Keisuke Takahata

It’s Not My Fault: Postdictive Modulation of Intentional Binding by Monetary Gains and Losses

Sense of agency refers to the feeling that one’s voluntary actions caused external events. Past studies have shown that compression of the subjective temporal interval between actions and external events, called intentional binding, is closely linked to the experience of agency. Current theories postulate that the experience of agency is constructed via predictive and postdictive pathways. One remaining problem is the source of human causality bias; people often make misjudgments on the causality of voluntary actions and external events depending on their rewarding or punishing outcomes. Although human causality bias implies that sense of agency can be modified by post-action information, convincing empirical findings for this issue are lacking. Here, we hypothesized that sense of agency would be modified by affective valences of action outcomes. To examine this issue, we investigated how rewarding and punishing outcomes following voluntary action modulate behavioral measures of agency using intentional binding paradigm and classical conditioning procedures. In the acquisition phase, auditory stimuli were paired with positive, neutral or negative monetary outcomes. Tone-reward associations were evaluated using reaction times and preference ratings. In the experimental session, participants performed a variant of intentional binding task, where participants made timing judgments for onsets of actions and sensory outcomes while playing simple slot games. Our results showed that temporal binding was modified by affective valences of action outcomes. Specifically, intentional binding was attenuated when negative outcome occurred, consistent with self-serving bias. Our study not only provides evidence for postdictive modification of agency, but also proposes a possible mechanism of human causality bias.

Quantification of Dopamine Transporter in Human Brain Using PET with 18F-FE-PE2I

18F-(E)-N-(3-iodoprop-2E-enyl)-2β-carbofluoroethoxy-3β-(4-methylphenyl)nortropane (18F-FE-PE2I) is a new PET radioligand with a high affinity and selectivity for the dopamine transporter (DAT). In nonhuman primates, 18F-FE-PE2I showed faster kinetics and less production of radiometabolites that could potentially permeate the blood–brain barrier than did 11C-PE2I. The aims of this study were to examine the quantification of DAT using 18F-FE-PE2I and to assess the effect of radiometabolites of 18F-FE-PE2I on the quantification in healthy humans. Methods: A 90-min dynamic PET scan was obtained for 10 healthy men after intravenous injection of 18F-FE-PE2I. Kinetic compartment model analysis with a metabolite-corrected arterial input function was performed. The effect of radiometabolites on the quantification was evaluated by time-stability analyses. The simplified reference tissue model (SRTM) method with the cerebellum as a reference region was evaluated as a noninvasive method of quantification. Results: After the injection of 18F-FE-PE2I, the whole-brain radioactivity showed a high peak (∼3–5 standardized uptake value) and fast washout. The radioactive uptake of 18F-FE-PE2I in the brain was according to the relative density of the DAT (striatum > midbrain > thalamus). The cerebellum showed the lowest uptake. Tissue time–activity curves were well described by the 2-tissue-compartment model (TCM), as compared with the 1-TCM, for all subjects in all regions. Time stability analysis showed stable estimation of total distribution volume with 60-min or longer scan durations, indicating the small effect of radiometabolites. Binding potentials in the striatum and midbrain were well estimated by the SRTM method, with modest intersubject variability. Although the SRTM method yielded a slight underestimation and overestimation in regions with high and low DAT densities, respectively, binding potentials by the SRTM method were well correlated to the estimates by the indirect kinetic method with 2-TCM. Conclusion: 18F-FE-PE2I is a promising PET radioligand for quantifying DAT. The binding potentials could be reliably estimated in both the striatum and midbrain using both the indirect kinetic and SRTM methods with a scan duration of 60 min. Although radiometabolites of 18F-FE-PE2I in plasma possibly introduced some effects on the radioactivity in the brain, the effects on estimated binding potential were likely to be small.

Occupancy of serotonin and norepinephrine transporter by milnacipran in patients with major depressive disorder: a positron emission tomography study with [11C]DASB and (S,S)-[18F]FMeNER-D2

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.

