Tracing the origin of hair follicle stem cells.

Tissue stem cells are generated from a population of embryonic progenitors through organ-specific morphogenetic events1,2. Although tissue stem cells are central to organ homeostasis and regeneration, it remains unclear how they are induced during development, mainly because of the lack of markers that exclusively label prospective stem cells. Here we combine marker-independent long-term 3D live imaging and single-cell transcriptomics to capture a dynamic lineage progression and transcriptome changes in the entire epithelium of the mouse hair follicle as it develops. We found that the precursors of different epithelial lineages were aligned in a 2D concentric manner in the basal layer of the hair placode. Each concentric ring acquired unique transcriptomes and extended to form longitudinally aligned, 3D cylindrical compartments. Prospective bulge stem cells were derived from the peripheral ring of the placode basal layer, but not from suprabasal cells (as was previously suggested3). The fate of placode cells is determined by the cell position, rather than by the orientation of cell division. We also identified 13 gene clusters: the ensemble expression dynamics of these clusters drew the entire transcriptional landscape of epithelial lineage diversification, consistent with cell lineage data. Combining these findings with previous work on the development of appendages in insects4,5, we describe the 'telescope model', a generalized model for the development of ectodermal organs in which 2D concentric zones in the placode telescope out to form 3D longitudinally aligned cylindrical compartments.

The basement membrane of hair follicle stem cells is a muscle cell niche.

The hair follicle bulge in the epidermis associates with the arrector pili muscle (APM) that is responsible for piloerection ("goosebumps"). We show that stem cells in the bulge deposit nephronectin into the underlying basement membrane, thus regulating the adhesion of mesenchymal cells expressing the nephronectin receptor, α8ß1 integrin, to the bulge. Nephronectin induces α8 integrin-positive mesenchymal cells to upregulate smooth muscle markers. In nephronectin knockout mice, fewer arrector pili muscles form in the skin, and they attach to the follicle above the bulge, where there is compensatory upregulation of the nephronectin family member EGFL6. Deletion of α8 integrin also abolishes selective APM anchorage to the bulge. Nephronectin is a Wnt target; epidermal ß-catenin activation upregulates epidermal nephronectin and dermal α8 integrin expression. Thus, bulge stem cells, via nephronectin expression, create a smooth muscle cell niche and act as tendon cells for the APM. Our results reveal a functional role for basement membrane heterogeneity in tissue patterning. PAPERCLIP:

Psychometric properties of the Alcohol Use Disorders Identification Test (AUDIT) across cross-cultural subgroups, genders, and sexual orientations: Findings from the International Sex Survey (ISS).

INTRODUCTION: Despite being a widely used screening questionnaire, there is no consensus on the most appropriate measurement model for the Alcohol Use Disorders Identification Test (AUDIT). Furthermore, there have been limited studies on its measurement invariance across cross-cultural subgroups, genders, and sexual orientations. AIMS: The present study aimed to examine the fit of different measurement models for the AUDIT and its measurement invariance across a wide range of subgroups by country, language, gender, and sexual orientation. METHODS: Responses concerning past-year alcohol use from the participants of the cross-sectional International Sex Survey were considered (N = 62,943; Mage: 32.73; SD = 12.59). Confirmatory factor analysis, as well as measurement invariance tests were performed for 21 countries, 14 languages, three genders, and four sexual-orientation subgroups that met the minimum sample size requirement for inclusion in these analyses. RESULTS: A two-factor model with factors describing 'alcohol use' (items 1-3) and 'alcohol problems' (items 4-10) showed the best model fit across countries, languages, genders, and sexual orientations. For the former two, scalar and latent mean levels of invariance were reached considering different criteria. For gender and sexual orientation, a latent mean level of invariance was reached. CONCLUSIONS: In line with the two-factor model, the calculation of separate alcohol-use and alcohol-problem scores is recommended when using the AUDIT. The high levels of measurement invariance achieved for the AUDIT support its use in cross-cultural research, capable also of meaningful comparisons among genders and sexual orientations.

Tracing the developmental origin of tissue stem cells.

