How does social support modify the association between psychological distress and risk of suicide death?

BACKGROUND: Social support (SS) has been reported as a factor preventing suicide death, but whether this association is independent of mental status is unclear. The present study examined the effect modification of SS on the association between psychological distress status and risk of suicide death. METHODS: Follow-up data for 43,015 subjects participating in a prospective cohort study were analyzed. At baseline, the subjects were asked about SS and mental status with the Kessler six-item Distress (K6) Scale. A Cox model was used to estimate the multivariate-adjusted hazard ratios (HRs) of suicide death according to two levels of psychological distress (K6 ≤ 4, K6 ≥ 5). The HRs in each SS subtype (emotional and instrumental) were also calculated. RESULTS: There was a significant association between SS and a lower risk of suicide death in the stratum of K6 ≥ 5, with an HR of 0.58 (95% confidence interval, 0.35-0.96). On the other hand, the association with the K6 ≤ 4 strata was not significant. CONCLUSION: SS appears to be associated with a lower risk of suicide death only among participants with moderate or severe psychological distress. These results imply that early detection of psychological distress and provision of SS is important for preventing suicide death.

Combined Healthy Lifestyle Behaviors and Disability-Free Survival: the Ohsaki Cohort 2006 Study.

BACKGROUND: Previous studies have suggested that a healthy lifestyle (HL) may prolong the years of life spent in good health. However, the impact of HL on disability-free survival (DFS) among the elderly is still uncertain. OBJECTIVE: To investigate the relationship between HL and DFS in the general elderly population. DESIGN: Prospective cohort study with a 10-year follow-up (2006-2016). PARTICIPANTS: 9910 community-dwelling elderly people (≥ 65 years). MAIN MEASURES: A HL index derived by summing the number of HL behaviors. Data on incident disability were retrieved from the public Long-term Care Insurance database. Multivariate-adjusted 50th percentile differences (PDs) in age at disability or death (months) and their 95% CIs were estimated with the Laplace regression model. KEY RESULTS: During the 10 years, 4562 disability or death events occurred. Participants who adhered to all three HL behaviors lived 17.1 (95% CI 12.7, 21.5) months longer without disability than those who adhered to zero or one. Each 1-point increase of the index score conferred 8.8 months additional life without disability. The tendency for the 50th PDs to increase with a higher HL index score did not differ according to age (< 75 or ≥ 75 years), sex, or the presence of chronic conditions (none, or ≥ 1 chronic condition). CONCLUSIONS: A combination of HL behaviors may substantially increase DFS, even for late-elderly (≥ 75 years), or elderly people with chronic conditions.

Psychological distress and completed suicide in Japan: A comparison of the impact of moderate and severe psychological distress.

It has already been established that severe psychological distress is a major risk factor for completed suicide. However, the impact (population attributable fraction; PAF) of moderate psychological distress on completed suicide has not been clarified. The present study investigated the association between various severities of psychological distress and completed suicide. We analyzed follow-up data covering a 7.3-year period (2006-2014) for 43,473 adults (aged ≥ 40 years) participating in a community-based, prospective cohort study. Psychological distress was measured using the K6 psychological distress scale at the baseline. Participants were classified into three groups according to their K6 score (low: 0-4; moderate: 5-12; severe: 13-24). Completed suicide was determined from a Japanese national database. The Cox model was used to estimate hazard ratios (HRs) for completed suicide. The PAFs of moderate and severe psychological distress for completed suicide were also estimated. The multivariate-adjusted HRs (95% confidence interval) for completed suicide were 2.37 (1.49-3.78) among participants with moderate psychological distress, and 4.16 (2.13-8.15) among those with severe psychological distress, relative to those with low psychological distress (P for trend < 0.001). The PAF of the moderate group for completed suicide was 26.8%, whereas that of the severe group was 10.9%. Not only severe but also moderate psychological distress was significantly associated with an increased risk of completed suicide. The PAF of moderate psychological distress for completed suicide was larger than that of severe psychological distress. Public health actions for suicide prevention should focus on moderate as well as severe psychological distress.