Superiority illusion arises from resting-state brain networks modulated by dopamine

The majority of individuals evaluate themselves as superior to average. This is a cognitive bias known as the “superiority illusion.” This illusion helps us to have hope for the future and is deep-rooted in the process of human evolution. In this study, we examined the default states of neural and molecular systems that generate this illusion, using resting-state functional MRI and PET. Resting-state functional connectivity between the frontal cortex and striatum regulated by inhibitory dopaminergic neurotransmission determines individual levels of the superiority illusion. Our findings help elucidate how this key aspect of the human mind is biologically determined, and identify potential molecular and neural targets for treatment for depressive realism.

Effects of Dopamine D2 Receptor Partial Agonist Antipsychotic Aripiprazole on Dopamine Synthesis in Human Brain Measured by PET with L-[β-11C]DOPA

Dopamine D2 receptor partial agonist antipsychotic drugs can modulate dopaminergic neurotransmission as functional agonists or functional antagonists. The effects of antipsychotics on presynaptic dopaminergic functions, such as dopamine synthesis capacity, might also be related to their therapeutic efficacy. Positron emission tomography (PET) was used to examine the effects of the partial agonist antipsychotic drug aripiprazole on presynaptic dopamine synthesis in relation to dopamine D2 receptor occupancy and the resulting changes in dopamine synthesis capacity in healthy men. On separate days, PET studies with [11C]raclopride and L-[β-11C]DOPA were performed under resting condition and with single doses of aripiprazole given orally. Occupancy of dopamine D2 receptors corresponded to the doses of aripiprazole, but the changes in dopamine synthesis capacity were not significant, nor was the relation between dopamine D2 receptor occupancy and these changes. A significant negative correlation was observed between baseline dopamine synthesis capacity and changes in dopamine synthesis capacity by aripiprazole, indicating that this antipsychotic appears to stabilize dopamine synthesis capacity. The therapeutic effects of aripiprazole in schizophrenia might be related to such stabilizing effects on dopaminergic neurotransmission responsivity.

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.

Sub-Doppler resolution 3.4 μm spectrometer with an efficient difference-frequency-generation source

We have developed a 3.4 mum spectrometer for sub-Doppler resolution molecular absorption spectroscopy. The source is based on the difference frequency generation using a 1.06 microm Nd:YAG laser, a 1.55 microm distributed-feedback laser diode, and a ridge waveguide periodically poled lithium niobate with a conversion efficiency of 9%/W. The generated radiation has a power level of about 300 microW, a linewidth of less than 100 kHz, and a continuous tuning range over 10 cm(-1). The spectrometer allows us to observe six saturated absorption lines of C12H(4) with 0.3-0.4 MHz width and 1.3%-1.7% depth relative to the corresponding linear absorption lines.

Quantitative Analysis of Amyloid Deposition in Alzheimer Disease Using PET and the Radiotracer 11C-AZD2184

Characteristic neuropathologic changes in Alzheimer disease (AD) are amyloid-β deposits and neurofibrillary tangles. Recently, a new radioligand for amyloid senile plaques, 11C-labeled 5-(6-{[tert-butyl(dimethyl)silyl]oxy}-1,3-benzothiazol-2-yl)pyridin-2-amine (11C-AZD2184), was developed, and it was reported to show rapid brain uptake followed by rapid washout. In this study, 11C-AZD2184 binding in control subjects and AD patients was examined in more detail by compartment model analysis using a metabolite-corrected arterial input function. The accuracy of simplified quantitative methods using a reference brain region was also evaluated. Methods: After intravenous bolus injection of 11C-AZD2184, a dynamic PET scan was obtained for 90 min in 6 control subjects and 8 AD patients. To obtain the arterial input function, arterial blood sampling and high-performance liquid chromatography analysis were performed. Results: Time–activity curves in all brain regions could be described using the standard 2-tissue-compartment model. The total distribution volume ratios to reference region (DVR) in cerebral cortical regions were significantly higher in AD patients than in control subjects. Although there was no conspicuous accumulation of radioactivity in white matter as compared with other amyloid radioligands, DVR values in the centrum semiovale were more than 1 for both control subjects and AD patients, suggesting binding to myelin. The standardized uptake value ratio calculated from integrated time–activity curves in brain regions and the reference region was statistically in good agreement with DVR. Conclusion: Although the white matter binding of 11C-AZD2184 may have some effect on cortical measurement, it can be concluded that the kinetic behavior of 11C-AZD2184 is suitable for quantitative analysis. The standardized uptake value ratio can be used as a validated measure of 11C-AZD2184 binding in clinical examinations without arterial input function.