Tissue stem cells are vital for organ homeostasis and regeneration owing to their ability to self-renew and differentiate into the various cell types that constitute organ tissue. These stem cells are formed during complex and dynamic organ development, necessitating spatial-temporal coordination of morphogenetic events and cell fate specification during this process. In recent years, technological advances have enabled the tracing of the cellular dynamics, states, and lineages of individual cells over time in relation to tissue morphological changes. These dynamic data have not only revealed the origin of tissue stem cells in various organs but have also led to an understanding of the molecular, cellular, and biophysical bases of tissue stem cell formation. Herein, we summarize recent findings on the developmental origin of tissue stem cells in the hair follicles, intestines, brain, skeletal muscles, and hematopoietic system, and further discuss how stem cell fate specification is coordinated with tissue topology.

Relationship between regional gray matter volumes and dopamine D2 receptor and transporter in living human brains.

Although striatal dopamine neurotransmission is believed to be functionally linked to the formation of the corticostriatal network, there has been little evidence for this regulatory process in the human brain and its disruptions in neuropsychiatric disorders. Here, we aimed to investigate associations of striatal dopamine transporter (DAT) and D2 receptor availabilities with gray matter (GM) volumes in healthy humans. Positron emission tomography images of D2 receptor (n = 34) and DAT (n = 17) captured with the specific radioligands [11 C]raclopride and [18 F]FE-PE2I, respectively, were acquired along with T1-weighted magnetic resonance imaging data in our previous studies, and were re-analyzed in this work. We quantified the binding potentials (BPND ) of these radioligands in the limbic, executive, and sensorimotor functional subregions of the striatum. Correlations between the radioligand BPND and regional GM volume were then examined by voxel-based morphometry. In line with the functional and anatomical connectivity, [11 C]raclopride BPND in the limbic striatum was positively correlated with volumes of the uncal/parahippocampal gyrus and adjacent temporal areas. Similarly, we found positive correlations between the BPND of this radioligand in the executive striatum and volumes of the prefrontal cortices and their adjacent areas as well as between the BPND in the sensorimotor striatum and volumes of the somatosensory and supplementary motor areas. By contrast, no significant correlation was found between [18 F]FE-PE2I BPND and regional GM volumes. Our results suggest unique structural and functional corticostriatal associations involving D2 receptor in healthy humans, which might be partially independent of the nigrostriatal pathway reflected by striatal DAT.

Autistic traits are associated with the functional connectivity of between-but not within-attention systems in the general population.

BACKGROUND: Previous studies have demonstrated that individuals with autism spectrum disorder (ASD) exhibit dysfunction in the three attention systems (i.e., alerting, orienting, and executive control) as well as atypical relationships among these systems. Additionally, other studies have reported that individuals with subclinical but high levels of autistic traits show similar attentional tendencies to those observed in ASD. Based on these findings, it was hypothesized that autistic traits would affect the functions and relationships of the three attention systems in a general population. Resting-state functional magnetic resonance imaging (fMRI) was performed in 119 healthy adults to investigate relationships between autistic traits and within- and between-system functional connectivity (FC) among the three attention systems. Twenty-six regions of interest that were defined as components of the three attention systems by a previous task-based fMRI study were examined in terms of within- and between-system FC. We assessed autistic traits using the Autism-Spectrum Quotient. RESULTS: Correlational analyses revealed that autistic traits were significantly correlated with between-system FC, but not with within-system FC. CONCLUSIONS: Our results imply that a high autistic trait level, even when subclinical, is associated with the way the three attention systems interact.

Multi-tasking epidermal stem cells: Beyond epidermal maintenance.

Over the past decade, multiple stem cell compartments have been identified within the epidermis. These stem cell pools have different transcriptional properties, proliferative modes and anatomical locations, and they maintain distinct epidermal compartments. The importance of this stem cell heterogeneity and compartmentalization has been understood as a key feature in epidermal homeostasis. However, recent studies have revealed that these heterogeneous stem cells themselves act as a niche for neighboring cells, thereby establishing spatially and temporally patterned epidermal-dermal functional units. These studies provide a new perspective for interpreting the biological significance of stem cell heterogeneity and compartmentalization beyond their role in epidermal maintenance.