Polyunsaturated fatty acids and risk of anorexia nervosa: A Mendelian randomization study.

PURPOSE: Observational studies have suggested that polyunsaturated fatty acids (PUFAs) decrease the risk of anorexia nervosa (AN). In the present study, we examined this hypothesis using a Mendelian randomization analysis. METHODS: We used summary statistics for single-nucleotide polymorphisms associated with plasma levels of n-6 (linoleic acid and arachidonic acid) and n-3 PUFAs (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) and the corresponding data for AN from a genome-wide association meta-analysis of 72,517 individuals (16,992 diagnosed AN cases and 55,525 controls). RESULTS: None of the genetically predicted PUFAs were significantly associated with the risk of AN; odds ratios (95 % confidence interval) per 1 standard deviation increase in PUFA levels were 1.03 (0.98, 1.08) for linoleic acid, 0.99 (0.96, 1.03) for arachidonic acid, 1.03 (0.94, 1.12) for alpha-linolenic acid, 0.98 (0.90, 1.08) for eicosapentaenoic acid, 0.96 (0.91, 1.02) for docosapentaenoic acid, and 1.01 (0.90, 1.36) for docosahexaenoic acid. LIMITATION: Only two types of fatty acids (LA and DPA) can be used for pleiotropy tests using the MR-Egger intercept test. CONCLUSION: This study does not support the hypothesis that PUFAs decrease the risk of AN.

Relationships between exploratory eye movement dysfunction and clinical symptoms in schizophrenia.

AIM: Many psychophysiological tests have been widely researched in the search for a biological marker of schizophrenia. The exploratory eye movement (EEM) test involves the monitoring of eye movements while subjects freely view geometric figures. Suzuki et al. (2009) performed discriminant analysis between schizophrenia and non-schizophrenia subjects using EEM test data; consequently, clinically diagnosed schizophrenia patients were identified as having schizophrenia with high probability (73.3%). The aim of the present study was to investigate the characteristics of schizophrenia patients who were identified as having schizophrenia on EEM discriminant analysis (SPDSE) or schizophrenia patients who were identified as not having schizophrenia on EEM discriminant analysis (SPDNSE). METHODS: The data for the 251 schizophrenia subjects used in the previous discriminant-analytic study were analyzed, and the demographic or symptomatic characteristics of SPDSE and SPDNSE were investigated. As for the symptomatic features, a factor analysis of the Brief Psychiatric Rating Scale (BPRS) rating from the schizophrenia subjects was carried out. RESULTS: Five factors were found for schizophrenia symptoms: excitement/hostility; negative symptoms; depression/anxiety; positive symptoms; and disorganization. SPDSE had significantly higher factor scores for excitement/hostility, negative symptoms and disorganization than SPDNSE. Furthermore, the BPRS total score for the SPDSE was significantly higher than that for the SPDNSE. CONCLUSION: SPDSE may be a disease subtype of schizophrenia with severe symptoms related to excitement/hostility, negative symptoms and disorganization, and EEM parameters may detect this subtype. Therefore, the EEM test may be one of the contributors to the simplification of the heterogeneity of schizophrenia.

Did Children in Single-Parent Households Have a Higher Probability of Emotional Instability during the COVID-19 Pandemic? A Nationwide Cross-Sectional Study in Japan.

The influence of public health measures against COVID-19 in Japan on child mental health by household type is unknown. This study aimed to investigate whether COVID-19 and the declaration of a state of emergency in Japan affected children's mental health between single-parent and two-parent households disproportionately. A large cross-sectional online survey was conducted from August to September 2020. The study included 3365 parents with children aged 0-14 years old who reported their children's mental status during the declared state of emergency. Emotional instability was reported dichotomously by parents. As the primary result, the probability of emotional instability was higher in single-parent households compared with that in two-parent households after adjustments for potential covariates; the adjusted prevalence ratio (95% CI) was 1.26 (1.07-1.49). Our findings suggest a disproportionate impact on children's mental health due to the pandemic.

Social Participation and Healthy Aging Among the Older Japanese: The Ohsaki Cohort 2006 Study.

