Tetsuya Ichimiya

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.

Reduced volume of the cerebellar vermis in neuroleptic-naive schizophrenia.

BACKGROUND Neuroimaging studies have suggested the possible role of the cerebellum in the pathophysiology of schizophrenia. However, no study has investigated the detailed structures of the cerebellum in patients without a history of neuroleptic medication. The objective of this study is to examine the volume of detailed structures of the cerebellum in neuroleptic-naive schizophrenic patients and to examine the relationship between cerebellar morphology and clinical symptoms. METHODS Magnetic resonance imaging scans were acquired from 20 male neuroleptic-naive schizophrenic patients and 20 healthy control subjects. We measured the volumes of the cerebrum, cerebellar hemisphere, cerebellar gray and white matter, and vermis. Symptoms were assessed with the Brief Psychiatric Rating Scale. Total Brief Psychiatric Rating Scale scores and subscale scores were used for analysis. RESULTS The volume of the vermis was significantly reduced in the schizophrenic group relative to the control group, whereas no significant differences were found in the volumes of other cerebellar structures and the cerebrum. Reduction in the vermal volume correlated with the total Brief Psychiatric Rating Scale Depression subscore and Paranoia subscore. CONCLUSIONS This study indicates that the volume of the vermis is reduced in patients with schizophrenia, and reduction in vermal volume is suggested to be related to the pathophysiology of the disease.

Decreased 5-HT1A receptor binding in amygdala of schizophrenia.

BACKGROUND On the basis of postmortem data and the pharmacological action of atypical antipsychotics, serotonin-1A receptors are of interest in the study of the pathophysiology of schizophrenia. To investigate serotonin-1A receptors in schizophrenia and their relation to symptoms, we measured the availability of serotonin-1A receptors in patients with schizophrenia using positron emission tomography with [carbonyl-(11)C]WAY-100635. METHODS Serotonin-1A receptor binding of 11 patients with schizophrenia (8 drug-naive and 3 drug-free) was compared with that of 22 age-matched and gender-matched healthy control subjects. Symptoms were assessed using the Positive and Negative Syndrome Scale. Serotonin-1A receptor binding in selected regions of interest was quantified by binding potential obtained by the reference tissue method. RESULTS The regional binding potential value was lower in the amygdala by about 19% in patients with schizophrenia than in normal controls. A significant negative correlation was observed between binding potential in the amygdala and the negative and depression/anxiety symptom scores on the five-symptom subscale of the Positive and Negative Syndrome Scale. CONCLUSIONS Decreased serotonin-1A receptor binding in the amygdala may underlie the affective components included in the symptoms of negative and depression/anxiety in schizophrenia.

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.

Template-Based Method for Multiple Volumes of Interest of Human Brain PET Images

Specific region-based analysis for the quantification of brain imaging is very time-consuming work and subject to errors in both accuracy and reproducibility. In this study, we assessed a two-step template-based method for defining volumes of interest (VOIs). The first step was the spatial transformation of the VOI template from a model MRI to an individual MRI with SPM99. The second step was to refine the transformed VOI to the individual gray matter of MRI using the intensity characteristics of this image with our developed software running on a PC type of computer. The reliability of the values of the final refined VOIs was investigated by comparing them to those of manually drawn VOIs. The template-based method was found to be both accurate and robust and can be used as a reliable alternative for the manual determination of VOIs.

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.

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.

Electroconvulsive Therapy Decreases Dopamine D 2 Receptor Binding in the Anterior Cingulate in Patients With Depression: A Controlled Study Using Positron Emission Tomography With Radioligand [ 11 C]FLB 457

OBJECTIVE Electroconvulsive therapy (ECT) has been confirmed as one of the most effective treatments in drug-resistant major depression. However, the mechanism of ECT is still poorly understood. Although several lines of studies have focused on its effect on dopamine neurotransmission, the effects of ECT on dopamine D(2) receptors in a living human brain have not been investigated. Using positron emission tomography (PET) scans with the radioligand [(11)C]FLB 457, we aimed to evaluate the effect of ECT on extrastriatal D(2) receptor binding in medicated patients with major depressive disorder (MDD). METHOD Seven patients with a DSM-IV diagnosis of MDD underwent PET scans before and after a series of 6-7 treatments with bilateral ECT. Eleven healthy controls were scanned for comparison. All participants were scanned at the National Institute of Radiological Sciences, Chiba, Japan, between November 2000 and September 2005. The parametric images of [(11)C]FLB 457 binding were generated on the basis of a simplified reference tissue model. Voxel-based methods were used to assess the effect of ECT on D(2) receptor binding. RESULTS There were no significant differences in D(2) receptor binding between patients with MDD and controls. All 7 patients showed clinical improvements in response to ECT treatment (P < .001). Significant changes in D(2) receptor binding, a mean of 25.2% reduction, were found in the right rostral anterior cingulate (AC) following ECT (P < .001). CONCLUSIONS Electroconvulsive therapy decreased D(2) receptor binding in the rostral AC in MDD patients responding to ECT. Our finding suggests that one of the biologic mechanisms of ECT could be related to dopaminergic alteration in the rostral AC.

Effect of electroconvulsive therapy on 5-HT1A receptor binding in patients with depression: a PET study with [11C]WAY 100635.

In our previous positron emission tomography (PET) study, we demonstrated that ECT decreased dopamine D2 receptor in major depressive disorder (MDD). Although many animal studies have focused on the effect of ECT on serotonergic neurotransmission, no human study has directly examined the effect of ECT on brain serotonin [5-hydroxytryptamine (5-HT)] 1A receptors (5-HT1ARs). Using PET with [11C]WAY 100635, we aimed to evaluate the effect of ECT on 5-HT1ARs in patients with MDD. Nine patients underwent PET scans before and after a series of 6-7 bilateral ECTs. Region-of-interest analysis was performed based on the simplified reference tissue model. There were no significant changes in 5-HT1AR binding in patients between before and after ECT. ECT did not alter [11C]WAY 100635 binding even after recovery from depressive episode. Although the present finding does not exclude the involvement of brain 5-HT1A systems in the antidepressant action of ECT, it may indicate the involvement of other neurotransmission mechanisms.

Quantitative Analysis for Estimating Binding Potential of the Brain Serotonin Transporter with [11C]McN5652:

[11C](+)McN5652 is a selective serotonin reuptake inhibitor with subnanomolar potency for the serotonin transporter, and is currently being used for positron emission tomography studies. However, quantification of the regional [11C](+)McN5652 binding potential in vivo is a controversial issue because of its complex characteristics. The authors examined the regional differences in nonspecific binding and proposed simple methods for estimating the binding potential of [11C](+)McN5652. The regional difference in nonspecific binding was evaluated by the activity ratio of the thalamus compared with the cerebellum for inactive-isomer [11C](−)McN5652 and [11C](+)McN5652 saturation studies. The distribution volume of the thalamus was approximately 1.16 times larger than that of the cerebellum. The thalamus-to-cerebellum distribution volume ratio was estimated by nonlinear least square and graphical methods, with and without arterial input function. The graphical method with k2′ without blood sampling was practical and most applicable for estimation of the distribution volume ratio because this method is more stable than the nonlinear least square method in the simulation study. Binding potential estimated with the distribution volume ratio of [11C](+)McN5652 and the correction with distribution volume ratio of [11C](−)McN5652 represent the most reliable parameters for the assessment of serotonin transporter binding.