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It is usually assumed that individuals rest during sleep. However, coordinated neural activity that presumably requires high energy consumption is increased during REM sleep. Here, using freely moving male transgenic mice, the local brain environment and astrocyte activity during REM sleep were examined using the fibre photometry method with an optical fibre inserted deep into the lateral hypothalamus, a region that is linked with controlling sleep and metabolic state of the entire brain. Optical fluctuations of endogenous autofluorescence of the brain parenchyma or fluorescence of sensors for Ca2+ or pH expressed in astrocytes were examined. Using a newly devised method for analysis, changes in cytosolic Ca2+ and pH in astrocytes and changes in the local brain blood volume (BBV) were extracted. On REM sleep, astrocytic Ca2+ decreases, pH decreases (acidification) and BBV increases. Acidification was unexpected, as an increase in BBV would result in efficient carbon dioxide and/or lactate removal, which leads to alkalinization of the local brain environment. Acidification could be a result of increased glutamate transporter activity due to enhanced neuronal activity and/or aerobic metabolism in astrocytes. Notably, optical signal changes preceded the onset of the electrophysiological property signature of REM sleep by ∼20–30 s. This suggests that changes in the local brain environment have strong control over the state of neuronal cell activity. With repeated stimulation of the hippocampus, seizure response gradually develops through kindling. After a fully kindled state was obtained with multiple days of stimuli, the optical properties of REM sleep at the lateral hypothalamus were examined again. Although a negative deflection of the detected optical signal was observed during REM sleep after kindling, the estimated component changed. The decrease in Ca2+ and increase in BBV were minimal, and a large decrease in pH (acidification) emerged. This acidic shift may trigger an additional gliotransmitter release from astrocytes, which could lead to a state of hyperexcitable brain. As the properties of REM sleep change with the development of epilepsy, REM sleep analysis may serve as a biomarker of epileptogenesis severity. REM sleep analysis may also predict whether a specific REM sleep episode triggers post-sleep seizures.

Plastic change of the neuronal system has traditionally been assumed to be governed primarily by the long-term potentiation/depression mechanisms of synaptic transmission. However, a rather simple shift in the ambient ion, transmitter and metabolite concentrations could have a pivotal role in generating plasticity upon the physiological process of learning and memory. Local brain environment and metabolic changes could also be the cause and consequences of the pathogenesis leading to epilepsy. Governing of the local brain environment is the primal function of astrocytes. The metabolic state of the entire brain is strongly linked to the activity of the lateral hypothalamus. In this study, plastic change of astrocyte reactions in the lateral hypothalamus was examined using epileptogenesis as an extreme form of plasticity. Fluorescent sensors for calcium or pH expressed in astrocytes were examined for up to one week by in vivo fibre photometry in freely moving transgenic male mice. Optical fluctuations on a timescale of seconds is difficult to assess because these signals are heavily influenced by local brain blood volume changes and pH changes. Using a newly devised method for the analysis of the optical signals, changes in Ca2+ and pH in astrocytes and changes in local brain blood volume associated with hippocampal-stimulated epileptic seizures were extracted. Following a transient alkaline shift in the astrocyte triggered by neuronal hyperactivity, a prominent acidic shift appeared in response to intensified seizure which developed with kindling. The acidic shift was unexpected as transient increase in local brain blood volume was observed in response to intensified seizures, which should lead to efficient extrusion of the acidic CO2. The acidic shift could be a result of glutamate transporter activity and/or due to the increased metabolic load of astrocytes leading to increased CO2 and lactate production. This acidic shift may trigger additional gliotransmitter release from astrocytes leading to the exacerbation of epilepsy. As all cellular enzymic reactions are influenced by Ca2+ and pH, changes in these parameters could also have an impact on the neuronal circuit activity. Thus, controlling the astrocyte pH and/or Ca2+ could be a new therapeutic target for treatment of epilepsy or prevention of undesired plasticity associated with epileptogenesis.

We recently developed a positron emission tomography (PET) probe, [sup18/supF]PM-PBB3, to detect tau lesions in diverse tauopathies, including mixed three-repeat and four-repeat (3R + 4R) tau fibrils in Alzheimer's disease (AD) and 4R tau aggregates in progressive supranuclear palsy (PSP). For wider availability of this technology for clinical settings, bias-free quantitative evaluation of tau images without a priori disease information is needed.We aimed to establish tau PET pathology indices to characterize PSP and AD using a machine learning approach and test their validity and tracer capabilities.Data were obtained from 50 healthy control subjects, 46 patients with PSP Richardson syndrome, and 37 patients on the AD continuum. Tau PET data from 114 regions of interest were subjected to Elastic Net cross-validation linear classification analysis with a one-versus-the-rest multiclass strategy to obtain a linear function that discriminates diseases by maximizing the area under the receiver operating characteristic curve. We defined PSP- and AD-tau scores for each participant as values of the functions optimized for differentiating PSP (4R) and AD (3R + 4R), respectively, from others.The discriminatory ability of PSP- and AD-tau scores assessed as the area under the receiver operating characteristic curve was 0.98 and 1.00, respectively. PSP-tau scores correlated with the PSP rating scale in patients with PSP, and AD-tau scores correlated with Mini-Mental State Examination scores in healthy control-AD continuum patients. The globus pallidus and amygdala were highlighted as regions with high weight coefficients for determining PSP- and AD-tau scores, respectively.These findings highlight our technology's unbiased capability to identify topologies of 3R + 4R versus 4R tau deposits. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The tendency to avoid punishment, called behavioral inhibition system, is an essential aspect of motivational behavior. Behavioral inhibition system is related to negative affect, such as anxiety, depression and pain, but its neural basis has not yet been clarified. To clarify the association between individual variations in behavioral inhibition system and brain 5-HT2A receptor availability and specify which brain networks were involved in healthy male subjects, using [18F]altanserin positron emission tomography and resting-state functional magnetic resonance imaging. Behavioral inhibition system score negatively correlated with 5-HT2A receptor availability in anterior cingulate cortex. A statistical model indicated that the behavioral inhibition system score was associated with 5-HT2A receptor availability, which was mediated by the functional connectivity between anterior cingulate cortex and left middle frontal gyrus, both of which involved in the cognitive control of negative information processing. Individuals with high behavioral inhibition system displays low 5-HT2A receptor availability in anterior cingulate cortex and this cognitive control network links with prefrontal-cingulate integrity. These findings have implications for underlying the serotonergic basis of physiologies in aversion.

