IBS related to their symptom-related cognition, and the altered cognition increases anxiety, leading to the possible development of a disabling condition.