Affinity States of Striatal Dopamine D2 Receptors in Antipsychotic-Free Patients with Schizophrenia.

Background: Dopamine D2 receptors are reported to have high-affinity (D2High) and low-affinity (D2Low) states. Although an increased proportion of D2High has been demonstrated in animal models of schizophrenia, few clinical studies have investigated this alteration of D2High in schizophrenia in vivo. Methods: Eleven patients with schizophrenia, including 10 antipsychotic-naive and 1 antipsychotic-free individuals, and 17 healthy controls were investigated. Psychopathology was assessed by Positive and Negative Syndrome Scale, and a 5-factor model was used. Two radioligands, [11C]raclopride and [11C]MNPA, were employed to quantify total dopamine D2 receptor and D2High, respectively, in the striatum by measuring their binding potentials. Binding potential values of [11C]raclopride and [11C]MNPA and the binding potential ratio of [11C]MNPA to [11C]raclopride in the striatal subregions were statistically compared between the 2 diagnostic groups using multivariate analysis of covariance controlling for age, gender, and smoking. Correlations between binding potential and Positive and Negative Syndrome Scale scores were also examined. Results: Multivariate analysis of covariance demonstrated a significant effect of diagnosis (schizophrenia and control) on the binding potential ratio (P=.018), although the effects of diagnosis on binding potential values obtained with either [11C]raclopride or [11C]MNPA were nonsignificant. Posthoc test showed that the binding potential ratio was significantly higher in the putamen of patients (P=.017). The Positive and Negative Syndrome Scale "depressed" factor in patients was positively correlated with binding potential values of both ligands in the caudate. Conclusions: The present study indicates the possibilities of: (1) a higher proportion of D2High in the putamen despite unaltered amounts of total dopamine D2 receptors; and (2) associations between depressive symptoms and amounts of caudate dopamine D2 receptors in patients with schizophrenia.

Epidermal Wnt/ß-catenin signaling regulates adipocyte differentiation via secretion of adipogenic factors.

It has long been recognized that the hair follicle growth cycle and oscillation in the thickness of the underlying adipocyte layer are synchronized. Although factors secreted by adipocytes are known to regulate the hair growth cycle, it is unclear whether the epidermis can regulate adipogenesis. We show that inhibition of epidermal Wnt/ß-catenin signaling reduced adipocyte differentiation in developing and adult mouse dermis. Conversely, ectopic activation of epidermal Wnt signaling promoted adipocyte differentiation and hair growth. When the Wnt pathway was activated in the embryonic epidermis, there was a dramatic and premature increase in adipocytes in the absence of hair follicle formation, demonstrating that Wnt activation, rather than mature hair follicles, is required for adipocyte generation. Epidermal and dermal gene expression profiling identified keratinocyte-derived adipogenic factors that are induced by ß-catenin activation. Wnt/ß-catenin signaling-dependent secreted factors from keratinocytes promoted adipocyte differentiation in vitro, and we identified ligands for the bone morphogenetic protein and insulin pathways as proadipogenic factors. Our results indicate epidermal Wnt/ß-catenin as a critical initiator of a signaling cascade that induces adipogenesis and highlight the role of epidermal Wnt signaling in synchronizing adipocyte differentiation with the hair growth cycle.

Neuroimaging studies of social cognition in schizophrenia.

Impaired social cognition is considered a core contributor to unfavorable psychosocial functioning in schizophrenia. Rather than being a unitary process, social cognition is a collection of multifaceted processes that recruit multiple brain structures, thus structural and functional neuroimaging techniques are ideal methodologies for revealing the underlying pathophysiology of impaired social cognition. Many neuroimaging studies have suggested that in addition to white-matter deficits, schizophrenia is associated with decreased gray-matter volume in multiple brain areas, especially fronto-temporal and limbic regions. However, few schizophrenia studies have examined associations between brain abnormalities and social cognitive disabilities. During the last decade, we have investigated structural brain abnormalities in schizophrenia using high-resolution magnetic resonance imaging, and our findings have been confirmed by us and others. By assessing different types of social cognitive abilities, structural abnormalities in multiple brain regions have been found to be associated with disabilities in social cognition, such as recognition of facial emotion, theory of mind, and empathy. These structural deficits have also been associated with alexithymia and quality of life in ways that are closely related to the social cognitive disabilities found in schizophrenia. Here, we overview a series of neuroimaging studies from our laboratory that exemplify current research into this topic, and discuss how it can be further tackled using recent advances in neuroimaging technology.