Histamine H3 receptor antagonists and inverse agonists have been extensively developed to treat sleep–wake, neurocognitive, and allied disorders. However, potential adverse effects, including insomnia, hampered the clinical use of these drugs, possibly due to their persistent interaction with the target molecules. The purpose of the present study was to estimate the pharmacokinetics and pharmacodynamics of enerisant, a novel antagonist and inverse agonist for histamine H3 receptors. To measure the histamine H3 receptor occupancy by enerisant, positron emission tomography studies using [11C]TASP457, a specific radioligand for histamine H3 receptors, were performed in 12 healthy men at baseline and at 2 h after oral administration of enerisant hydrochloride. For three of these subjects, two additional scans were performed at 6 and 26 h after the administration. Relationships between the receptor occupancy by enerisant and its dose and plasma concentrations were then analyzed. Administration of enerisant hydrochloride decreased the radioligand binding in a dose-dependent manner. The estimated receptor occupancy values at 2 h varied as a function of its dose or plasma concentration. The time course of the occupancy showed persistently high levels (> 85%) in the two subjects with higher doses (25 and 12.5 mg). The occupancy was also initially high at 2 h and 6 h with the lower dose of 5 mg, but it decreased to 69.7% at 26 h. The target engagement of enerisant was demonstrated in the brains of living human subjects. The occupancy of histamine H3 receptors by enerisant at 2 h can be predicted by applying the plasma concentration of enerisant to Hill’s plot. The preliminary time-course investigation showed persistently high brain occupancy with high doses of enerisant despite the decreasing plasma concentration of the drug. Five milligrams or less dose would be appropriate for the treatment for narcolepsy with initially high occupancy allowing for effective treatment of narcolepsy, and then the occupancy level would be expected to decrease to a level to avoid this drug’s unwanted side effect of insomnia at night, although further research is warranted to confirm the statement since the expected decrease is based on the finding in one subject. This study was retrospectively registered with ClinicalTrials.gov (NCT04631276) on November 17, 2020.

Histamine H receptor antagonists and inverse agonists have been extensively developed to treat sleep-wake, neurocognitive, and allied disorders. However, potential adverse effects, including insomnia, hampered the clinical use of these drugs, possibly due to their persistent interaction with the target molecules. The purpose of the present study was to estimate the pharmacokinetics and pharmacodynamics of enerisant, a novel antagonist and inverse agonist for histamine H receptors.

Positron emission tomography (PET) has been used to investigate changes in the concentration of endogenous neurotransmitters. Recently, this technique has been applied to the imaging of serotonin2A receptors using [18F]altanserin. In these measurements, a reduction in binding potential (BP) suggests an increase in endogenous serotonin levels caused by pharmacological or cognitive stimulations, and the sensitivity of BP reduction depends on the characteristics of [18F]altanserin. In this study, we evaluated an analytical method for estimating the changes in endogenous serotonin levels based on PET scans with [18F]altanserin at baseline and stimulated states and validated it using simulations and small animal PET studies. First, in the simulations, the time-activity curves at baseline and the stimulated states were generated using an extended compartment model including the competition for the receptors between the administered [18F]altanserin and endogenous serotonin. In the stimulated state, the magnitude and onset of the endogenous serotonin elevation were altered to varying degrees. In these time-activity curves, BP was estimated using the simplified reference tissue model (SRTM), and the reduction in BP was evaluated by comparison with that of the baseline state. Next, the proposed method was applied to mouse PET studies. Endogenous serotonin levels were elevated by treatment with selective serotonin reuptake inhibitors (SSRIs), and PET studies were performed twice, once with and once without treatment. In both scans, BP was estimated using the SRTM with the cerebellum as a reference region, and the reduction in BP after SSRI treatment was evaluated. In the simulations, the BP estimate of the stimulated state was smaller than that of the baseline state, and their reduction was related to the amount of change in the serotonin concentration. BP reduction was also affected by the onset of serotonin elevation. In the mouse studies, the BP of the cerebral cortex decreased in the scans with SSRI treatment. The reduction in BP estimated using the SRTM from [18F]altanserin-PET studies at baseline and in stimulated states can detect changes in the binding conditions of serotonin2A receptors. This may be useful for investigating the elevation of endogenous serotonin levels caused by stimulations.

