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The 2015 consensus statement published by the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group and the European Cooperation in Science and Technology ( COST) Action ASL in Dementia aimed to encourage the implementation of robust arterial spin labeling (ASL) perfusion MRI for clinical applications and promote consistency across scanner types, sites, and studies. Subsequently, the recommended 3D pseudo-continuous ASL sequence has been implemented by most major MRI manufacturers. However, ASL remains a rapidly and widely developing field, leading inevitably to further divergence of the technique and its associated terminology, which could cause confusion and hamper research reproducibility. On behalf of the ISMRM Perfusion Study Group, and as part of the ISMRM Open Science Initiative for Perfusion Imaging (OSIPI), the ASL Lexicon Task Force has been working on the development of an ASL Lexicon and Reporting Recommendations for perfusion imaging and analysis, aiming to (1) develop standardized, consensus nomenclature and terminology for the broad range of ASL imaging techniques and parameters, as well as for the physiological constants required for quantitative analysis; and (2) provide a community-endorsed recommendation of the imaging parameters that we encourage authors to include when describing ASL methods in scientific reports/papers. In this paper, the sequences and parameters in (pseudo-)continuous ASL, pulsed ASL, velocity-selective ASL, and multi-timepoint ASL for brain perfusion imaging are included. However, the content of the lexicon is not intended to be limited to these techniques, and this paper provides the foundation for a growing online inventory that will be extended by the community as further methods and improvements are developed and established., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Fulfilling potentials of ultrahigh field for pseudo-Continuous Arterial Spin Labeling (pCASL) has been hampered by B1/B0 inhomogeneities that affect pCASL labeling, background suppression (BS), and the readout sequence. This study aimed to present a whole-cerebrum distortion-free three-dimensional (3D) pCASL sequence at 7T by optimizing pCASL labeling parameters, BS pulses, and an accelerated Turbo-FLASH (TFL) readout. A new set of pCASL labeling parameters (G ave = 0.4 mT/m, G ratio = 14.67) was proposed to avoid interferences in bottom slices while achieving robust labeling efficiency (LE). An OPTIM BS pulse was designed based on the range of B1/B0 inhomogeneities at 7T. A 3D TFL readout with 2D-CAIPIRINHA undersampling (R = 2 × 2) and centric ordering was developed, and the number of segments (N seg ) and flip angle (FA) were varied in simulation to achieve the optimal trade-off between SNR and spatial blurring. In-vivo experiments were performed on 19 subjects. The results showed that the new set of labeling parameters effectively achieved whole-cerebrum coverage by eliminating interferences in bottom slices while maintaining a high LE. The OPTIM BS pulse achieved 33.3% higher perfusion signal in gray matter (GM) than the original BS pulse with a cost of 4.8-fold SAR. Incorporating a moderate FA (8 ° ) and N seg (2), whole-cerebrum 3D TFL-pCASL imaging was achieved with a 2 × 2 × 4 mm 3 resolution without distortion and susceptibility artifacts compared to 3D GRASE-pCASL. In addition, 3D TFL-pCASL showed a good to excellent test-retest repeatability and potential of higher resolution (2 mm isotropic). The proposed technique also significantly improved SNR when compared to the same sequence at 3T and simultaneous multislice TFL-pCASL at 7T. By combining a new set of labeling parameters, OPTIM BS pulse, and accelerated 3D TFL readout, we achieved high resolution pCASL at 7T with whole-cerebrum coverage, detailed perfusion and anatomical information without distortion, and sufficient SNR., Competing Interests: Declaration of Competing Interest Samantha J. Ma is an employee of Siemens Healthcare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

This review article provides an overview of developments for arterial spin labeling (ASL) perfusion imaging in the body (i.e., outside of the brain). It is part of a series of review/recommendation papers from the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group. In this review, we focus on specific challenges and developments tailored for ASL in a variety of body locations. After presenting common challenges, organ-specific reviews of challenges and developments are presented, including kidneys, lungs, heart (myocardium), placenta, eye (retina), liver, pancreas, and muscle, which are regions that have seen the most developments outside of the brain. Summaries and recommendations of acquisition parameters (when appropriate) are provided for each organ. We then explore the possibilities for wider adoption of body ASL based on large standardization efforts, as well as the potential opportunities based on recent advances in high/low-field systems and machine-learning. This review seeks to provide an overview of the current state-of-the-art of ASL for applications in the body, highlighting ongoing challenges and solutions that aim to enable more widespread use of the technique in clinical practice., (© 2023 International Society for Magnetic Resonance in Medicine.)