Norepinephrine transporter occupancy by nortriptyline in patients with depression: a positron emission tomography study with (S,S)-[¹8F]FMeNER-D2.

Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is a NET-selective tricyclic antidepressant (TCAs) that has been widely used for the treatment of depression. Previous positron emission tomography (PET) studies have reported over 80% serotonin transporter occupancy with clinical doses of selective serotonin reuptake inhibitors (SSRIs), but there has been no report of NET occupancy in patients treated with relatively NET-selective antidepressants. In the present study, we used PET and (S,S)-[18¹8F]FMeNER-D2 to investigate NET occupancies in the thalamus in 10 patients with major depressive disorder taking various doses of nortriptyline, who were considered to be responders to the treatment. Reference data for the calculation of occupancy were derived from age-matched healthy controls. The result showed approximately 50-70% NET occupancies in the brain as a result of the administration of 75-200 mg/d of nortriptyline. The estimated effective dose (ED50) and concentration (EC50) required to induce 50% occupancy was 65.9 mg/d and 79.8 ng/ml, respectively. Furthermore, as the minimum therapeutic level of plasma nortriptyline for the treatment of depression has been reported to be 70 ng/ml, our data indicate that this plasma nortriptyline concentration corresponds to approximately 50% NET occupancy measured with PET, suggesting that more than 50% of central NET occupancy would be appropriate for the nortriptyline treatment of patients with depression.

Oncogenic Kras induces spatiotemporally specific tissue deformation through converting pulsatile into sustained ERK activation.

Tissue regeneration and maintenance rely on coordinated stem cell behaviours. This orchestration can be impaired by oncogenic mutations leading to cancer. However, it is largely unclear how oncogenes perturb stem cells' orchestration to disrupt tissue. Here we used intravital imaging to investigate the mechanisms by which oncogenic Kras mutation causes tissue disruption in the hair follicle. Through longitudinally tracking hair follicles in live mice, we found that KrasG12D, a mutation that can lead to squamous cell carcinoma, induces epithelial tissue deformation in a spatiotemporally specific manner, linked with abnormal cell division and migration. Using a reporter mouse capture real-time ERK signal dynamics at the single-cell level, we discovered that KrasG12D, but not a closely related mutation HrasG12V, converts ERK signal in stem cells from pulsatile to sustained. Finally, we demonstrated that interrupting sustained ERK signal reverts KrasG12D-induced tissue deformation through modulating specific features of cell migration and division.

Profiling and assessing the risks of image- and performance-enhancing drugs use during the COVID-19 lockdown.

Background: Image and Performance-Enhancing Drugs (IPEDs) can enhance mental and physical capabilities and impact one's overall health. Initially confined in sport environments, IPEDs use has become increasingly widespread in a high-performing society. The present study was aimed at profiling IPEDs use during the COVID-19 lockdown among an international sample of young adults. Methods: A cross-sectional observational study was carried out in eight countries (United Kingdom, Italy, Lithuania, Hungary, Portugal, Spain, Brazil, and Japan) between April and May 2020. The survey questionnaire included validated measurements such as Exercise Addiction Inventory (EAI), Appearance Anxiety Inventory (AAI), and Self-Compassion Scale (SCS) as well as questions about the type of IPEDs, purchasing methods and socio-demographic information. Results: A total of 736 IPEDs users were included in the survey. Their mean age was 33.05 years (±SD = 10.06), and 64.2% were female participants. Overall, 6.8% were found at risk of exercise addiction (EAI >24), 27.6% presented high levels of appearance anxiety, and 24.9% revealed low levels of emotional regulation's self-compassion. Most participants (55.6%) purchased IPEDs through pharmacies/specialized shops, while 41.3% purchased IPEDs on the Internet. Online IPEDs buyers were mainly men who had higher scores on the Exercise Addiction Inventory. One or more IPEDs classifiable as "potentially risky" were used by 66.3% of the sample. Users of "potentially risky IPEDs" were younger and primarily men. They showed higher scores both on the Exercise Addiction Inventory and Appearance Anxiety Inventory. Conclusion: This study profiled users of IPEDs when the most restrictive COVID-19 lockdown policies were implemented in all the participating countries. More targeted post-COVID 19 prevention strategies should be implemented according to the emerged socio-demographic and psychopathological traits and cross-cultural differences emerged. Longitudinal studies will also be needed to determine the long-term effect of the COVID-19 lockdown on IPEDs consumption.

