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Yoshiro Okubo

Publications and source records attributed to Yoshiro Okubo.

At least 37 records · Page 2Linked to original sources
PubMed2004

An fMRI study of differential neural response to affective pictures in schizophrenia.

Although emotional dysfunction is considered a fundamental symptom of schizophrenia, studies investigating the neural basis of emotional dysfunction in schizophrenia are few. Using functional magnetic resonance imaging (fMRI) and a task viewing affective pictures, we aimed to examine automatic emotional response and to elucidate the neural basis of impaired emotional processing in schizophrenia. Fifteen healthy volunteers and 15 schizophrenics were studied. During the scans, the subjects were instructed to indicate how each of the presented pictures made them feel. Whole brain activities in response to the affective pictures were measured by fMRI. Controls recruited the neural circuit including amygdaloid-hippocampal region, prefrontal cortex, thalamus, basal ganglia, cerebellum, midbrain, and visual cortex while viewing unpleasant pictures. Despite an equal behavioral result to controls, the patients showed less activation in the components of the circuit (right amygdala, bilateral hippocampal region, medial prefrontal cortex (MPFC), basal ganglia, thalamus, cerebellum, midbrain, and visual cortex). This study demonstrated functional abnormalities in the neural circuit of emotional processing in schizophrenia. In particular, decreased activation in the right amygdala and MPFC appears to be an important finding related to dysfunctional emotional behavior in schizophrenia.

Adult↗
PubMed2004

Brain activation associated with evaluative processes of guilt and embarrassment: an fMRI study.

We aimed to investigate the neural substrates associated with evaluative process of moral emotions. Using functional magnetic resonance imaging (fMRI), we examined the similarities and differences between evaluative process of guilt and that of embarrassment at the neural basis level. Study of the neural basis of judgments of moral emotions might contribute to a better understanding of the amoral behavior observed in neurological and psychiatric disorders. Nineteen healthy volunteers were studied. The participants read sentences carrying neutral, guilty, or embarrassing contents during the scans. Both guilt and embarrassment conditions commonly activated the medial prefrontal cortex (MPFC), left posterior superior temporal sulcus (STS), and visual cortex. Compared to guilt condition, embarrassment condition produced greater activation in the right temporal cortex (anterior), bilateral hippocampus, and visual cortex. Most of these regions have been implicated in the neural substrate of social cognition or Theory of Mind (ToM). Our results support the idea that both are self-conscious emotions, which are social emotions requiring the ability to represent the mental states of others. At the same time, our functional fMRI data are in favor of the notion that evaluative process of embarrassment might be a more complex process than that of guilt.

Adult↗
PubMed2004

Estimation of the time-course of dopamine D2 receptor occupancy in living human brain from plasma pharmacokinetics of antipsychotics.

Although the kinetic profile of antipsychotics at dopamine D2 receptor sites has been suggested to be important for antipsychotic action and dosing schedule, the kinetic profiles of the respective antipsychotic drugs in the brain have not yet been clearly defined. We aimed to estimate the time-course of dopamine D2 receptor occupancy from plasma pharmacokinetics and the apparent in-vivo affinity parameter (ED50; concentration required to induce 50% occupancy). Dopamine D2 receptor occupancies and plasma concentrations of risperidone were measured in five patients with schizophrenia using positron emission tomography with [11C]FLB 457. Measured dopamine D2 occupancies were compared with those estimated from plasma kinetics and in-vivo ED50. The time-course of dopamine D2 receptor occupancy was simulated with altered plasma kinetics or apparent in-vivo affinity parameters of the drug. Mean half-life of dopamine D2 receptor occupancy of risperidone was 80.2 h while that of the plasma concentration was 17.8 h. Dopamine D2 receptor occupancy estimated from plasma pharmacokinetics and in-vivo ED50 was within 1 S.D. of the mean measured occupancy. When the ED50 value was changed to one-tenth and 10-fold, the simulated half-life of receptor occupancy changed to 117.6 h and 27.3 h respectively. Using plasma pharmacokinetics and in-vivo ED50, the time-course of receptor occupancy could be calculated. Simulation of drug kinetics at receptors would provide useful information for the evaluation of antipsychotics.