Positron emission tomography (PET) has been used to investigate changes in the concentration of endogenous neurotransmitters. Recently, this technique has been applied to the imaging of serotonin receptors using [18F]altanserin. In these measurements, a reduction in binding potential (BP) suggests an increase in endogenous serotonin levels caused by pharmacological or cognitive stimulations, and the sensitivity of BP reduction depends on the characteristics of [18F]altanserin. In this study, we evaluated an analytical method for estimating the changes in endogenous serotonin levels based on PET scans with [18F]altanserin at baseline and stimulated states and validated it using simulations and small animal PET studies.

Objective We aimed to estimate in vivo 211At-labeled meta-benzylguanidine (211At-MABG) absorbed doses by the two dose conversion methods, using 131I-MIBG biodistribution data from a previously reported neuroblastoma xenograft model. Additionally, we examined the effects of different cell lines and time limitations using data from two other works. Methods We used the framework of the Monte Carlo method to create 3200 virtual experimental data sets of activity concentrations (kBq/g) to get the statistical information. Time activity concentration curves were produced using the fitting method of a genetic algorithm. The basic method was that absorbed doses of 211At-MABG were calculated based on the medical internal radiation dose formalism with the conversion of the physical half-life time of 131I to that of 211At. We have further improved the basic method, that is a novel dose conversion method, RAP (RAtio of Pharmacokinetics), using percent injected dose/g. Results Virtual experiments showed that 211At-MABG and 131I-MIBG had similar properties of initial activity concentrations and biological components, but the basic method did not simulate the 211At-MABG dose. Simulated 211At-MABG doses from 131I-MIBG using the RAP method were in agreement with those from 211At-MABG, so that their boxes overlapped in the box plots. The RAP method showed applicability to the different cell lines, but it was difficult to predict long-term doses from short-term experimental data. Conclusions The present RAP dose conversion method could estimate 211At-MABG absorbed doses from the pharmacokinetics of 131I-MIBG with some limitations. The RAP method would be applicable to a large number of subjects for targeted nuclide therapy.

Purpose Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measures changes in the concentration of an administered contrast agent to quantitatively evaluate blood circulation in a tumor or normal tissues. This method uses a pharmacokinetic analysis based on the time course of a reference region, such as muscle, rather than arterial input function. However, it is difficult to manually define a homogeneous reference region. In the present study, we developed a method for automatic extraction of the reference region using a clustering algorithm based on a time course pattern for DCE-MRI studies of patients with prostate cancer. Methods Two feature values related to the shape of the time course were extracted from the time course of all voxels in the DCE-MRI images. Each voxel value of T1-weighted images acquired before administration were also added as anatomical data. Using this three-dimensional feature vector, all voxels were segmented into five clusters by the Gaussian mixture model, and one of these clusters that included the gluteus muscle was selected as the reference region. Results Each region of arterial vessel, muscle, and fat was segmented as a different cluster from the tumor and normal tissues in the prostate. In the extracted reference region, other tissue elements including scattered fat and blood vessels were removed from the muscle region. Conclusions Our proposed method can automatically extract the reference region using the clustering algorithm with three types of features based on the time course pattern and anatomical data. This method may be useful for evaluating tumor circulatory function in DCE-MRI studies.

Objective: Positron emission tomography (PET) scans of imaging receptors require 60–90-min dynamic acquisition for quantitative analysis. Head movement is often observed during scanning, which hampers the reliable estimation of quantita- tive parameters. This study evaluated image-based motion correction by frame-to-frame realignment for PET studies with [11C]raclopride and [11C]FLB 457 acquired by an Eminence SET-3000GCT/X and investigated the effect of this correction on the quantitative outcomes. Methods: First, an optimal method for estimating motion parameters was evaluated by computer simulation. Simulated emis- sion sinograms were reconstructed to the PET images with or without attenuation correction using a μ-map of the transmis- sion scan. Six motion parameters were estimated frame-by-frame by registering each frame of the PET images to several types of reference images and the reliability of registration was compared. Next, in [11C]raclopride and [11C]FLB 457 studies in normal volunteers, six motion parameters for each frame were estimated by the registration method determined from the simulation results. Head movement was corrected by realigning the PET images reconstructed with a motion-included μ-map in which a mismatch between the transmission and emission scans was corrected. After this correction, time-activity curves (TAC) for the striatum or cerebral cortex were obtained and the binding potentials of the receptors (BPND) were estimated using the simplified reference tissue model. Results: In the simulations, the motion parameters could be reliably estimated by registering each frame of the non-attenua- tion-corrected PET images to their early-phase frame. The motion parameters in the human studies were also obtained using the same method. After correction, a discontinuity of TACs in the striatum and cerebral cortex was remarkably improved and the BPND values in these regions increased. Compared to the motion-corrected PET images reconstructed using the measured μ-map, the images reconstructed using the motion-included μ-map did not result in a remarkable improvement of BPND in the striatum of [11C]raclopride studies, while the BPND in the cerebral cortex changed in some [11C]FLB 457 studies in which large head movement was observed. Conclusions: In PET receptor imaging, head movement during dynamic scans can be corrected by frame-to-frame realign- ment. This method is easily applicable to clinical studies and provides reliable TACs and BPND.