Cross-cultural validation and measurement invariance of anxiety and depression symptoms: A study of the Brief Symptom Inventory (BSI) in 42 countries.

BACKGROUND: Depression and anxiety are among the most prevalent mental health issues experienced worldwide. However, whereas cross-cultural studies utilize psychometrically valid and reliable scales, fewer can meaningfully compare these conditions across different groups. To address this gap, the current study aimed to psychometrically assess the Brief Symptomatology Index (BSI) in 42 countries. METHODS: Using data from the International Sex Survey (N = 82,243; Mage = 32.39; SDage = 12.52; women: n = 46,874; 57 %), we examined the reliability of depression and anxiety symptom scores of the BSI-18, as well as evaluated evidence of construct, invariance, and criterion-related validity in predicting clinically relevant variables across countries, languages, genders, and sexual orientations. RESULTS: Results corroborated an invariant, two-factor structure across all groups tested, exhibiting excellent reliability estimates for both subscales. The 'caseness' criterion effectively discriminated among those at low and high risk of depression and anxiety, yielding differential effects on the clinical criteria examined. LIMITATIONS: The predictive validation was not made against a clinical diagnosis, and the full BSI-18 scale was not examined (excluding the somatization sub-dimension), limiting the validation scope of the BSI-18. Finally, the study was conducted online, mainly by advertisements through social media, ultimately skewing our sample towards women, younger, and highly educated populations. CONCLUSIONS: The results support that the BSI-12 is a valid and reliable assessment tool for assessing depression and anxiety symptoms across countries, languages, genders, and sexual orientations. Further, its caseness criterion can discriminate well between participants at high and low risk of depression and anxiety.

Why Do People Watch Pornography? Cross-Cultural Validation of the Pornography Use Motivations Scale (PUMS) and Its Short Form (PUMS-8).

Motivations for pornography use may vary across gender identities, sexual orientations, and geographical regions, warranting examination to promote individual and public health. The aims of this study were to validate the Pornography Use Motivations Scale (PUMS) in a diverse, multicultural sample, and develop a short form (PUMS-8) that can assess a wide range of pornography use motivations. Using data from 42 countries (N = 75,117; Mage = 32.07; SDage = 12.37), enabled us to thoroughly evaluate the dimensionality, validity, and reliability of the Pornography Use Motivations Scale (PUMS), leading to the development of the more concise PUMS-8 short scale. Additionally, language-, nationality-, gender-, and sexual-orientation-based measurement invariance tests were conducted to test the comparability across groups. Both the PUMS and the PUMS-8 assess eight pornography use motivations, and both demonstrated excellent psychometric properties. Sexual Pleasure emerged as the most frequent motivation for pornography use across countries, genders, and sexual orientations, while differences were observed concerning other motivations (e.g. self-exploration was more prevalent among gender-diverse individuals than men or women). The motivational background of pornography use showed high similarity in the examined countries. Both the PUMS and the PUMS-8 are reliable and valid measurement tools to assess different types of motivations for pornography use across countries, genders, and sexual orientations. Both scales are recommended for use in research and clinical settings.

Cross-Cultural Adult ADHD Assessment in 42 Countries Using the Adult ADHD Self-Report Scale Screener.