BACKGROUND: Our study examined the association between social participation and healthy aging using a community-based cohort study among Japanese older adults. METHODS: This prospective study was conducted in Ohsaki City, Japan, and included 7226 participants aged ≥65 years at the baseline survey in 2006. We obtained information on frequency of participation in 3 types of community activities (ie, neighborhood activities, hobbies, and volunteer activities) at baseline. Exposure was measured by the number of types of community activities participated in and participants were categorized into 4 groups (ie, none, 1 type, 2 types, and 3 types). The primary outcome was healthy aging as assessed by a questionnaire survey conducted in 2017, and was defined as meeting the following 4 criteria: free of disability, free of depression, high health-related quality of life, and high life satisfaction. We used multiple logistic regression models to calculate the corresponding odds ratios and 95% confidence intervals. RESULTS: During 11 years of follow-up, 574 (7.9%) participants attained healthy aging. Compared with participants not participating in any activity, the multivariable-adjusted odds ratios (95% confidence intervals) were 1.90 (1.40, 2.59) for those participating in 1 type, 2.49 (1.84, 3.38) for 2 types, and 3.06 (2.30, 4.07) for 3 types (p for trend < .0001). Furthermore, for each type of community activity, a higher frequency of participation was related to higher probability of healthy aging. CONCLUSIONS: Our study suggests that social participation is associated with the promotion of healthy aging, and that the benefits were observed across different types of community activities.

Association between maternal infertility treatment and child neurodevelopment: findings from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study in Miyagi and Iwate Prefectures, Japan.

OBJECTIVES: This study aimed to examine the association between infertility treatment and neurodevelopment in children at 2 and 3.5 years of age. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: The study population consisted of mother-child pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study in Miyagi and Iwate Prefectures, Japan. Pregnant women were recruited in obstetric clinics or hospitals and their children were followed up by the questionnaire. OUTCOME MEASURES: The children's neurodevelopmental outcomes were assessed at 2 and 3.5 years of age using the Ages and Stages Questionnaire, third edition (ASQ-3), which consists of questions on five developmental domains. We performed a multivariate logistic regression analysis of the association between infertility treatment (including ovulation induction (OI), artificial insemination with husband's sperm (AIH) and assisted reproductive technology (ART)) and the clinical range of ASQ-3. RESULTS: Of 9655 mother-child pairs, 273 (2.8%) and 487 (5.0%) were conceived through OI/AIH and ART, respectively. The odds of having developmental delays at 2 years of age were higher in children conceived through OI/AIH (OR, 1.36; 95% CI 1.00 to 1.85) and ART (OR, 1.36; 95% CI 1.07 to 1.72) than in those conceived naturally. Additionally, OI/AIH and ART were significantly associated with communication (OR, 1.93; 95% CI 1.25 to 2.98) and gross motor (OR, 1.50; 95% CI 1.08 to 2.09) delays, respectively. There were no statistically significant differences in the odds of having developmental delays at 3.5 years of age in children conceived through OI/AIH (OR, 1.13; 95% CI 0.79 to 1.61) and ART (OR, 1.03; 95% CI 0.78 to 1.37). CONCLUSION: In this study, we found a significant association between infertility treatment and children's neurodevelopment at 2 years of age, whereas no statistically significant differences were found at 3.5 years of age.

Contribution of dopamine D1 and D2 receptors to amygdala activity in human.

Several animal studies have demonstrated functional roles of dopamine (DA) D1 and D2 receptors in amygdala activity. However, the contribution of DA D1 and D2 receptors to amygdala response induced by affective stimuli in human is unknown. To investigate the contribution of DA receptor subtypes to amygdala reactivity in human, we conducted a multimodal in vivo neuroimaging study in which DA D1 and D2 receptor bindings in the amygdala were measured with positron emission tomography (PET), and amygdala response induced by fearful faces was assessed by functional magnetic resonance imaging (fMRI) in healthy volunteers. We used multimodality voxelwise correlation analysis between fMRI signal and DA receptor binding measured by PET. DA D1 binding in the amygdala was positively correlated with amygdala signal change in response to fearful faces, but DA D2 binding in the amygdala was not related to amygdala signal change. DA D1 receptors might play a major role in enhancing amygdala response when sensory inputs are affective.