Purpose: To present a pulse sequence and mathematical models for quantification of blood-brain barrier water exchange and permeability., Methods: Motion-compensated diffusion-weighted (MCDW) gradient-and-spin echo (GRASE) pseudo-continuous arterial spin labeling (pCASL) sequence was proposed to acquire intravascular/extravascular perfusion signals from five postlabeling delays (PLDs, 1590-2790 ms). Experiments were performed on 11 healthy subjects at 3 T. A comprehensive set of perfusion and permeability parameters including cerebral blood flow (CBF), capillary transit time (τ c ), and water exchange rate (k w ) were quantified, and permeability surface area product (PS w ), total extraction fraction (E w ), and capillary volume (V c ) were derived simultaneously by a three-compartment single-pass approximation (SPA) model on group-averaged data. With information (i.e., V c and τ c ) obtained from three-compartment SPA modeling, a simplified linear regression of logarithm (LRL) approach was proposed for individual k w quantification, and E w and PS w can be estimated from long PLD (2490/2790 ms) signals. MCDW-pCASL was compared with a previously developed diffusion-prepared (DP) pCASL sequence, which calculates k w by a two-compartment SPA model from PLD = 1800 ms signals, to evaluate the improvements., Results: Using three-compartment SPA modeling, group-averaged CBF = 51.5/36.8 ml/100 g/min, k w  = 126.3/106.7 min -1 , PS w  = 151.6/93.8 ml/100 g/min, E w  = 94.7/92.2%, τ c  = 1409.2/1431.8 ms, and V c  = 1.2/0.9 ml/100 g in gray/white matter, respectively. Temporal SNR of MCDW-pCASL perfusion signals increased 3-fold, and individual k w maps calculated by the LRL method achieved higher spatial resolution (3.5 mm 3 isotropic) as compared with DP pCASL (3.5 × 3.5 × 8 mm 3 )., Conclusion: MCDW-pCASL allows visualization of intravascular/extravascular ASL signals across multiple PLDs. The three-compartment SPA model provides a comprehensive measurement of blood-brain barrier water dynamics from group-averaged data, and a simplified LRL method was proposed for individual k w quantification., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background and Purpose: Faciobrachial dystonic seizures (FBDS) and hyponatremia are the distinct clinical features of autoimmune encephalitis (AE) caused by antibodies against leucine-rich glioma-inactivated 1 (LGI1). The present study aims to explore the pathophysiological patterns and neural mechanisms underlying these symptoms., Methods: We included 30 patients with anti-LGI1 AE and 30 controls from a retrospective observational cohort. Whole-brain metabolic pattern analysis was performed to assess the pathological network of anti-LGI1 AE, as well as the symptom networks associated with FBDS. Logistic regression was applied to explore independent predictors of FBDS. Finally, we used a multiple regression model to investigate the hyponatremia-associated brain network and its effect on serum sodium levels., Results: The pathological network of anti-LGI1 AE involved hypermetabolism in the cerebellum, subcortical structures and Rolandic area, as well as hypometabolism in the medial prefrontal cortex. The symptom network of FBDS included hypometabolism in the cerebellum and Rolandic area (p FDR  <0.05). Hypometabolism in the cerebellum was an independent predictor of FBDS (p < 0.001). Hyponatremia-associated network highlighted a negative effect on the caudate nucleus, frontal and temporal white matter. The metabolism of the hypothalamus was negatively associated with (Pearson's R = -0.180, p = 0.342), while not the independent predictor for serum sodium level (path c' = -7.238, 95% confidence interval = -30.947 to 16.472)., Conclusions: Our results provide insights into the whole-brain metabolic patterns of patients with anti-LGI1 AE, including the symptom network associated with FBDS and the hyponatremia-associated brain network. The findings help us to understand the neural mechanisms underlying anti-LGI1 AE and to evaluate the progress of this disease., (© 2022 European Academy of Neurology.)