私たちは、131I-MIBG の治療を経た後、211At-MABG治療を受ける患者を想定した場合、131I-MIBG 治療時に受けたであろうシンチグラフィやSPECT診断の結果を利用して、211At-MABGの線量評価ができるかもしれないと予想した。臨床データはないけれども、動物実験では、131I-MIBG（メタヨードベンジルグアニジン）と211At-MABGの薬剤動態がよく似ていることが報告されている。そこで、本発表では、動物実験の結果を利用して、131I-MIBGと211At-MABGの薬剤動態の違いを解析し、線量推定の可能性について検討を報告する。, QST高崎サイエンスフェスタ2021

Background We recently reported a new absorbed dose conversion method, RAP (RAtio of Pharmacokinetics), for 211At-meta-astatobenzylguanidine (211At-MABG) using a single biodistribution measurement, the percent injected dose/g. However, there were some mathematical ambiguities in determining the optimal timing of a single measurement of the percent injected dose/g. Thus, we aimed to mathematically reconstruct the RAP method and to examine the optimal timing of a single measurement. Methods We derived a new formalism of the RAP dose conversion method at time t. In addition, we acquired a formula to determine the optimal timing of a single measurement of the percent injected dose/g, assuming the one-compartment model for biological clearance. Results We investigated the new formalism’s performance using a representative RAP coefficient with radioactive decay weighting. Dose conversions by representative RAP coefficients predicted the true [211At]MABG absorbed doses with an error of 10% or less. The inverses of the representative RAP coefficients plotted at 4 h post-injection, which was the optimal timing reported in the previous work, were very close to the new inverses of the RAP coefficients 4 h post-injection. Next, the behavior of the optimal timing was analyzed by radiolabeled compounds with physical half-lives of 7.2 h and 10 d on various biological clearance half-lives. Behavior maps of optimal timing showed a tendency to converge to a constant value as the biological clearance half-life of a target increased. The areas of optimal timing for both compounds within a 5% or 10% prediction error were distributed around the optimal timing when the biological clearance half-life of a target was equal to that of the reference. Finally, an example of RAP dose conversion was demonstrated for [211At]MABG. Conclusions The RAP dose conversion method renovated by the new formalism was able to estimate the [211At]MABG absorbed dose using a similar pharmacokinetics, such as [131I]MIBG. The present formalism revealed optimizing imaging time points on absorbed dose conversion between two radiopharmaceuticals. Further analysis and clinical data will be needed to elucidate the validity of a behavior map of the optimal timing of a single measurement for targeted alpha-nuclide therapy.

【目的】非アルツハイマー型認知症のタウオパチーである進行性核上性麻痺(PSP)において，18F-PM-PBB3をプローブとするタウ病変PET画像による客観的な自動診断法を開発する．【方法】対象は健常高齢者(HC) 43例 (69.2 ± 7.0 [平均 ± 標準偏差]歳，女性 48.8%)，PSP 42例 (71.5 ± 7.1歳，女性 35.7%，MDS-PSP診断基準でprobable)，疾患対照としてパーキンソン病患者(PD) 8例 (70.6 ± 6.4歳，女性 12.5%) で，機械学習訓練用(75%)と診断能評価用(25%)に分けて解析した(stratified shuffle splitで10セット分作成)．マルチアトラス法を用いて脳実質112カ所の関心領域(ROI)を同定し，病変が少ない小脳皮質とのプローブ集積比(SUVR)を算出した．値は年齢，性別で補正し標準化した．各領域のSUVRと重み係数の積の総和(PSP tauスコア)によるPSP群対，HC+PD群の弁別能が最も高くなるように，機械学習(elastic net CV)により重み係数の最適化を行った．得られたスコアと重症度の相関も解析した．【結果】淡蒼球，中脳，被殻などが重み係数の高い弁別に重要なROIであった．評価用10セットデータのPSP tauスコアを平均化して解析した診断能は正確度 96.7%, 感度 95.1%, 特異度 98.0%であった．PSP tauスコアと重症度(PSP rating scale)は有意な相関を認めた(Spearman’s rs = 0.4, p = 0.009).【結論】18F-PM-PBB3 PETを用いてPSPの自動診断および重症度の予測に有望な手法を開発した．, 第40回日本認知症学会学術集会

The tendency to avoid punishment, called behavioral inhibition system, is an essential aspect of motivational behavior. Behavioral inhibition system is related to negative affect, such as anxiety, depression and pain, but its neural basis has not yet been clarified. To clarify the association between individual variations in behavioral inhibition system and brain 5-HT

Positron emission tomography (PET) with [First, the reproducibility of BP estimation using the dual-bolus injection approach was evaluated using PET scans without stimulation in nine healthy volunteers. A 90-min scan was performed with bolus injections of [In the PET scans without stimulation, the dual-bolus injection approach showed a smaller MAD (2%) between BPOur results indicate that the cognitive task-induced changes in dopamine-related systems may be complex and difficult to measure accurately using PET scans. However, the proposed dual-bolus injection approach provided reliable BP estimates with high reproducibility, suggesting that it has the potential to improve the accuracy of PET scans for measuring changes in dopamine concentrations.