Adult↗
PubMed2004

Neural damage due to temporal lobe epilepsy: dual-nuclei (proton and phosphorus) magnetic resonance spectroscopy study.

The aim of this study was to evaluate the usefulness of proton and phosphorus (1H and 31P) magnetic resonance spectroscopy (MRS) for temporal lobe epilepsy (TLE) patients, and to evaluate neural damage and metabolite dysfunction in the TLE patient brain. We performed 1H and 31P MRS of medial temporal lobes (MTL) in the same TLE patients (n = 14) with a relatively wide range of severity from almost seizure-free to intractable, and calculated the ratio of N-acetylasparate to choline-containing compounds and creatine + phosphocreatine (NAA/Cho + Cr) in 1H MRS and inorganic phosphate to all main peaks (%Pi) in 31P MRS. There was no significant correlation between NAA/(Cho + Cr) and %Pi in each side (ipsilateral, r = -0.20; contralateral, r =-0.19). The values of NAA/(Cho + Cr) showed a significant difference between ipsilateral and contralateral MTLs to the focus of TLE patients (P < 0.01, paired t-test). Although %Pi also had a tendency to show the laterality of TLE, there was no significance. Ipsilateral (r = -0.90, P < 0.0001) and contralateral (r = -0.70, P < 0.005) NAA/(Cho + Cr) decreases and contralateral %Pi increase (r = 0.81, P < 0.001) had significant correlation with seizure frequency. 1H MRS provides more important information concerning neuronal dysfunction in MTL of TLE patients than 31P MRS.

Adult↗
PubMed2004

Landiolol attenuates acute hemodynamic responses but does not reduce seizure duration during maintenance electroconvulsive therapy.

Maintenance electroconvulsive therapy (mECT) is an outpatient procedure that requires further consideration in terms of management of ambulatory anesthesia. Although many adjunctive drugs for stabilizing hemodynamic changes during ECT have been reported, side-effects of these drugs may delay recovery and discharge from hospital. The effects of landiolol, a novel ultra-short-acting beta-adrenergic blocker, have been measured on seizure duration, hemodynamic changes, recovery from anesthesia, and cognitive function during mECT under propofol anesthesia. A total of 10 patients with depression in the remission phase, were studied in a randomized, double-blind, placebo-controlled, crossover manner. Administration of 0.1 mg/kg of landiolol immediately before anesthesia significantly blunted the increase in heart rate and blood pressure during convulsions compared with placebo; landiolol was not associated with excessive hypotension or bradycardia. Landiolol did not affect seizure duration, recovery from anesthesia, or cognitive function before or after ECT. These results suggest that landiolol can be used effectively and safely during mECT.

Adrenergic beta-Antagonists↗
PubMed2004

Low dopamine d(2) receptor binding in subregions of the thalamus in schizophrenia.

OBJECTIVE: Several structural and functional brain imaging studies have pointed to a disturbance of thalamic subnuclei in patients with schizophrenia. The dopamine hypothesis of schizophrenia has, however, not been thoroughly examined in terms of this complex structure, which has connections with most brain regions of central interest in schizophrenia research. The aim of the present study was to examine dopamine D(2) receptor binding in subregions of the thalamus in patients with schizophrenia. METHOD: The authors used positron emission tomography and the radioligand [(11)C]FLB457 to examine dopamine D(2) receptor binding in thalamic subregions of 10 drug-naive patients with schizophrenia. Binding potential was calculated by the reference tissue method and used as an index for dopamine D(2) receptor binding. Comparisons were made with 19 healthy subjects. Subregions of interest were defined on individual magnetic resonance images using a percentage-based operational approach. Clinical symptoms were rated by using the Brief Psychiatric Rating Scale (BPRS). RESULTS: The [(11)C]FLB457 binding potential was lower in the central medial and posterior subregions of the thalamus in patients with schizophrenia. At a functional level, there was a significant negative correlation between binding potential and BPRS positive symptom scores. CONCLUSIONS: The subregions with low D(2) receptor binding comprise primarily the dorsomedial nucleus and pulvinar, two important components in circuitries previously suggested in the pathophysiology of schizophrenia. Aberrant dopaminergic neurotransmission in thalamic subregions might be a mechanism underlying positive symptoms in schizophrenia.