Objective: Insulin resistance can increase the risk of cognitive dysfunction and dementia. Our purpose is to use 18F-FDG PET imaging to explore the effect of insulin resistance on brain glucose metabolism in cognitively normal subjects., Methods: A total of 189 cognitively normal subjects who underwent PET examinations were enrolled. The homeostasis model assessment of insulin resistance (HOMA-IR) was used to evaluate the presence of insulin resistance. Multivariate linear regression and generalized additive models were used to analyze the association between HOMA-IR and glucose metabolism in the whole brain and evaluate the effects of various covariates. The SPM12 software was used to evaluate the regional effect of insulin resistance on brain glucose metabolism., Results: After being fully adjusted for confounding factors, HOMA-IR showed an approximately linear negative correlation with brain glucose metabolism (β = -0.219, T = -3.331, P = 0.021). Compared with normal subjects, insulin-resistant subjects had reduced glucose metabolism in bilateral middle temporal gyrus, bilateral middle frontal gyrus, right precentral gyrus, right inferior frontal gyrus, right cuneiform lobe and bilateral cerebellar regions. In cognitively normal subjects, systemic insulin resistance has a significant effect on brain glucose metabolism., Conclusions: 18F-FDG brain PET imaging could be helpful for the early diagnosis and treatment of changes in brain glucose metabolism caused by insulin resistance., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To optimize pseudo-continuous arterial spin labeling (pCASL) for 7 T, and to further improve the labeling efficiency with parallel RF transmission transmit B 1 ( B 1 + ) shimming., Methods: pCASL parameters were optimized based on B 1 + / B 0 field distributions at 7 T with simulation. To increase labeling efficiency, the B 1 + amplitude at inflowing arteries was increased with parallel RF transmission B 1 + shimming. The "indv-shim" with shimming weights calculated for each individual subject, and the "univ-shim" with universal weights calculated on a group of 12 subjects, were compared with circular polarized (CP) shim. The optimized pCASL sequences with three B 1 + shimming modes (indv-shim, univ-shim, and CP-shim) were evaluated in 6 subjects who underwent two repeated scans 24 hours apart, along with a pulsed ASL sequence. Quantitative metrics including mean B 1 + amplitude, perfusion, and intraclass correlation coefficient were calculated. The optimized 7T pCASL was compared with standard 3T pCASL on 5 subjects, using spatial SNR and temporal SNR., Results: The optimal pCASL parameter set (RF duration/gap = 300/250 us, G ave = 0.6 mT / m , g R a t i o = 10 ) achieved robust perfusion measurement in the presence of B 1 + / B 0 inhomogeneities. Both indv-shim and univ-shim significantly increased B 1 + amplitude compared with CP-shim in simulation and in vivo experiment (P < .01). Compared with CP-shim, perfusion signal was increased by 9.5% with indv-shim (P < .05) and by 5.3% with univ-shim (P = .35). All three pCASL sequences achieved fair to good repeatability (intraclass correlation coefficient ≥ 0.5). Compared with 3T pCASL, the optimized 7T pCASL achieved 78.3% higher spatial SNR and 200% higher temporal SNR., Conclusion: The optimized pCASL achieved robust perfusion imaging at 7 T, while both indv-shim and univ-shim further increased labeling efficiency., (© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Studies have shown that attention bias can affect behavioral indicators in patients with depression, but it is still unclear how this bias affects the brain network topology of patients with mild depression (MD). Therefore, a novel functional brain network analysis and hierarchical clustering methods were used to explore the abnormal brain topology of MD patients based on EEG signals during the visual search paradigm. The behavior results showed that the reaction time of MD group was significantly higher than that of normal group. The results of functional brain network indicated significant differences in functional connections between the two groups, the amount of inter-hemispheric long-distance connections are much larger than intra-hemispheric short-distance connections. Patients with MD showed significantly lower local efficiency and clustering coefficient, destroyed community structure of frontal lobe and parietal-occipital lobe, frontal asymmetry, especially in beta band. In addition, the average value of long-distance connections between left frontal and right parietal-occipital lobes presented significant correlation with depressive symptoms. Our results suggested that MD patients achieved long-distance connections between the frontal and parietal-occipital regions by sacrificing the connections within the regions, which might provide new insights into the abnormal cognitive processing mechanism of depression.

Purpose: Thermogenesis of brown adipose tissue (BAT) is controlled by central modulating mechanisms, although changes in brain metabolism of BAT-positive subjects with different genders are still unclear. We hypothesized that changes in regional cerebral glucose metabolic activity were associated with BAT activities, and this association differed in different genders., Methods: Brain glucose metabolism of 26 BAT-positive and 26 BAT-negative healthy subjects was compared using a brain fluorodeoxyglucose (FDG)-PET scan, and gender differences in BAT-related brain functional networks and effect of sex hormones were assessed by comparing the brain PET images of BAT-positive and BAT-negative subjects of different genders and postmenopausal female subjects., Results: Compared with controls, BAT-positive male subjects had a significant hypermetabolic area in the right extranuclear and significant hypometabolic areas in the right inferior parietal lobule and right inferior frontal gyrus; while at the same threshold, BAT-positive female subjects had richer hypermetabolic regions, including bilateral limbic lobes, bilateral frontal lobes, right cerebellum, left sublobar, and right parietal lobe. However, BAT-positive postmenopause female subjects only showed significant hypometabolic regions in left lingual gyrus., Conclusions: BAT-related brain functional networks are different between male and female subjects. Female networks are more significant and more concentrated while male networks are smaller and more dispersed, and these gender differences may be related to sex hormones.

For ASL perfusion imaging in clinical settings the current guidelines recommends pseudo-continuous arterial spin labeling with segmented 3D readout. This combination achieves the best signal to noise ratio with reasonable resolution but is prone to motion artifacts due to the segmented readout. Motion robust single-shot 3D acquisitions suffer from image blurring due to the T2 decay of the sampled signals during the long readout. To tackle this problem, we propose an accelerated 3D-GRASE sequence with a time-dependent 2D-CAIPIRINHA sampling pattern. This has several advantages: First, the single-shot echo trains are shortened by the acceleration factor; Second, the temporal incoherence between measurements is increased; And third, the coil sensitivity maps can be estimated directly from the averaged k-space data. To obtain improved perfusion images from the undersampled time series, we developed a variational image reconstruction approach employing spatio-temporal total-generalized-variation (TGV) regularization. The proposed ASL-TGV method reduced the total acquisition time, improved the motion robustness of 3D ASL data, and the image quality of the cerebral blood flow (CBF) maps compared to those by a standard segmented approach. An evaluation was performed on 5 healthy subjects including intentional movement for 2 subjects. Single-shot whole brain CBF-maps with high resolution 3.1 × 3.1 × 3 mm and image quality can be acquired in 1min 46sec. Additionally high quality CBF- and arterial transit time (ATT) -maps from single-shot multi-post-labeling delay (PLD) data can be gained with the proposed method. This method may improve the robustness of 3D ASL in clinical settings, and may be applied for perfusion fMRI., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Using structure-guided design, several cell based assays, and microdosed positron emission tomography (PET) imaging, we identified a series of highly potent, selective, and brain-penetrant oxazole-4-carboxamide-based inhibitors of glycogen synthase kinase-3 (GSK-3). An isotopologue of our first-generation lead, [ 3 H]PF-367, demonstrates selective and specific target engagement in vitro, irrespective of the activation state. We discovered substantial ubiquitous GSK-3-specific radioligand binding in Tg2576 Alzheimer's disease (AD), suggesting application for these compounds in AD diagnosis and identified [ 11 C]OCM-44 as our lead GSK-3 radiotracer, with optimized brain uptake by PET imaging in nonhuman primates. GSK-3β-isozyme selectivity was assessed to reveal OCM-51, the most potent (IC 50 = 0.030 nM) and selective (>10-fold GSK-3β/GSK-3α) GSK-3β inhibitor known to date. Inhibition of CRMP2 T514 and tau phosphorylation, as well as favorable therapeutic window against WNT/β-catenin signaling activation, was observed in cells.