目的： 18F-PM-PBB3 PETは進行性核上性麻痺（PSP）を含む前頭側頭葉変性症（FTLD）のタウ病変を可視化するが、FTLDでは小脳にもタウが沈着しうるため、小脳以外を参照領域とした薬剤の定量が望ましい場合がある。本研究ではヒストグラムによるFTLDの参照領域の最適化を目的とした。 方法：健常者（HC）39例、PSP患者40例および他のFTLD患者5例の18F-PM-PBB3 PET画像を解析した。位置合わせしたMR画像をもとに灰白質・白質のボクセル値をそれぞれヒストグラム化し、二峰性ガウス分布にフィットさせた。低い方の分布から参照領域を抽出し、小脳皮質を参照領域とした場合とそれぞれSUVR画像を作成し、鑑別能について比較した。 結果： HCとPSP患者とで、ROC曲線に基づくAUCは灰白質（0.928）、白質（0.917）、小脳（0.908）を参照領域とした順に高かった。また他のFTLD患者においても、灰白質を参照領域とすることで、高感度に視覚評価での弁別が可能だった。 結論：ヒストグラムを用いた参照領域の最適化は、FTLDにおける18F-PM-PBB3 PETの診断能を改善させる可能性がある。, 第61回に本核医学会学術総会

昨年の学会にて、私達は、新たな線量変換法であるRAP法を発表した。この手法は、アルファ線がん治療薬として期待されている211Atで標識した211At-MABG（メタアスタトベンジルグアニジン）の線量を、131I-MIBG（メタヨードベンジルグアニジン）の体内動態を主に利用して推定する方法である。RAP法では、ある一時点における、211At-MABGと131I-MIBGの両者の体内分布データ（%ID/g）を取得（測定）する必要がある。しかし、この１回測定を行うタイミングについての検討が不十分であった。そこで、生物学的半減期など想定される条件の中で、１回測定のタイミングと変換後の線量との関係について解析を進めている。学会にて本研究の最新成果を発表する。, 第61回日本核医学会学術総会

昨年の学会にて、私達は、新たな線量変換法であるRAP法を発表した。この手法は、アルファ線がん治療薬として期待されている211Atで標識した211At-α核種を標識した薬剤である211At-MABG（メタアスタトベンジルグアニジン）の臓器や組織における吸収線量を、211At-MABGと類似した動態を示す131I -MIBG（メタヨードベンジルグアニジン）の薬剤動態を用いて推定する方法の検討を進めている。最近、私たちは、「131I -MIBGの薬剤動態を用いて、211At-MABGの1回撮像（シンチグラフィ など）のみで吸収線量を評価できる」線量変換方法としてRAP（RAtio of Pharmacokinetics）法を提案した。しかし、撮像のタイミングについては未だ検討が不十分であった。そこで、方程式を構築することにより、撮像の最適なタイミングの基礎検討を行ったので、その成果を発表する。, 第2回標的アイソトープ治療線量評価研究会

私たちが提案した線量変換方法であるRAP（RAtio of Pharmacokinetics）法は、「核医学治療に用いるα核種を標識した薬剤の動態を、類似した動態を示す核医学診断が可能な薬剤の動態を把握することにより、１回の撮像（シンチグラフィ など）のみで評価できる」技術を用いた患者に優しい線量変換方法（線量評価法）である。しかし、撮像のタイミングについては未だ指針がない。そこで、本発表では撮像のタイミングに関する基礎的検討について発表する。, 第58回アイソトープ・放射線研究発表会

Rationale The tendency to avoid punishment, called behavioral inhibition system, is an essential aspect of motivational behavior. Behavioral inhibition system is related to negative affect, such as anxiety, depression and pain, but its neural basis has not yet been clarified. Objectives To clarify the association between individual variations in behavioral inhibition system and brain 5-HT2A receptor availability and specify which brain networks were involved in healthy male subjects, using [18F]altanserin positron emission tomography and resting-state functional magnetic resonance imaging. Results Behavioral inhibition system score negatively correlated with 5-HT2A receptor availability in anterior cingulate cortex. A statistical model indicated that the behavioral inhibition system score was associated with 5-HT2A receptor availability, which was mediated by the functional connectivity between anterior cingulate cortex and left middle frontal gyrus, both of which involved in the cognitive control of negative information processing. Conclusions Individuals with high behavioral inhibition system displays low 5-HT2A receptor availability in anterior cingulate cortex and this cognitive control network links with prefrontal-cingulate integrity. These findings have implications for underlying the serotonergic basis of physiologies in aversion.

Unlike an electrical circuit, the hardware of the brain is susceptible to change. Repeated electrical brain stimulation mimics epileptogenesis. After such “kindling” process, a moderate stimulus would become sufficient in triggering a severe seizure. Here, we report that optogenetic neuronal stimulation can also convert the rat brain to a hyperexcitable state. However, continued stimulation once again converted the brain to a state that was strongly resistant to seizure induction. Histochemical examinations showed that moderate astrocyte activation was coincident with resilience acquisition. Administration of an adenosine A1 receptor antagonist instantly reverted the brain back to a hyperexcitable state, suggesting that hyperexcitability was suppressed by adenosine. Furthermore, an increase in basal adenosine was confirmed using in vivo microdialysis. Daily neuron-to-astrocyte signaling likely prompted a homeostatic increase in the endogenous actions of adenosine. Our data suggest that a certain stimulation paradigm could convert the brain circuit resilient to epilepsy without exogenous drug administration.