OBJECTIVE: We analyzed adult ADHD symptoms in a cross-cultural context, including investigating the occurrence and potential correlates of adult ADHD and psychometric examination of the Adult ADHD Self-Report Scale (ASRS) Screener. METHOD: Our analysis is based on a large-scale research project involving 42 countries (International Sex Survey, N=72,627, 57% women, Mage=32.84; SDage=12.57). RESULTS: The ASRS Screener demonstrated good reliability and validity, along with partial invariance across different languages, countries, and genders. The occurrence of being at risk for adult ADHD was relatively high (21.4% for women, 18.1% for men). The highest scores were obtained in the US, Canada, and other English-speaking Western countries, with significantly lower scores among East Asian and non-English-speaking European countries. Moreover, ADHD symptom severity and occurrence were especially high among gender-diverse individuals. Significant associations between adult ADHD symptoms and age, mental and sexual health, and socioeconomic status were observed. CONCLUSIONS: Present results show significant cross-cultural variability in adult ADHD occurrence as well as highlight important factors related to adult ADHD. Moreover, the importance of further research on adult ADHD in previously understudied populations (non-Western countries) and minority groups (gender-diverse individuals) is stressed. Lastly, the present analysis is consistent with previous evidence showing low specificity of adult ADHD screening instruments and contributes to the current discussion on accurate adult ADHD screening and diagnosis.

The short version of the Sexual Distress Scale (SDS-3): Measurement invariance across countries, gender identities, and sexual orientations.

Background: The three-item Sexual Distress Scale (SDS-3) has been frequently used to assess distress related to sexuality in public health surveys and research on sexual wellbeing. However, its psychometric properties and measurement invariance across cultural, gender and sexual subgroups have not yet been examined. This multinational study aimed to validate the SDS-3 and test its psychometric properties, including measurement invariance across language, country, gender identity, and sexual orientation groups. Methods: We used global survey data from 82,243 individuals (Mean age=32.39 years; 40.3 % men, 57.0 % women, 2.8 % non-binary, and 0.6 % other genders) participating in the International Sexual Survey (ISS; https://internationalsexsurvey.org/) across 42 countries and 26 languages. Participants completed the SDS-3, as well as questions regarding sociodemographic characteristics, including gender identity and sexual orientation. Results: Confirmatory factor analysis (CFA) supported a unidimensional factor structure for the SDS-3, and multi-group CFA (MGCFA) suggested that this factor structure was invariant across countries, languages, gender identities, and sexual orientations. Cronbach's α for the unidimensional score was 0.83 (range between 0.76 and 0.89), and McDonald's ω was 0.84 (range between 0.76 and 0.90). Participants who did not experience sexual problems had significantly lower SDS-3 total scores (M = 2.99; SD=2.54) compared to those who reported sexual problems (M = 5.60; SD=3.00), with a large effect size (Cohen's d = 1.01 [95 % CI=-1.03, -0.98]; p < 0.001). Conclusion: The SDS-3 has a unidimensional factor structure and appears to be valid and reliable for measuring sexual distress among individuals from different countries, gender identities, and sexual orientations.

Occupancy of serotonin and norepinephrine transporter by milnacipran in patients with major depressive disorder: a positron emission tomography study with [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2).

Antidepressants used for treatment of depression exert their efficacy by blocking reuptake at serotonin transporters (5-HTT) and/or norepinephrine transporters (NET). Recent studies suggest that serotonin and norepinephrine reuptake inhibitors that block both 5-HTT and NET have better tolerability than tricyclic antidepressants and may have higher efficacy compared to selective serotonin reuptake inhibitors. Previous positron emission tomography (PET) studies have reported >80% 5-HTT occupancy with clinical doses of antidepressants, but there has been no report of NET occupancy in patients treated with antidepressants. In the present study, we investigated both 5-HTT and NET occupancies by PET using radioligands [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2), in six patients, each with major depressive disorder (MDD), using various doses of milnacipran. Our data show that mean 5-HTT occupancy in the thalamus was 33.0% at 50 mg, 38.6% at 100 mg, 60.0% at 150 mg and 61.5% at 200 mg. Mean NET occupancy in the thalamus was 25.3% at 25 mg, 40.0% at 100 mg, 47.3% at 125 mg and 49.9% at 200 mg. Estimated ED(50) was 122.5 mg with the dose for 5-HTT and 149.9 mg for NET. Both 5-HTT and NET occupancies were observed in a dose-dependent manner. Both 5-HTT and NET occupancies were about 40% by milnacipran at 100 mg, the dose most commonly administered to MDD patients.