Background: Chronic subdural hematoma (CSDH) is commonly encountered in the elderly patients and the recurrence rate is still high, therefore, identifying risk factors for CSDH recurrence is essential. The present study aimed to identify clinical and radiological factors predicting the recurrence of CSDH., Methods: We retrospectively identified 461 patients with CSDH who underwent surgical evacuation in our department. Univariable analyses were performed at first, variables with a P-value of <0.05 were entered into multivariable logistic regression model. Kendall's tau-b test was used to evaluate the relationship between brain atrophy and postoperative pneumocephalus., Results: Univariable analyses revealed that patients with the following characteristics have a higher recurrence rate, including age ≥80 years, antiplatelet and/or anticoagulant use, GOS = 3, the volume of drainage ≥100 ml, midline shift ≥10 mm, severe brain atrophy, severe postoperative pneumocephalus. Multivariable logistic regression demonstrated that midline shift ≥10 mm, severe brain atrophy, severe postoperative pneumocephalus, and volume of drainage ≥100 ml were independent risk factors for CSDH recurrence. Kendall's tau-b test revealed that there was no correlation between brain atrophy and postoperative pneumocephalus., Conclusions: Midline shift ≥10 mm, severe brain atrophy, severe postoperative pneumocephalus, and volume of drainage ≥100 ml were independent risk factors for CSDH recurrence, CSDH patients with these characteristics should be taken precautions of recurrence and a closely follow-up should be carried out., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Most patients with bilateral chronic subdural hematomas (bCSDH) undergo initial bilateral evacuation. Risk factors associated with the recurrence of bCSDH after initial bilateral evacuation have not been published to date. In this study, we aimed to identify risk factors related to recurrence of bCSDH after initial bilateral evacuation, and to develop a prognostic grading system for clinical reference., Methods: This study included 102 patients with bCSDH who underwent initial bilateral evacuation. Predictors of recurrence were identified via univariate analysis and multivariate logistic regression analysis. A prognostic grading system was created based on the independent predictors combined with a cutoff value. All cases were scored according to the prognostic grading system, and the recurrence rates of the different scores were reanalyzed., Results: Anticoagulant use (odds ratio [OR], 84.266; 95% confidence interval [CI], 13.113-541.522; P < 0.001), severe brain atrophy (OR, 11.551; 95% CI, 2.558-52.163; P = 0.001), and postoperative pneumocephalus volume (PostPV) (OR, 0.978; 95% CI, 0.957-1.000; P = 0.049) were independent risk factors for the recurrence of bCSDH after initial bilateral evacuation. The cutoff value of PostPV was >20.9484 cm 3 . A prognostic grading system was then developed, and the recurrence rates based on score were determined. Rates were 2.8% for a score of 0-1, 28.1% for a score of 2-3, and 100% for a score of 4-5, showing a significant increase in risk with increasing score (P < 0.001)., Conclusions: Anticoagulant use, severe brain atrophy, and PostPV were identified as independent risk factors for recurrence of bCSDH after initial bilateral evacuation. The prognostic grading system for recurrence of bCSDH after initial bilateral evacuation is reliable and applicable for clinical reference., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Noncontrast enhanced dynamic magnetic resonance angiography delineates the pattern of dynamic blood flow of the cerebral vasculature. A model-free solution was proposed to quantify arterial blood flow (aBF) by using the monotonic property of the residual function., Theory and Methods: Analytical simulations and in-vivo studies were performed to evaluate the performance of the proposed method by comparing the aBF values generated from the proposed and conventional singular value decomposition methods. The aBF values were compared with blood flow velocity measured by 2D phase contrast MRI, and compared between balanced steady-state free precession-based radial and spoiled GRE-based Cartesian acquisitions. Hemodynamic parametric maps were generated in 1 patient with arteriovenous malformation., Results: The proposed method generates reliable aBF measurement at different signal-to-noise ratio levels, whereas overestimation/underestimation of aBF was observed when a high/low threshold was applied in the singular value decomposition method. Average aBF in large vascular branches was 214.4 and 214.5 mL/mL/min with radial and Cartesian acquisitions, respectively. Significant correlations were found between aBF and blood flow velocity measured by phase contrast MRI (P = 0.0008), and between Cartesian and radial acquisitions (P < 0.0001). Altered hemodynamics were observed at the lesion site of the arteriovenous malformation patient., Conclusion: A robust analytical solution was proposed for quantifying aBF. This model-free method is robust to noise, and its clinical value in the diagnosis of cerebrovascular disorders awaits further evaluation., (© 2019 International Society for Magnetic Resonance in Medicine.)