Effect of risperidone on high-affinity state of dopamine D2 receptors: a PET study with agonist ligand [11C](R)-2-CH3O-N-n-propylnorapomorphine.

The increased proportion of the high-affinity state of dopamine D2/3 receptors (D2,high) is assumed to correlate with dopamine hypersensitivity, implying a relationship with psychotic symptoms observed in psychiatric disorders such as schizophrenia. [11C](R)-2-CH3O-N-n-propylnorapomorphine ([11C]MNPA), which has an agonistic property to dopamine D2 receptors (D2Rs), is expected to bind preferentially to D2,high. The occupancy of dopamine D2Rs by antagonists to receptors has not been investigated using [11C]MNPA. We compared dopamine D2R occupancies by risperidone, an antagonist to receptors, between [11C]MNPA and [11C]raclopride to confirm whether risperidone occupies D2,high and D2,low at almost identical proportions. PET studies were performed on 11 healthy men under resting condition and following oral administration of a single dose of risperidone (0.5-2.0 mg). Striatal receptor occupancy for each radioligand was calculated. The relationship between dose or plasma concentration of risperidone and dopamine D2R occupancy was calculated. Striatal dopamine D2R occupancies measured with [11C]MNPA and [11C]raclopride were 22-65% and 24-69%, respectively. In the striatum, ED50 values measured with [11C]MNPA and [11C]raclopride were 0.98 and 1.03 mg, respectively. The striatal ED50 values as calculated from plasma concentration were 9.15 ng/ml and 8.01 ng/ml, respectively. Almost identical occupancies and ED50 values were observed between the two radioligands, indicating that risperidone bound to D2,high and D2,low at almost identical proportions in a dose-dependent manner.

Serotonergic neurotransmission in the living human brain: a positron emission tomography study using [¹¹C]dasb and [¹¹C]WAY100635 in young healthy men.

The central serotonergic (5-HT) system is closely involved in regulating various mental functions such as mood and emotion. In this system, the serotonin transporter (5-HTT) and the 5-HT(1A) receptor play important roles in the pathophysiology and treatment of mood and anxiety disorders. However, only a few integrated databases have considered the intraindividual relationship between pre- and postsynaptic serotonergic transmission. In the present study, we constructed a database of 5-HTT and 5-HT(1A) receptors using positron emission tomography (PET) with [¹¹C]DASB and [¹¹C]WAY100635, respectively. Seventeen healthy young men participated in this study. After anatomic standardization of original images, BP(ND) was calculated on a voxel-by-voxel basis using reference tissue methods. The highest binding to 5-HTT was observed in the dorsal raphe nucleus, striatum, and thalamus; moderate binding, in the insula and cingulate cortex; and very low binding, in the cerebral neocortex. In contrast, the highest binding to 5-HT(1A) receptors was seen in the hippocampal regions, insula, neocortical regions, and dorsal raphe nucleus, and very low binding was found in the thalamus and basal ganglia. These distribution patterns were in agreement with those reported in human postmortem studies and previous PET investigations. In addition, exploratory analysis indicated significant negative correlations between the BP(ND) values with both radiotracers in certain regions of the brain, such as the cingulate, insula, and frontal, temporal and parietal cortices (Pearson's correlation, P < 0.05). These databases facilitate the understanding of the regional distribution of serotonergic neurotransmission function in the living human brain and the pathophysiology of various neuropsychiatric disorders.

Midbrain volume increase in patients with panic disorder.