Adult↗
PubMed2003

No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human brain measured by PET.

The human serotonin transporter (5-HTT) gene has a polymorphism in the 5'-flanking promoter region that is called the serotonin transporter gene-linked polymorphic region (5-HTTLPR). In lymphoblast cell lines, the promoter activity of the 5-HTT gene is dependent on 5-HTTLPR allelic variants. The transcriptional activity of the l allele was more than twice as high as that of the s allele. The s allele is considered to be associated with mood disorders and anxiety-related personality traits. To evaluate the functional differences of 5-HTTLPR in the brain in vivo, we examined the allelic variations of 5-HTTLPR and measured 5-HTT binding in the living human brain using positron emission tomography (PET) with C(11)-labeled trans-1, 2, 4, 5, 6, 10-beta-hexahydro-6-[4-(methylthio) phenyl]pyrrolo[2,1-a]isoquinoline (McN5652) as a ligand. Twenty-seven healthy male subjects participated in this study. Although the human lymphoblast cells with the l/l genotype was reported to produce higher concentrations of both mRNA and protein of 5-HTT than those with the l/s or s/s genotype in a human lymphoblast in vitro study, 5-HTT binding in vivo was not significantly different among subjects with the three genotypes (l/l: 0.842 +/- 0.184, l/s: 0.708 +/- 0.118, s/s: 0.825 +/- 0.209). In conclusion, this study does not support the assumption that the genotype-dependent differences of 5-HTTLPR directly contributes to the regulation of the 5-HTT binding site in the living human brain.

Adult↗
PubMed2003

[(11)C]PE2I: a highly selective radioligand for PET examination of the dopamine transporter in monkey and human brain.

The aim of this study was to explore the potential of a new selective dopamine transporter (DAT) compound as a radioligand for positron emission tomography (PET) examination of DAT in the human brain. The high affinity DAT compound N-(3-iodoprop-2 E-enyl)-2beta-carbomethoxy-3beta-(4-methylphenyl)nortropane (PE2I) was radiolabelled by the O-methylation approach and the binding was characterised by PET in cynomolgus monkeys and a healthy man. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography. O-methylation of the corresponding free acid precursor with [(11)C]methyl triflate gave high radiochemical yield (80%) and specific radioactivity (55 GBq/ microM). [(11)C]PE2I binding in cynomolgus monkeys was nine times higher in the striatum than in the cerebellum at peak equilibrium, which appeared 55-65 min after injection. Displacement and pretreatment measurements using unlabelled beta-CIT, GBR 12909, cocaine, citalopram and maprotiline confirmed that [(11)C]PE2I binds selectively to DAT. In a preliminary study in one human subject the radioactivity ratios of the striatum and substantia nigra to the cerebellum were 10 and 1.8, respectively, at peak equilibrium, which appeared at 40-50 min and 20 min, respectively, after injection. The fraction of the total radioactivity in monkey and human plasma representing unchanged [(11)C]PE2I was 15-20% at 40 min after injection. The present characterisation of binding in monkey and man suggests that [(11)C]PE2I is a suitable PET radioligand for quantitative regional examination of DAT in man.

Adult↗
PubMed2003

Regional cerebral blood flow in depressed patients with white matter magnetic resonance hyperintensity.

BACKGROUND: Functional neuroimaging studies have consistently demonstrated decreased regional cerebral blood flow (rCBF) or metabolism in the frontal lobe, temporal lobe, or anterior cingulate gyrus of depressed patients. On the other hand, white matter hyperintensity as defined by magnetic resonance imaging (MRI) has been the most consistently replicated finding in structural neuroimaging studies on depression; however, these functional and structural neuroimaging findings of depression have not been well integrated. We aimed to clarify the possible associations of MRI-defined subcortical hyperintensities with rCBF changes in depressed patients. METHODS: Twelve depressed patients with subcortical hyperintensities defined by MRI, 11 depressed patients without MRI hyperintensities, and 25 healthy volunteers underwent 99mTc ECD SPECT. Group comparisons of their rCBF and correlation analysis between MRI hyperintensity and rCBF in patients were performed with a voxel-based analysis using statistical parametric mapping (SPM) software. RESULTS: Depressed patients showed decreased rCBF compared with control subjects in the frontal lobe, temporal lobe, and anterior cingulate gyrus whether subcortical hyperintensity existed or not; however, the patients with MRI hyperintensity showed decreased rCBF in the thalamus, basal ganglia, and brainstem in addition to cortical areas. Further, the score for white matter hyperintensity correlated negatively with rCBF in subcortical brain structures, including the thalamus and right basal ganglia. CONCLUSION: Our study indicates that depressed patients with MRI hyperintensities may have dysfunction in subcortical brain structures in addition to dysfunction in the fronto-temporal cortical structures.