Positron emission tomography (PET) scans of imaging receptors require 60–90-min dynamic acquisition for quantitative analysis. Head movement is often observed during scanning, which hampers the reliable estimation of quantitative parameters. This study evaluated image-based motion correction by frame-to-frame realignment for PET studies with [11C]raclopride and [11C]FLB 457 acquired by an Eminence SET-3000GCT/X and investigated the effect of this correction on the quantitative outcomes. First, an optimal method for estimating motion parameters was evaluated by computer simulation. Simulated emission sinograms were reconstructed to the PET images with or without attenuation correction using a µ-map of the transmission scan. Six motion parameters were estimated frame-by-frame by registering each frame of the PET images to several types of reference images and the reliability of registration was compared. Next, in [11C]raclopride and [11C]FLB 457 studies in normal volunteers, six motion parameters for each frame were estimated by the registration method determined from the simulation results. Head movement was corrected by realigning the PET images reconstructed with a motion-included µ-map in which a mismatch between the transmission and emission scans was corrected. After this correction, time-activity curves (TAC) for the striatum or cerebral cortex were obtained and the binding potentials of the receptors (BPND) were estimated using the simplified reference tissue model. In the simulations, the motion parameters could be reliably estimated by registering each frame of the non-attenuation-corrected PET images to their early-phase frame. The motion parameters in the human studies were also obtained using the same method. After correction, a discontinuity of TACs in the striatum and cerebral cortex was remarkably improved and the BPND values in these regions increased. Compared to the motion-corrected PET images reconstructed using the measured µ-map, the images reconstructed using the motion-included µ-map did not result in a remarkable improvement of BPND in the striatum of [11C]raclopride studies, while the BPND in the cerebral cortex changed in some [11C]FLB 457 studies in which large head movement was observed. In PET receptor imaging, head movement during dynamic scans can be corrected by frame-to-frame realignment. This method is easily applicable to clinical studies and provides reliable TACs and BPND.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measures changes in the concentration of an administered contrast agent to quantitatively evaluate blood circulation in a tumor or normal tissues. This method uses a pharmacokinetic analysis based on the time course of a reference region, such as muscle, rather than arterial input function. However, it is difficult to manually define a homogeneous reference region. In the present study, we developed a method for automatic extraction of the reference region using a clustering algorithm based on a time course pattern for DCE-MRI studies of patients with prostate cancer.

We performed multi-b and multi-diffusion-time diffusion-weighted magnetic resonance imaging on aquaporin-4-expressing (AQ) and -non-expressing (noAQ) cells, and demonstrated a clear difference between the signals from the two cell types. The data were interpreted using a two-compartment (intra and extracellular spaces) model including inter-compartmental exchange. It was also assumed that restricted diffusion of water molecules inside the cells leads to the intracellular diffusion coefficient being inversely proportional to the diffusion-time. Estimates of the water-exchange-times obtained with this model are compared to those measured using an independent optical imaging technique (coherent anti-Stokes Raman scattering imaging, CARS). For both techniques it was found that the exchange-time estimated for the noAQ cells was significantly longer than that for the AQ cells.

Histamine HTo measure the histamine HAdministration of enerisant hydrochloride decreased the radioligand binding in a dose-dependent manner. The estimated receptor occupancy values at 2 h varied as a function of its dose or plasma concentration. The time course of the occupancy showed persistently high levels ( 85%) in the two subjects with higher doses (25 and 12.5 mg). The occupancy was also initially high at 2 h and 6 h with the lower dose of 5 mg, but it decreased to 69.7% at 26 h.The target engagement of enerisant was demonstrated in the brains of living human subjects. The occupancy of histamine HThis study was retrospectively registered with ClinicalTrials.gov (NCT04631276) on November 17, 2020.

[Objective] We aim to establish a diagnostic system for progressive supranuclear palsy (PSP) by tau positron emission tomography (PET) with 18F-PM-PBB3. [Methods] We employed the data of 24 healthy controls (HC; age 67.5 ± 5.1 [mean ± SD] y, 9 males); 30 PSP (71.4 ± 8.2 y, 21 males, PSP rating scale [PSPRS] 41.1 ± 17.7) who met the MDS-PSP criteria and showed a typical topological pattern of 18F-PM-PBB3 PET observed in PSP. All data were corrected by age and sex, and standardized for analysis. Standardized uptake value ratios using the cerebellar cortex as reference region were obtained in 112 volumes of interests (VOIs) by the multi-atlas method. The Elastic Net cross validation analysis was applied to the set of VOIs to determine which VOIs useful for discriminating PSP from HC. The obtained coefficients were applied to each individual data to calculate and define as PSP score. We tested PSP score for validation to 10 HC (68.9 ± 7.4 y, 7 males) and 5 PSP cases (73.0 ± 7.8 y, 3 males, PSPRS 46.6 ± 11.3) in a new cohort. We also evaluated association between PSP score and disease severity measured by PSPRS. [Results] Globus pallidus, putamen and midbrain were selected as pivotal VOIs calculating PSP score. PSP score for training and validation data showed accuracy of 94.4% and 80%, precision of 93.3% and 100%, and recall of 96.6% and 62.5%. Moreover, PSPRS correlated well with PSP score (Spearman’s rs = 0.56, p < 0.001). [Conclusions] Automated analysis system of tau PET with 18F-PM-PBB3 would be a promising tool both for diagnosing and predicting disease severity in PSP., 第62回日本神経学会学術大会