AIM: Although recent studies suggest abnormalities of the cerebral cortex, limbic structures, and brain stem regions in panic disorder (PD), the extent to which the midbrain is associated with PD pathophysiology is unclear. The aim of this study was to investigate structural abnormalities of the midbrain using magnetic resonance imaging and to determine if there is a clinical correlation between midbrain volume and clinical measurements in patients with PD. METHODS: Thirty-eight patients with PD (PD group) and 38 healthy controls (HC group) participated in this study. The midbrain was measured with a manual tracing method with high spatial resolution magnetic resonance imaging. The Panic Disorder Severity Scale and Global Assessment of Functioning were used to examine the correlation between volume abnormality and clinical symptoms and functioning in the PD group. RESULTS: Relative midbrain volume was larger in the PD group than in the HC group. The relative volume of the dorsal midbrain was larger in the PD group, while the volume of the ventral midbrain was not. We found a significant positive correlation between relative dorsal midbrain volume and total Panic Disorder Severity Scale score, and a significant negative correlation between relative dorsal midbrain volume and Global Assessment of Functioning score in the PD group. CONCLUSIONS: Our findings suggest that the dorsal midbrain is associated with PD pathophysiology. The midbrain volume increase may reflect PD severity.

Association between weight loss since the age of 20 years and the risk of suicide death: A population-based cohort study.

BACKGROUND: Past studies have demonstrated that body mass index (BMI) is inversely associated with the risk of suicide death. However, to our knowledge, no study has investigated the association between long-term weight change and the risk of suicide death. The purpose of this study was to investigate the association between weight change from the age of 20 years to middle or older age and the risk of suicide death in a population-based cohort. METHODS: We analyzed follow-up data for 41,746 participants aged ≥40 years and calculated percent weight change from age 20 years to that at the survey baseline (mean age: 61.2 years). A Cox model was used to estimate the multivariate-adjusted hazard ratios (HRs) for suicide death. RESULTS: The mean duration of follow up was 6.9 years, and suicide death was documented for 80 persons. Weight loss >5% (WL) was associated with a significantly higher risk of suicide death, with a multivariate-adjusted HR of 1.92 (95% confidence interval: 1.02-3.63). On the other hand, weight gain tended to be associated with a lower risk of suicide death. The significantly higher risk of suicide death observed among those showing WL did not change after excluding participants with a history of disease or psychological distress. LIMITATIONS: No information was given regarding the reasons for weight change and suicide death. CONCLUSIONS: The present results suggest that physicians should pay attention to individuals who lose weight from early adulthood because they could be at increased risk for suicide.

Effects of the antipsychotic risperidone on dopamine synthesis in human brain measured by positron emission tomography with L-[beta-11C]DOPA: a stabilizing effect for dopaminergic neurotransmission?

Effects of antipsychotic drugs have widely been considered to be mediated by blockade of postsynaptic dopamine D(2) receptors. Effects of antipsychotics on presynaptic functions of dopaminergic neurotransmission might also be related to therapeutic effects of antipsychotics. To investigate the effects of antipsychotics on presynaptic functions of dopaminergic neurotransmission in relation with occupancy of dopamine D(2) receptors, changes in dopamine synthesis capacity by antipsychotics and occupancy of dopamine D(2) receptors were measured by positron emission tomography (PET) in healthy men. PET studies using [(11)C]raclopride and L-[beta-(11)C]DOPA were performed under resting condition and oral administration of single dose of the antipsychotic drug risperidone on separate days. Although occupancy of dopamine D(2) receptors corresponding dose of risperidone was observed, the changes in dopamine synthesis capacity by the administration of risperidone were not significant, nor was the relation between the occupancy of dopamine D(2) receptors and these changes. A significant negative correlation was observed between the baseline dopamine synthesis capacity and the changes in dopamine synthesis capacity by risperidone, indicating that this antipsychotic can be assumed to stabilize the dopamine synthesis capacity. The therapeutic effects of risperidone in schizophrenia might be related to such stabilizing effects on dopaminergic neurotransmission responsivity.

Posterior orbitofrontal sulcogyral pattern associated with orbitofrontal cortex volume reduction and anxiety trait in panic disorder.