Adult↗
PubMed2003

High levels of serotonin transporter occupancy with low-dose clomipramine in comparative occupancy study with fluvoxamine using positron emission tomography.

CONTEXT: Serotonin transporters (5-HTT) are regarded as one of the major therapeutic targets of antidepressants. However, there have only been a few studies about 5-HTT occupancy, and in particular, data concerning classical antidepressants are still limited. OBJECTIVE: To investigate the relationship between 5-HTT occupancy and a wide range of antidepressant dosing protocols. DESIGN, SETTING, AND PARTICIPANTS: Antidepressant occupancies of 5-HTT were measured using positron emission tomography (PET) with [11C](+)McN5652. Twenty-seven healthy volunteers were measured with and without pretreatment with single low doses of antidepressants, and long-term doses were evaluated in 10 patients. Scan data were collected between December 12, 1995, and August 7, 2002, and data were analyzed during the 2001-2002 period at the National Institute of Radiological Sciences (Chiba, Japan). Intervention Four different doses of clomipramine hydrochloride (5-50 mg) and 3 different doses of fluvoxamine maleate (12.5-50 mg) were used for single administration. Long-term doses were 20 to 250 mg per day for clomipramine hydrochloride, and 25 to 200 mg per day for fluvoxamine maleate. Main Outcome Measure Occupancies in the thalamus were calculated using the individual baseline of [11C](+)McN5652 for single-dose studies and 2 long-term-dose studies, and the mean value of healthy volunteers as the baseline for 8 long-term-dose studies. The average data from inactive enantiomers [11C](-)McN5652 were used for the estimation of nonspecific binding. RESULTS: Occupancy of 5-HTT increased in a curvilinear manner. Even 10 mg of clomipramine hydrochloride showed approximately 80% occupancy, which was comparable with that of 50 mg of fluvoxamine maleate. Estimated median effective dose (ED50) of clomipramine hydrochloride was 2.67 mg for oral dose and 1.42 ng/mL for plasma concentration; those of fluvoxamine maleate were 18.6 mg and 4.19 ng/mL, respectively. CONCLUSIONS: Clinical doses of clomipramine and fluvoxamine occupied approximately 80% of 5-HTT, and dose escalation would have minimal effect on 5-HTT blockade. Ten milligrams of clomipramine hydrochloride was enough to occupy 80% of 5-HTT in vivo.

Adult↗
PubMed2003

Brain perfusion SPECT in patients with corticobasal degeneration: analysis using statistical parametric mapping.

We sought to determine the characteristics of brain perfusion in patients with corticobasal degeneration (CBD) using single photon emission computed tomography (SPECT) and statistical parametric mapping (SPM). Thirteen patients with CBD and 10 age-matched healthy volunteers were examined using brain perfusion SPECT and (99m)Tc-ethyl cysteinate dimer (ECD). Regional cerebral blood flow (rCBF) measurements were performed noninvasively using a graphic analysis method. Both the absolute rCBF data (raw data) and the adjusted rCBF data (global CBF normalized to 50 ml/100 g/min) were used in the SPM analysis. A significant decrease in the absolute rCBF was observed in extended areas of the brain in CBD patients compared to the control group. These areas included the frontal, parietal, and temporal cortices; basal ganglia; thalamus; and pontocerebellar regions. Our results suggest that the extent of the reduced rCBF region in CBD patients is more widespread than previously reported.

Aged↗
PubMed2003

Sleep spindles in human prefrontal cortex: an electrocorticographic study.