Positron emission tomography (PET) has been used to investigate changes in the concentration of endogenous neurotransmitters. Recently, this technique has been applied to the imaging of serotoninFirst, in the simulations, the time-activity curves at baseline and the stimulated states were generated using an extended compartment model including the competition for the receptors between the administered [In the simulations, the BP estimate of the stimulated state was smaller than that of the baseline state, and their reduction was related to the amount of change in the serotonin concentration. BP reduction was also affected by the onset of serotonin elevation. In the mouse studies, the BP of the cerebral cortex decreased in the scans with SSRI treatment.The reduction in BP estimated using the SRTM from [

In nociceptive processing, the descending antinociceptive system (DAS) is well known to include a number of descending pathways.As the main pathway of DAS, the locus coeruleus (A6) – spinal horn circuit including the noradrenergic (NAergic) system andthe periaqueductal gray-rostral ventromedial medulla (B3) – spinal horn circuit including the serotonergic (5-HTergic) system are well known.OtherNAergic or 5-HTegic systems, however,are less well known. Some studies have reported that A5/A7 noradrenaline (NA) neurons or B2 serotonin (5-HT, 5-hydroxytryptamine) neurons partially participate in DAS.In this study, we recorded G-CaMP6 green fluorescence signal intensities in theA5/A7/B2 sites of awake mice in response to acute tail pinch stimuli, acute heat stimuli, and in the context of a noninvasive control test, using fiber photometry with acalcium imaging system.We first introduced G-CaMP6 in the A5/A7 NA neuronal soma or B2 5-HT neuronal soma, using transgenic mice carrying tetracycline-controlled transactivator transgene (tTA) under the control of either a dopamine β-hydroxylase promoter or a tryptophan hydroxylase-2 and by the site-specific injection of adeno-associated virus (AAV-TetO(3G)-G-CaMP6).The specific expression patterns of G-CaMP6 were clearly confirmed in the A5/A7 areasand B2 area.After confirming the specific expression patterns of G-CaMP6, we recorded G-CaMP6 green fluorescence signals in these sites fromawake mice in response to acute nociceptive stimuli.G-CaMP6 fluorescence intensity in the A5, A7, and B2 groups wasrapidly increased by acute nociceptive stimuli,soon returning to baseline fluorescence intensity.This was not observed in the context of the noninvasive control test.Weused mCherry red fluorescent protein as a control indicator. mCherry fluorescence intensity was not significantly changed by acute nociceptive stimuli or in the noninvasive control test in any of the groups. These results clearly indicate that acute nociceptive stimuli rapidly increase the activities of A5/A7 NA neurons or B2 5-HT neurons, suggesting that A5/A7 NA neurons or B2 5-HT neurons play important roles in nociceptive processing in the central nervous system.

We aimed to estimate in vivoWe used the framework of the Monte Carlo method to create 3200 virtual experimental data sets of activity concentrations (kBq/g) to get the statistical information. Time activity concentration curves were produced using the fitting method of a genetic algorithm. The basic method was that absorbed doses ofVirtual experiments showed thatThe present RAP dose conversion method could estimate

In the central nervous system, the A6 noradrenaline (NA) and the B3 serotonin (5-HT) cell groups are well-recognized players in the descending antinociceptive system, while other NA/5-HT cell groups are not well characterized. A5/A7 NA and B2 5-HT cells project to the spinal horn and form descending pathways. We recorded G-CaMP6 green fluorescence signal intensities in the A5/A7 NA and the B2 5-HT cell groups of awake mice in response to acute tail pinch stimuli, acute heat stimuli, and in the context of a non-noxious control test, using fiber photometry with a calcium imaging system. We first introduced G-CaMP6 in the A5/A7 NA or B2 5-HT neuronal soma, using transgenic mice carrying the tetracycline-controlled transactivator transgene under the control of either a dopamine β-hydroxylase or a tryptophan hydroxylase-2 promoters and by the site-specific injection of adeno-associated virus (AAV-TetO(3G)-G-CaMP6). After confirming the specific expression patterns of G-CaMP6, we recorded G-CaMP6 green fluorescence signals in these sites in awake mice in response to acute nociceptive stimuli. G-CaMP6 fluorescence intensity in the A5, A7, and B2 cell groups was rapidly increased in response to acute nociceptive stimuli and soon after, it returned to baseline fluorescence intensity. This was not observed in the non-noxious control test. The results indicate that acute nociceptive stimuli rapidly increase the activities of A5/A7 NA or B2 5-HT neurons but the non-noxious stimuli do not. The present study suggests that A5/A7 NA or B2 5-HT neurons play important roles in nociceptive processing in the central nervous system. We suggest that A5/A7/B2 neurons may be new therapeutic targets. All performed procedures were approved by the Institutional Animal Use Committee of Kagoshima University (MD17105) on February 22, 2018.