Objective: To find risk factors for contralateral hematoma progression (CHP) in bilateral chronic subdural hematomas after initial unilateral evacuation., Methods: We retrospectively analyzed 53 patients with bilateral chronic subdural hematomas who underwent unilateral surgical evacuation in our department. Risk factors for CHP were identified by univariate analysis, a P value <0.05 were entered into multivariate logistic regression model and a predictive receiver operating characteristic curve model., Results: The progression rate was 32.08%, the average progression interval was 2.32 months. The progression rate of the homogeneous hypodense group was significantly higher than that of the other density group (P = 0.017). The limited type of contralateral hematoma had a significantly lower progression rate than that of the widespread type (P = 0.001). Both pre- and postoperative volume of contralateral hematoma were significantly more in the CHP group compared with the contralateral hematoma without progression group (P = 0.031 and P = 0.001, respectively). Of the 4 risk factors, only postoperative volume of contralateral hematoma was an independent risk factor in multivariate logistic regression model (P = 0.033; 95% confidence interval, 1.005-1.124). The cut-off values of contralateral hematoma volume before and after operation were 29.27 cm 3 and 37.84 cm 3 , respectively., Conclusions: Contralateral hematoma volume after operation is an independent risk predictor for CHP after unilateral evacuation. An additional surgery on contralateral hematoma or medical treatment should be taken into consideration if the volume is >37.84 cm 3 in the first cranial computed tomography scan after surgery., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To present a novel MR pulse sequence and modeling algorithm to quantify the water exchange rate (k w ) across the blood-brain barrier (BBB) without contrast, and to evaluate its clinical utility in a cohort of elderly subjects at risk of cerebral small vessel disease (SVD)., Methods: A diffusion preparation module with spoiling of non-Carr-Purcell-Meiboom-Gill signals was integrated with pseudo-continuous arterial spin labeling (pCASL) and 3D gradient and spin echo (GRASE) readout. The tissue/capillary fraction of the arterial spin labeling (ASL) signal was separated by appropriate diffusion weighting (b = 50 s/mm 2 ). k w was quantified using a single-pass approximation (SPA) model with total generalized variation (TGV) regularization. Nineteen elderly subjects were recruited and underwent 2 MRIs to evaluate the reproducibility of the proposed technique. Correlation analysis was performed between k w and vascular risk factors, Clinical Dementia Rating (CDR) scale, neurocognitive assessments, and white matter hyperintensity (WMH)., Results: The capillary/tissue fraction of ASL signal can be reliably differentiated with the diffusion weighting of b = 50 s/mm 2 , given ~100-fold difference between the (pseudo-)diffusion coefficients of the 2 compartments. Good reproducibility of k w measurements (intraclass correlation coefficient = 0.75) was achieved. Average k w was 105.0 ± 20.6, 109.6 ± 18.9, and 94.1 ± 19.6 min -1 for whole brain, gray and white matter. k w was increased by 28.2%/19.5% in subjects with diabetes/hypercholesterolemia. Significant correlations between k w and vascular risk factors, CDR, executive/memory function, and the Fazekas scale of WMH were observed., Conclusion: A diffusion prepared 3D GRASE pCASL sequence with TGV regularized SPA modeling was proposed to measure BBB water permeability noninvasively with good reproducibility. k w may serve as an imaging marker of cerebral SVD and associated cognitive impairment., (© 2018 International Society for Magnetic Resonance in Medicine.)

Background: 3D pseudocontinuous arterial spin labeling (pCASL) with a single post-labeling delay time is commonly used to measure cerebral blood flow (CBF). Multi-phase pCASL has been developed to simultaneously estimate CBF and arterial transit time (ATT)., Purpose: To evaluate the clinical feasibility of multi-phase 3D pCASL in pediatric patients, and to compare the estimation of ATT and CBF via linear weighted-delay and traditional non-linear iterative curve-fitting routines., Material & Methods: Forty patients (average age: 8.6 y, 5 d-22.4 y) referred for routine brain MRI underwent additional 5-7 min of pCASL scans at 3T using 5 PLDs between 300 and 2300 ms. Data were post-processed by two algorithms for estimating CBF and ATT. Average CBF and ATT values were computed for vascular territories including the anterior, middle and posterior cerebral arteries as well as regions based on the Alberta Stroke Program Early CT Score template. Pearson correlation coefficients and linear regression were used for statistical analysis. The clinical value of multi-phase CASL was evaluated by a neuroradiologist based on asymmetric CBF and ATT maps in patients., Results: All pCASL scans were successfully completed, generating diagnostic results. CBF computed from weighted-delay and curve-fitting methods agreed strongly, with Pearson correlation coefficients ranging from 0.97-0.99 across the measured regions (p < 0.05). Correlation coefficients for ATT ranged from 0.87-0.96 (p < 0.05). CBF and ATT maps were found to add valuable information to clinical diagnosis in 17 of 40 pediatric patients., Conclusion: Our preliminary results demonstrate the feasibility and potential clinical utility of multi-phase pCASL for simultaneous CBF and ATT quantification in pediatric patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Visualizing the in vivo activity of monoamine oxidase B (MAO-B) is a valuable tool in the ongoing investigation of astrogliosis in neurodegeneration. Existing strategies for imaging changes in MAO enzyme expression or activity have utilized the irreversible suicide inhibitors or high-affinity reversibly binding inhibitors as positron emission tomography (PET) ligands. As an alternative approach, we developed 4-methyl-7-[(1-[ 11 C]methyl-1,2,3,6-tetrahydropyridin-4-yl)oxy]-2 H-chromen-2-one ([ 11 C]Cou) as a metabolic trapping agent for MAO-B. Trapping of [ 11 C]Cou in rhesus monkey brain demonstrated MAO-B selectivity. In this work, we have attempted to improve on the in vivo pharmacokinetics of [ 11 C]Cou by using the deuterium kinetic isotope effect (KIE) to slow the MAO-B-mediated oxidation step and thus reduce the rate of trapping in brain tissues. However, in vitro assays of enzyme kinetics and in vivo PET imaging of pharmacokinetics in primate brain showed no effects of deuterium substitution on the tetrahydropyridine ring of [ 11 C]Cou. The results are possibly due to masking of the KIE by a second step in the overall metabolism of the new imaging agent.