To investigate the sleep spindle activity of the human prefrontal cortex (PFC), we simultaneously recorded whole nights of polysomnographic and electrocorticographic (ECoG) activities during the natural sleep of epileptic patients. Subjects were nine patients with intractable epilepsy who had subdural electrodes surgically attached to the orbital (seven cases), medial (three cases), or dorsolateral (two cases) PFC, and in one case to the frontal pole. To examine spindle frequencies, fast Fourier transformation (FFT) and auto-correlation analyses were performed on the PFC ECoG and Cz EEG data, primarily on epochs of stage 2 sleep. Lower sigma band ECoG oscillations of about 12 Hz were widely distributed across all prefrontal cortical areas including the frontal limbic regions, but none of the PFC sigma frequency peaks coincided with the faster (about 14 Hz) Cz EEG sleep spindles. Combining our results with anatomical and electrophysiological facts, it is suggested that the thalamofrontal circuit involving the rostral reticular and the mediodorsal nucleus of the thalamus is responsible for the generation of 12 Hz frontal spindles in humans.

Adult↗
PubMed2003

Correlation between electroencephalography and heart rate variability during sleep.

It is known that autonomic nervous activities change in correspondence with sleep stages. However, the characteristics of continuous fluctuations in nocturnal autonomic nerve tone have not been clarified in detail. The study aimed to determine the possible correlation between the electroencephalogram (EEG) and autonomic nervous activities, and to clarify in detail the nocturnal fluctuations in autonomic nerve activities. Overnight EEGs and electrocardiograms of seven healthy males were obtained. These EEGs were analyzed by fast Fourier transformation algorithm to extract delta, sigma and beta power. Heart rate and heart rate variability (HRV) were calculated in consecutive 5-min epochs. The HRV indices of low frequency (LF), high frequency (HF) and LF/HF ratio were calculated from the spectral analysis of R-R intervals. The sleep stages were manually scored according to Rechtschaffen and Kales' criteria. Low frequency and LF/HF were significantly lower during non-rapid eye movement (NREM) than REM, and were lower in stages 3 and 4 than in stages 1 and 2. Furthermore, delta EEG showed inverse correlations with LF (r = - 0.44, P < 0.001) and LF/HF (r = - 0.41, P < 0.001). In contrast, HF differed neither between REM and NREM nor among NREM sleep stages. Detailed analysis revealed that correlation was evident from the first to third NREM, but not in the fourth and fifth NREM. Delta EEG power showed negative correlations with LF and LF/HF, suggesting that sympathetic nervous activities continuously fluctuate in accordance with sleep deepening and lightening.

Adult↗
PubMed2003

Inhibitory effect of hippocampal 5-HT1A receptors on human explicit memory.

OBJECTIVE: Recent studies have indicated that the serotonergic (5-HT) system plays important roles in memory function. However, the specific relationship between 5-HT(1A) receptors and memory function is not clear in the human brain. To clarify this relationship, the authors determined the availability of 5-HT(1A) receptors in the human brain and the relationship between regional receptor binding and memory function. METHOD: Using positron emission tomography (PET) with [(11)C]WAY-100635, the authors examined 5-HT(1A) receptors and assessed their relationship with memory function. The 5-HT(1A )agonist tandospirone was then administered to investigate the effect of 5-HT(1A) receptor stimulation on cognitive function and neuroendocrinological response. RESULTS: There was a significant negative correlation between explicit memory function and 5-HT(1A) receptor binding localized in the bilateral hippocampus where the postsynaptic 5-HT(1A) receptors are enriched. Furthermore, the administration of tandospirone dose-dependently impaired explicit verbal memory, while other cognitive functions showed no significant changes. The change in memory function paralleled those of body temperature and secretion of growth hormone, which were reported to be induced by the stimulation of postsynaptic 5-HT(1A) receptors. CONCLUSIONS: Postsynaptic 5-HT(1A )receptors localized in the hippocampal formation have a negative influence on explicit memory function, which raises the possibility that the antagonistic effect of postsynaptic 5-HT(1A) receptors in the hippocampus leads to improvement of human memory function. Drugs that work as antagonists on postsynaptic 5-HT(1A) receptors may be favorable for improved control of memory impairment.