Background α-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor is a primary mediator of fast glutamatergic excitatory signaling in the brain and has been implicated in diverse neuropsychiatric diseases. We recently developed a novel positron emission tomography (PET) ligand, 2-(1-(3-([11C]methylamino)phenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitrile ([11C]HMS011). This compound is a radiolabelled derivative of perampanel, an antiepileptic drug acting on AMPA receptors, and was demonstrated to have promising in vivo properties in the rat and monkey brains. In the current study, we performed a human PET study using [11C]HMS011 to evaluate its safety and kinetics. Four healthy male subjects underwent a 120-min PET scan after injection of [11C]HMS011. Arterial blood sampling and metabolite analysis were performed to obtain parent input functions for three of the subjects using high-performance liquid chromatography. Regional distribution volumes (V Ts) were calculated based on kinetic models with and without considering radiometabolite in the brain. The binding was also quantified using a reference tissue model with white matter as reference. Results Brain uptake of [11C]HMS011 was observed quickly after the injection, followed by a rapid clearance. Three hydrophilic and one lipophilic radiometabolites appeared in the plasma, with notable individual variability. The kinetics in the brain with apparent radioactivity retention suggested that the lipophilic radiometabolite could enter the brain. A dual-input graphical model, an analytical model designed in consideration of a radiometabolite entering the brain, well described the kinetics of [11C]HMS011. A reference tissue model showed small radioligand binding potential (BP*ND) values in the cortical regions (BP*ND = 0–0.15). These data suggested specific binding component of [11C]HMS011 in the brain. Conclusions Kinetic analyses support some specific binding of [11C]HMS011 in the human cortex. However, this ligand may not be suitable for practical AMPA receptor PET imaging due to the small dynamic range and metabolite in the brain.

The central dopaminergic system is of major importance in the pathophysiology of Parkinson's disease, schizophrenia, and other neuropsychiatric disorders. In the present study, the normative data of dopaminergic neurotransmission functions in the midbrain, consisting of neuromelanin, dopamine synthesis, dopamine transporters and dopamine D2 receptors, were constructed using magnetic resonance (MR) imaging and positron emission tomography (PET). PET studies with L-[β-11C]DOPA, [18F]FE-PE2I and [11C]FLB457 and MRI studies were performed on healthy young men. Neuromelanin accumulation measured by MRI was compared with dopaminergic functions, dopamine synthesis capacity, dopamine transporter binding and dopamine D2 receptor binding measured by PET in the substantia nigra. Although neuromelanin is synthesized from DOPA and dopamine in dopaminergic neurons, neuromelanin accumulation did not correlate with dopamine synthesis capacity in young healthy subjects. The role of dopamine transporters in the substantia nigra is considered to be the transport of dopamine into neurons, and therefore dopamine transporter binding might be related to neuromelanin accumulation; however, no significant correlation was observed between them. A positive correlation between dopamine D2 receptor binding and neuromelanin accumulation was observed, indicating a feedback mechanism by dopaminergic autoreceptors. Discrepancies in regional distribution between neuromelanin accumulation and dopamine synthesis capacity, dopamine transporter binding or dopamine D2 receptor binding were observed in the substantia nigra.

Objectives In PET studies for neuroreceptors, tracer kinetics are described by the two-tissue compartment model (2-TCM), and binding parameters, including the total distribution volume (V T), non-displaceable distribution volume (V ND), and binding potential (BPND), can be determined from model parameters estimated by kinetic analysis. The stability of binding parameter estimates depends on the kinetic characteristics of radioligands. To describe these kinetic characteristics, we previously developed a two-phase graphic plot analysis in which V ND and V T can be estimated from the x-intercept of regression lines for early and delayed phases, respectively. In this study, we applied this graphic plot analysis to visual evaluation of the kinetic characteristics of radioligands for neuroreceptors, and investigated a relationship between the shape of these graphic plots and the stability of binding parameters estimated by the kinetic analysis with 2-TCM in simulated brain tissue time-activity curves (TACs) with various binding parameters. Methods 90-min TACs were generated with the arterial input function and assumed kinetic parameters according to 2-TCM. Graphic plot analysis was applied to these simulated TACs, and the curvature of the plot for each TAC was evaluated visually. TACs with several noise levels were also generated with various kinetic parameters, and the bias and variation of binding parameters estimated by kinetic analysis were calculated in each TAC. These bias and variation were compared with the shape of graphic plots. Results The graphic plots showed larger curvature for TACs with higher specific binding and slower dissociation of specific binding. The quartile deviations of V ND and BPND determined by kinetic analysis were smaller for radioligands with slow dissociation. Conclusions The larger curvature of graphic plots for radioligands with slow dissociation might indicate a stable determination of V ND and BPND by kinetic analysis. For investigation of the kinetics of radioligands, such kinetic characteristics should be considered.

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.

The beneficial effects of psychostimulant drugs in the treatment of psychiatric disorders occur because they increase the extracellular dopamine concentration by inhibiting re-uptake of extracellular dopamine at dopamine transporters. However, the psychological effects at low dopamine transporter occupancy have not been well demonstrated. The purpose of the study was to evaluate the psychological effects, dopamine transporter occupancy, and dopamine release induced by a single oral administration of a clinical dose of mazindol. Ten healthy male volunteers were orally administered a placebo and a clinical dose of mazindol (1.5 mg) on separate days. The psychological effects of mazindol were assessed using a visual analogue scale to detect alterations in the state of consciousness. The amount of blockade of dopamine transporters was assessed using positron emission tomography with [18F]FE-PE2I and extracellular dopamine release was measured as the amount of change in [11C]raclopride binding. Following administration of a clinical dose of mazindol, the dopamine transporters were blocked by 24–25 %, and the binding potential of [11C]raclopride was reduced by 2.8–4.6 %. The differences of a score measuring derealisation and depersonalization associated with a positive basic mood were significantly correlated with the change in the [11C]raclopride binding in the limbic striatum. A subtle alteration in the state of consciousness was detected with a correlation to the changes in the [11C]raclopride binding, which implies that a subtle alteration in extracellular dopamine concentration in the limbic striatum by a small amount of dopamine transporter occupancy can affect the state of consciousness. UMIN000008232