In vivo positron emission tomography (PET) imaging of the γ-aminobutyric acid (GABA) receptor complex has been accomplished using radiolabeled benzodiazepine derivatives, but development of specific presynaptic radioligands targeting the neuronal membrane GABA transporter type 1 (GAT-1) has been less successful. The availability of new structure-activity studies of GAT-1 inhibitors and the introduction of a GAT-1 inhibitor (tiagabine, Gabatril) into clinical use prompted us to reinvestigate the syntheses of PET ligands for this transporter. Initial synthesis and rodent PET studies of N-[ 11 C]methylnipecotic acid confirmed the low brain uptake of that small and polar molecule. The common design approach to improve blood-brain barrier permeability of GAT-1 inhibitors is the attachment of a large lipophilic substituent. We selected an unsymmetrical bis-aromatic residue attached to the ring nitrogen by a vinyl ether spacer from a series recently reported by Wanner and coworkers. Nucleophilic aromatic substitution of an aryl chloride precursor with [ 18 F]fluoride was used to prepare the desired candidate radiotracer ( R, E/ Z)-1-(2-((4-fluoro-2-(4-[ 18 F]fluorobenzoyl)styryl)oxy)ethyl)piperidine-3-carboxylic acid (( R, E/ Z)-[ 18 F]10). PET studies in rats showed no brain uptake, which was not altered by pretreatment of animals with the P-glycoprotein inhibitor cyclosporine A, indicating efflux by Pgp was not responsible. Subsequent PET imaging studies of ( R, E/ Z)-[ 18 F]10 in rhesus monkey brain showed very low brain uptake. Finally, to test if the free carboxylic acid group was the likely cause of poor brain uptake, PET studies were done using the ethyl ester derivative of ( R, E/ Z)-[ 18 F]10. Rapid and significant monkey brain uptake of the ester was observed, followed by a slow washout over 90 min. The blood-brain barrier permeability of the ester supports a hypothesis that the free acid function limits brain uptake of nipecotic acid-based GAT-1 radioligands, and future radiotracer efforts should investigate the use of carboxylic acid bioisosteres.

Siemens SMART neuro attenuation correction (SNAC) is a new type of calculated attenuation correction (CAC) method. This article aimed to evaluate the effect of SNAC on the quantitative analysis of brain positron emission tomography (PET) imaging.Brain PET images of 52 healthy participants after reconstructed by SNAC and CT attenuation correction (CTAC) were analyzed qualitatively by visual analysis, and quantitatively by Scenium software to compare their contrast, signal-to-noise ratio (SNR) as well as the mean standardized uptake value (SUVmean) of different brain regions.Compared with CTAC, reconstruction of images by SNAC significantly reduced the SNR by 17.3% (P < .001), but not affected the contrast (P = .440). In addition, the SUVmean of different brain regions in images reconstructed by SNAC is increased, but still significantly correlated with that by CTAC (r = 0.988, P < .001), with a coefficient of R = 0.976 in linear regression analysis. Moreover, the mean percent difference of SUVmean between images reconstructed with SNAC and CTAC was 8.03% ± 5.38%, varying significantly in the range of -7.56% to 75.31% among 10 different brain regions (F = 35.702, P < .001) and showed greater percent difference in the peripheral brain regions than in the mesial brain regions.Image reconstruction by SNAC has greater effect on quantitative analysis by increasing SUVmean of different brain regions to varying degrees, but has little influence on the brain PET image quality. Moreover, it simplifies examination process and reduces radiation dose, which is beneficial to pediatric patients as well as serial scans to monitor therapy.

Neuropeptides play an important role in the physiological functions of the human body. The physiological activities such as pain, sleep, mood, learning and memory are affected by neuropeptides. Neuropeptides mainly exist in the nerve tissue of the body, and a small amount of them are distributed in body fluid and organs. At present, analysis of large-scale identification of neuropeptides in whole brain tissue is still challenging. Therefore, high-throughput detection of these neuropeptides is greatly significant to understand the composition and function of neuropeptides. In this study, 1 830 endogenous peptides and 99 novel putative neuropeptides were identified by extraction of endogenous peptides from whole brain tissue of mice by liquid phase tandem mass spectrometry (LC-MS / MS). The identification of these endogenous peptides provides not only a reference value in the treatment and mechanism studies of diseases and the development of drugs, but also the basis for the study of a new neuropeptides and their functions.