Adult↗
PubMed2002

In vivo drug action of tandospirone at 5-HT1A receptor examined using positron emission tomography and neuroendocrine response.

RATIONALE: Tandospirone is a selective 5-hydroxytryptamine (HT)(1A) receptor agonist and is clinically used as an anxiolytic in Japan. However, there are no data concerning the occupancy of these receptors by tandospirone in the living human brain. OBJECTIVES: The aim of this study was to assess the effect of tandospirone on in vivo 5-HT(1A) receptor binding of [(11)C]WAY 100635 using positron emission tomography (PET) and the neuroendocrine effect. METHODS: In the PET study, seven healthy volunteers were scanned three times following an oral dose of placebo or tandospirone (30 mg or 60 mg). The binding potential of [(11)C]WAY 100635 was estimated for six regions: prefrontal cortex, temporal cortex, anterior cingulate cortex, parietal cortex, hippocampus and dorsal raphe nucleus. In the neuroendocrine study, six volunteers received a single oral dose of tandospirone (60 mg) or placebo in a randomized double-blind, cross-over design, and then the plasma levels of growth hormone and cortisol and the body temperature were measured. RESULTS: Tandospirone (60 mg) induced a significant decrease in body temperature and an increase in the plasma concentration of growth hormone. However, there was no significant reduction of [(11)C]WAY 100635 binding following the administration of 30 mg or 60 mg tandospirone. CONCLUSION: Despite the significant effect on growth hormone and body temperature, a clinical dose of tandospirone had a negligible effect on [(11)C]WAY 100635 binding. This indicates that the agonist produces a pharmacological effect without measurable occupancy, and a new index other than occupancy will be required for the in vivo evaluation of agonists.

Adult↗
PubMed2002

Age-related decline of serotonin transporters in living human brain of healthy males.

There is growing interest in serotonin transporter (5-HTT) function in the human brain, since alteration in 5-HTT has been suggested in a variety of neurophychiatric disorders. Age-related decline in postsynaptic 5-HT receptors has been demonstrated in postmortem human studies and in vivo imaging studies, and has been assumed to be related to changes in mental function in the normal aging process. However, few studies have investigated the aging effect on 5-HTT in human brain in vivo, since the availability of suitable ligands has been limited. To investigate the aging effect on 5-HTT in living human brain, we performed positron emission tomography (PET) scans with a selective ligand for 5-HTT, [11C](+)McN5652. We examined 28 healthy male volunteers aged between 20 and 79 years. The uptake was quantified in the thalamus and midbrain by graphical analysis with the cerebellum as a reference tissue, and binding potential (BP) was used for the index of 5-HTT binding. There was a significant age-related decline in BP in the thalamus and midbrain. The decline in [11C](+)McN5652 binding was 9.6% per decade in the thalamus and 10.5% per decade in the midbrain.

Adult↗
PubMed2002

Serotonin transporter binding in patients with mood disorders: a PET study with [11C](+)McN5652.

BACKGROUND: Several lines of studies have suggested the involvement of serotonin transporter (5-HTT) in the pathophysiology of mood disorders. The aim of this study was to examine whether 5-HTT binding was altered in patients with mood disorders using positron emission tomography (PET). METHODS: Thirteen antidepressant-naive or -free patients with mood disorders and 21 age-matched healthy control subjects participated in this study. The patients consisted of 7 with major depressive disorder (MDD) and 6 with bipolar disorder (BD). Positron emission tomography scans were performed using a selective ligand for 5-HTT, [11C](+)McN5652. The uptake was quantified in the thalamus and midbrain by graphical method with reference tissue, and binding potential (BP) was used for the index of 5-HTT binding. RESULTS: Binding potential in the thalamus was significantly increased in patients with mood disorders as compared to control subjects, whereas BP in the midbrain did not differ between the groups. Subgroup comparison showed that MDD patients had significantly higher BP in the thalamus compared to control subjects. Binding potential of the thalamus was higher by approximately 22% in the combined patients and 23% in MDD patients relative to control subjects. CONCLUSIONS: These findings may suggest the possibility of altered 5-HTT in patients with mood disorders. Functional abnormality in the thalamus may be involved in the pathophysiology of mood disorders.

Adult↗