AIMS: The posterior region of the orbitofrontal cortex (OFC), which forms its sulcogyral pattern during neurodevelopment, receives multisensory inputs. The purpose of the present study was to assess the relationship between posterior OFC sulcogyral pattern and OFC volume difference in patients with panic disorder. METHODS: The anatomical pattern of the posterior orbital sulcus (POS) was classified into three subtypes (absent POS, single POS, double POS) using 3-D high-spatial resolution magnetic resonance images obtained from 28 patients with panic disorder and 28 age- and gender-matched healthy controls. Optimized voxel-based morphometry (VBM) was performed to assess OFC volume differences between the two groups by subtype. Categorical regression analysis was applied to examine the association of POS subtypes with State-Trait Anxiety Inventory and Revised Neuroticism-Extraversion-Openness Personality Inventory scores. RESULTS: No significant difference was found in POS subtype distribution between control subjects and patients with panic disorder. VBM, however, indicated volume reduction in the right posterior-medial OFC region in panic disorder patients with absent POS and single POS. Single POS was positively associated with Trait-Anxiety (beta = 0.446, F = 6.409, P = 0.020), and absent POS was negatively associated with Trait-Anxiety (beta = -0.394, F = 5.341, P = 0.032) and Neuroticism trait (beta = -0.492, F = 6.989, P = 0.017). CONCLUSIONS: POS subtypes may be relevant to volume reduction in OFC and the anxiety trait in patients with panic disorder. These findings suggest that volume reduction in OFC in panic disorder may be associated with neurodevelopment.

Emotional support (giving or receiving) and risk of incident dementia: The Ohsaki Cohort 2006 Study.

Previous studies have suggested that emotional support may promote cognition; however, the effects of giving or receiving emotional support on incident dementia remain unclear. Therefore, we sought to investigate the relationship between emotional support (giving or receiving) and incident dementia. In December 2006, we conducted a prospective cohort study of 31,694 Japanese individuals aged ≥65 years who lived in Ohsaki City, Miyagi Prefecture, Japan. A self-reported questionnaire including items on emotional support and lifestyle factors was distributed. After excluding those who did not provide consent or responses to all items, 13,636 eligible responses were analyzed for this study. According to responses of "yes" or "no" for emotional support, we made two categories for both giving (gave or did not give) and receiving (received or did not receive) emotional support. Furthermore, we combined giving and receiving emotional support into four categories ("giving = no & receiving = no", "giving = no & receiving = yes", "giving = yes & receiving = no", "giving = yes & receiving = yes"). Data on incident dementia were retrieved from the Long-term Care Insurance Database in which participants were followed up for 5.7 years. Using multivariate Cox proportional hazards models, we found that compared with participants who did not give emotional support to others, those who did give had a lower risk of dementia (multivariate-adjusted hazard ratio [HR]: 0.61 (95% confidence interval [CI]: 0.52, 0.71)). However, a nonsignificant relationship was observed for receiving emotional support. Additionally, compared to "giving = no & receiving = no" for emotional support, "giving = no & receiving = yes" showed a higher risk of dementia (multivariate-adjusted HR: 1.51 [95% CI: 1.07, 2.14]).

Effect of a financial incentive (shopping point) on increasing the number of daily walking steps among community-dwelling adults in Japan: a randomised controlled trial.

OBJECTIVE: The aim of this study was to investigate the effect of a financial incentive on the number of daily walking steps among community-dwelling adults in Japan. STUDY DESIGN: Two-arm, parallel-group randomised controlled trial. SETTING/PARTICIPANTS: We recruited physically inactive community-dwelling adults from Sendai city, Japan. Eligible participants were randomly allocated to an intervention or a wait list control group. Pedometers were used to assess the mean number of daily steps in three periods: baseline (weeks 1-3), intervention (weeks 4-6) and follow-up (weeks 7-9). INTERVENTION: The intervention group was offered a financial incentive (shopping points) to meet the target number of increased daily steps in the intervention period. MAIN OUTCOME MEASURES: The primary outcome was an increase in the mean number of daily steps in the intervention and follow-up periods compared with baseline. RESULTS: Seventy-two participants (69.4% women; mean age, 61.2±16.2 years; mean number of daily steps at baseline, 6364±2804) were randomised to the intervention (n=36) and control groups (n=36). During the intervention period, the increase in mean daily steps was significantly higher in the intervention group (1650, 95% CI=1182 to 2119) than in the control group (514, 95% CI=136 to 891; p<0.001). However, the difference between groups was not significant at follow-up after the incentives were removed (p=0.311). In addition, compared with controls, a significantly higher proportion of participants in the intervention group showed an increase in mean daily steps of ≥1000 (69.4% vs 30.6%, respectively; OR=5.17, 95% CI=1.89 to 14.08). There were no adverse effects from the intervention. CONCLUSIONS: The present results suggest that financial incentives are effective in promoting short-term increases in physical activity. TRIAL REGISTRATION NUMBER: UMIN000033276.