Given the limited studies and conflicting findings, the transport character of ginsenosides crossing the blood-brain barrier (BBB) remains unclear. The present study was designed to qualitatively determine the distribution of ginsenosides in brain tissues after oral administration of ginseng total saponins, using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) combined with immunohistochemistry. In brain tissue homogenates, ginsenoside Rg1 was detectable and no other ginsenosides or their metabolites were found. No ginsenosides were detected in cerebrospinal fluid. Immunohistochemistry staining of brain tissue sections by using anti-ginsenoside polyclonal antibodies revealed the localization of ginsenosides in brain tissues. Furthermore, immunofluorescence double staining revealed that ginsenosides widely existed in vascular endotheliocytes and astrocytes, and in few neurons. These results indicated that Rg1 was the main component that entered the brain after oral administration of ginseng total saponins and that ginsenosides could cross the BBB, although the transport capability of ginsenosides through the BBB may be poor., (Copyright © 2018 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Aim: To assess the effects of different high-resolution image reconstruction methods on the quality of images and quantitatively compare their accuracy in human brain PET images., Materials and Methods: Brain images were reconstructed using six algorithms including back-projection (B), B+time of flight (TOF), ordered subsets expectation maximization (OSEM), OSEM+TOF, OSEM+point spread function (PSF), and OSEM+PSF+TOF. The qualities of images including the spatial resolution, contrast, and signal-to-noise ratio (SNR) were compared qualitatively and quantitatively, and the mean standardized uptake value (SUVmean) of different brain regions obtained by different reconstruction algorithms were also compared., Results: The contrast of images obtained by the six reconstruction algorithms was not significantly different (P>0.05). PSF significantly improved the spatial resolution and SNR by 23.8%. Combined PSF significantly increased the SUVmean of all brain regions, except the mesial temporal lobe and part of the basal ganglia. Application of TOF did not obviously increase the resolution and contrast, but improved SNR by up to 11.9%. Compared with OSEM and OSEM+PSF, application of OSEM+TOF and OSEM+PSF+TOF evidently affected the SUVmean of some brain regions and resulted in differentiation phenomena. TOF obviously increased the SUVmean of the temporal lobe, but significantly reduced that of the cingulate and paracingulate gyri, mesial temporal lobe, and cerebellum., Conclusion: PSF was the most effective reconstruction algorithm to improve the quality of brain images. The combined PSF algorithm could increase the SUVmean and made it closer to the actual standardized uptake value. The combined TOF algorithm should be applied with caution in quantitative analysis.

Purpose: H102, a novel β-sheet breaker peptide, was encapsulated into liposomes to reduce its degradation and increase its brain penetration through intranasal administration for the treatment of Alzheimer's disease (AD)., Methods: The H102 liposomes were prepared using a modified thin film hydration method, and their transport characteristics were tested on Calu-3 cell monolayers. The pharmacokinetics in rats' blood and brains were also investigated. Behavioral experiments were performed to evaluate the improvements on AD rats' spatial memory impairment. The neuroprotective effects were tested by detecting acetylcholinesterase (AchE), choline acetyltransferase (ChAT) and insulin degrading enzyme (IDE) activity and conducting histological assays. The safety was evaluated on rats' nasal mucosa and cilia., Results: The liposomes prepared could penetrate Calu-3 cell monolayers consistently. After intranasal administration, H102 could be effectively delivered to the brain, and the AUC of H102 liposomes in the hippocampus was 2.92-fold larger than that of solution group. H102 liposomes could excellently ameliorate spatial memory impairment of AD model rats, increase the activities of ChAT and IDE and inhibit plaque deposition, even in a lower dosage compared with H102 intranasal solution. H102 nasal formulations showed no toxicity on nasal mucosa., Conclusions: The H102-loaded liposome prepared in this study for nasal administration is stable, effective and safe, which has great potential for AD treatment.

Sorafenib, an active multi-kinase inhibitor, has been widely used as a chemotherapy drug to treat advanced clear-cell renal cell carcinoma patients. In spite of the relative safety, sorafenib has been shown to exert a negative impact on cognitive functioning in cancer patients, specifically on learning and memory; however, the underlying mechanism remains unclear. In this study, an NMR-based metabolomics approach was applied to investigate the neurochemical effects of sorafenib in rats. Male rats were once daily administrated with 120 mg/kg sorafenib by gavage for 3, 7, and 28 days, respectively. NMR-based metabolomics coupled with histopathology examinations for hippocampus, prefrontal cortex (PFC), and striatum were performed. The (1)H NMR spectra data were analyzed by using multivariate pattern recognition techniques to show the time-dependent biochemical variations induced by sorafenib. Excellent separation was obtained and distinguishing metabolites were observed between sorafenib-treated and control rats. A total of 36 differential metabolites in hippocampus of rats treated with sorafenib were identified, some of which were significantly changed. Furthermore, these modified metabolites mainly reflected the disturbances in neurotransmitters, energy metabolism, membrane, and amino acids. However, only a few metabolites in PFC and striatum were altered by sorafenib. Additionally, no apparent histological changes in these three brain regions were observed in sorafenib-treated rats. Together, our findings demonstrate the disturbed metabonomics pathways, especially, in hippocampus, which may underlie the sorafenib-induced cognitive deficits in patients. This work also shows the advantage of NMR-based metabolomics over traditional approach on the study of biochemical effects of drugs.