PET quantification of the norepinephrine transporter in human brain with (S,S)-18F-FMeNER-D2

Norepinephrine transporter (NET) in the brain plays important roles in human cognition and the pathophysiology of psychiatric disorders. Two radioligands, (S,S)-11C-MRB and (S,S)-18F-FMeNER-D2, have been used for imaging NETs in the thalamus and midbrain (including locus coeruleus) using PET in humans. However, NET density in the equally important cerebral cortex has not been well quantified because of unfavorable kinetics with (S,S)-11C-MRB and defluorination with (S,S)-18F-FMeNER-D2, which can complicate NET quantification in the cerebral cortex adjacent to the skull containing defluorinated 18F radioactivity. In this study, we have established analysis methods of quantification of NET density in the brain including the cerebral cortex using (S,S)-18F-FMeNER-D2 PET. Methods: We analyzed our previous (S,S)-18F-FMeNER-D2 PET data of 10 healthy volunteers dynamically acquired for 240 min with arterial blood sampling. The effects of defluorination on the NET quantification in the superficial cerebral cortex was evaluated by establishing a time stability of NET density estimations with an arterial input 2-tissue-compartment model, which guided the less-invasive reference tissue model and area under the time–activity curve methods to accurately quantify NET density in all brain regions including the cerebral cortex. Results: Defluorination of (S,S)-18F-FMeNER-D2 became prominent toward the latter half of the 240-min scan. Total distribution volumes in the superficial cerebral cortex increased with the scan duration beyond 120 min. We verified that 90-min dynamic scans provided a sufficient amount of data for quantification of NET density unaffected by defluorination. Reference tissue model binding potential values from the 90-min scan data and area under the time–activity curve ratios of 70- to 90-min data allowed for the accurate quantification of NET density in the cerebral cortex. Conclusion: We have established methods of quantification of NET densities in the brain including the cerebral cortex unaffected by defluorination using (S,S)-18F-FMeNER-D2. These results suggest that we can accurately quantify NET density with a 90-min (S,S)-18F-FMeNER-D2 scan in broad brain areas.

Increased left anterior insular and inferior prefrontal activity in post-stroke mania

BackgroundPost-stroke mania is an infrequent complication after stroke, and the mechanisms underlying this disorder remain unclear. Although a contralesional release phenomenon has been implicated in post-stroke mania, empirical findings are lacking.Case presentationWe present a case report of post stroke mania. Single photon emission tomography (SPECT) was performed twice, during the manic state and during the remitted euthymic state. The first SPECT study performed during the manic state demonstrated hypoperfusion in the right temporal and frontal regions due to right putaminal hemorrhage. It also showed hyperperfusion in the inferior lateral prefrontal lobe, the temporal lobe, and the medial and lateral parts of the parietal lobe in the left hemisphere. The second SPECT study performed during the euthymic state demonstrated moderate improvement in the hypoperfusion in the right fronto-temporal regions. Furthermore, compared to the findings on the first SPECT study, the second study showed that the focal hyperperfusion in the anterior insular cortex, inferior lateral prefrontal lobes, and superior-middle temporal gyrus in the left hemisphere had vanished.ConclusionIncreased left inferior prefrontal and anterior insular activity and reduced extensive right fronto-temporal lobe activity are involved in the development of post-stroke mania.