Differential contributions of prefrontal and hippocampal dopamine D(1) and D(2) receptors in human cognitive functions.

Dopamine D(1) receptors in the prefrontal cortex (PFC) are important for prefrontal functions, and it is suggested that stimulation of prefrontal D(1) receptors induces an inverted U-shaped response, such that too little or too much D(1) receptor stimulation impairs prefrontal functions. Less is known of the role of D(2) receptors in cognition, but previous studies showed that D(2) receptors in the hippocampus (HPC) might play some roles via HPC-PFC interactions. We measured both D(1) and D(2) receptors in PFC and HPC using positron emission tomography in healthy subjects, with the aim of elucidating how regional D(1) and D(2) receptors are differentially involved in frontal lobe functions and memory. We found an inverted U-shaped relation between prefrontal D(1) receptor binding and Wisconsin Card Sorting Test performance. However, prefrontal D(2) binding has no relation with any neuropsychological measures. Hippocampal D(2) receptor binding showed positive linear correlations not only with memory function but also with frontal lobe functions, but hippocampal D(1) receptor binding had no association with any memory and prefrontal functions. Hippocampal D(2) receptors seem to contribute to local hippocampal functions (long-term memory) and to modulation of brain functions outside HPC ("frontal lobe functions"), which are mainly subserved by PFC, via the HPC-PFC pathway. Our findings suggest that orchestration of prefrontal D(1) receptors and hippocampal D(2) receptors might be necessary for human executive function including working memory.

Quantitative PET analysis of the dopamine D2 receptor agonist radioligand 11C-(R)-2-CH3O-N-n-propylnorapomorphine in the human brain.

UNLABELLED: It has been demonstrated in vitro that the dopamine D(2) receptor has 2 interconvertible affinity states for endogenous dopamine, referred to as the high- and the low-affinity states. (11)C-(R)-2-CH(3)O-N-n-propylnorapomorphine ((11)C-MNPA) is a new agonist radioligand for in vivo imaging of the high-affinity state of dopamine D(2) receptors using PET. In the present study, the kinetics of (11)C-MNPA were examined for the first time, to our knowledge, in the human brain and analyzed using quantitative approaches with or without an arterial input function. METHODS: A 90-min dynamic PET scan was obtained for 10 healthy men after an intravenous injection of (11)C-MNPA. The binding potential (BP(ND)) was calculated using the indirect kinetic method, a kinetic compartment analysis with a metabolite-corrected arterial input function. BP(ND) was also calculated by the simplified reference tissue model (SRTM) and transient equilibrium methods, both with the cerebellum as the reference brain region. The results of the quantitative methods were compared in a cross-validation approach. RESULTS: The highest regional radioactivity was observed in the putamen. BP(ND) values obtained by kinetic analysis were 0.82 +/- 0.09, 0.59 +/- 0.11, and 0.28 +/- 0.06, respectively, in the putamen, caudate, and thalamus. BP(ND) values obtained by the SRTM and transient equilibrium methods were in good agreement with those obtained by the indirect kinetic method (r = 0.98 and r = 0.93, respectively). For all quantification methods, the BP(ND) values based on data acquired from 0 to 60 min were in good agreement with those based on data acquired from 0 to 90 min (r = 0.90-0.99). CONCLUSION: The regional distribution of (11)C-MNPA binding was in good agreement with previous PET studies of dopamine D(2) receptors in the human brain using antagonist radioligands. The results support routine use of the SRTM and transient equilibrium methods, that is, methods that do not require an arterial input function and need a scan time of only about 60 min. (11)C-MNPA should thus be useful for clinical research on the pathophysiology of neuropsychiatric disorders and estimation of dopamine D(2) receptor occupancy by dopaminergic drugs.