Test-retest reproducibility of dopamine D2/3 receptor binding in human brain measured by PET with [11C]MNPA and [11C]raclopride.

PURPOSE: Dopamine D receptors (DRs) have two affinity states for endogenous dopamine, referred to as high-affinity state (D ), which has a high affinity for endogenous dopamine, and low-affinity state (D ). The density of D can be measured with (R)-2-CHO-N-n-propylnorapomorphine ([C]MNPA), while total density of D and D (DRs) can be measured with [C]raclopride using positron emission tomography (PET). Thus, the ratio of the binding potential (BP) of [C]MNPA to that of [C]raclopride ([C]MNPA/[C]raclopride) may reflect the proportion of the density of D to that of DRs. In the caudate and putamen, [C]MNPA/[C]raclopride reflects the proportion of the density of D to that of DRs. To evaluate the reliability of the PET paradigm with [C]MNPA and [C]raclopride, we investigated the test-retest reproducibility of non-displaceable BP (BP ) measured with [C]MNPA and of [C]MNPA/[C]raclopride in healthy humans. METHODS: Eleven healthy male volunteers underwent two sets of PET studies on separate days that each included [C]MNPA and [C]raclopride scans. BP values in the caudate and putamen were calculated. Test-retest reproducibility of BP of [C]MNPA and [C]MNPA/[C]raclopride was assessed by intra-subject variability (absolute variability) and test-retest reliability (intraclass correlation coefficient: ICC). RESULTS: The absolute variability of [C]MNPA BP was 5.30 ± 3.96 % and 12.3 ± 7.95 % and the ICC values of [C]MNPA BP were 0.72 and 0.82 in the caudate and putamen, respectively. The absolute variability of [C]MNPA/[C]raclopride was 6.11 ± 3.68 % and 11.60 ± 5.70 % and the ICC values of [C]MNPA/[C]raclopride were 0.79 and 0.80 in the caudate and putamen, respectively. CONCLUSION: In the present preliminary study, the test-retest reproducibility of BP of [C]MNPA and of [C]MNPA/[C]raclopride was reliable in the caudate and putamen.

Information flow and dynamic functional connectivity during electroconvulsive therapy in patients with depression.

BACKGROUND: Electroconvulsive therapy is effectively used for treatment-resistant depression; however, its neural mechanism is largely unknown. Resting-state functional magnetic resonance imaging is promising for monitoring outcomes of electroconvulsive therapy for depression. This study aimed to explore the imaging correlates of the electroconvulsive therapy effects on depression using Granger causality analysis and dynamic functional connectivity analyses. METHODS: We performed advanced analyses of resting-state functional magnetic resonance imaging data at the beginning and intermediate stages and end of the therapeutic course to identify neural markers that reflect or predict the therapeutic effects of electroconvulsive therapy on depression. RESULTS: We demonstrated that information flow between the functional networks analyzed by Granger causality changes during electroconvulsive therapy, and this change was correlated with the therapeutic outcome. Information flow and the dwell time (an index reflecting the temporal stability of functional connectivity) before electroconvulsive therapy are correlated with depressive symptoms during and after treatment. LIMITATIONS: First, the sample size was small. A larger group is needed to confirm our findings. Second, the influence of concomitant pharmacotherapy on our results was not fully addressed, although we expected it to be minimal because only minor changes in pharmacotherapy occurred during electroconvulsive therapy. Third, different scanners were used the groups, although the acquisition parameters were the same; a direct comparison between patient and healthy participant data was not possible. Thus, we presented the data of the healthy participants separately from that of the patients as a reference. CONCLUSIONS: These results show the specific properties of functional brain connectivity.