As the key organ of human, the brain has projection area corresponding to every part of the body, indicating that the damage on human body will locate a corresponding projection area in the brain. The primary injury on the distal end will produce secondary lesion in the projection area of brain, featuring as "bipolar lesions". The volume transmission (VT) theory and propagated sensation along meridians (PSAM) in TCM provide core guidance for the treatment of "bipolar lesions". The tendency to lesion of PSAM is achieved through volume transmission, which is also called "propagated sensation tendency to lesion of VT". From three aspects, VT can treat bipolar lesions, formatting a ring closed path. With VT as main treatment and wiring transmission as supplemented treatment, it has a more comprehensive guidance for treatment, and this theory may play an essential guiding role in the future treatment development for diseases.

Background: Nicotine is rapidly absorbed from cigarette smoke and therefore induces a number of chronic illnesses with the widespread use of tobacco products. Studies have shown a few cerebral metabolites modified by nicotine; however, endogenous metabolic profiling in brain has not been well explored., Results: H NMR-based on metabonomics was applied to investigate the endogenous metabolic profiling of brain hippocampus, nucleus acumens (NAc), prefrontal cortex (PFC) and striatum. We found that nicotine significantly increased CPP in mice, and some specific cerebral metabolites differentially changed in nicotine-treated mice. These modified metabolites included glutamate, acetylcholine, tryptamine, glucose, lactate, creatine, 3-hydroxybutyrate and nicotinamide-adenine dinucleotide (NAD), which was closely associated with neurotransmitter and energy source. Additionally, glutathione and taurine in hippocampus and striatum, phosphocholine in PFC and glycerol in NAc were significantly modified by nicotine, implying the dysregulation of anti-oxidative stress response and membrane metabolism., Conclusions: Nicotine induces significant metabonomic alterations in brain, which are involved in neurotransmitter disturbance, energy metabolism dysregulation, anti-oxidation and membrane function disruptions, as well as amino acid metabolism imbalance. These findings provide a new insight into rewarding effects of nicotine and the underlying mechanism.

Phage-displayed TGN peptide-decorated polymeric micelle-like polyplexes based on pegylated poly(2-(dimethylamino) ethyl methacrylate) (PEG-PDMAEMA) were prepared for efficient brain-targeted gene delivery. The diblock copolymers Methoxy-PEG-PDMAEMA and Maleimide-PEG-PDMAEMA were synthesized by the atom transfer radical polymerization method. The TGN ligand, a 12-amino acid peptide that could facilitate blood-brain barrier (BBB) targeting, was conjugated to the PEG terminus of the copolymer via a maleimide-mediated covalent binding procedure. TGN-PEG-PDMAEMA was complexed with plasmid DNA to yield polyplexes. The physiochemical properties of the polyplexes, such as morphology, particle size, zeta potential, cytotoxicity and DNA complex formation ability, were studied prior to the successful in vitro and in vivo transfection. The TGN-PEG-PDMAEMA/DNA polyplexes maintained their stable nano-size, were characterized by good condensation capacity and low toxicity and even provided higher cellular uptake than the unmodified polyplexes (PEG-PDMAEMA/DNA polyplexes). Confocal microscopy studies showed that the DNA of TGN-PEG-PDMAEMA/DNA polyplexes entered into the nuclei through the endosome/lysosome pathway. The transfection efficiency of TGN-modified polyplexes was higher than that of unmodified polyplexes both in vitro and in vivo. The results obtained from frozen sections indicated the widespread expression of an exogenous gene in the mouse brain after intravenous injection. Therefore, the results demonstrate that the TGN-decorated PEG-PDMAEMA developed in this study could be utilized as a potential vehicle for gene delivery to the brain., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Comprehensive cerebral metabolites involved in morphine dependence have not been well explored. To gain a better understanding of morphine dependence and withdrawal therapy in a model highly related to humans, metabolic changes in brain hippocampus and prefrontal cortex (PFC) of rhesus monkeys were measured by (1) H-nuclear magnetic resonance spectroscopy, coupled with partial least squares and orthogonal signal correction analysis. The results showed that concentrations of myoinositol (M-Ins) and taurine were significantly reduced, whereas lactic acid was increased in hippocampus and PFC of morphine-dependent monkeys. Phosphocholine and creatine increased in PFC but decreased in hippocampus after chronic treatment of morphine. Moreover, N-acetyl aspartate (NAA), γ-aminobutyric acid, glutamate, glutathione, methionine, and homocysteic acid also changed in these brain regions. These results suggest that chronic morphine exposure causes profound disturbances of neurotransmitters, membrane, and energy metabolism in the brain. Notably, morphine-induced dysregulations in NAA, creatine, lactic acid, taurine, M-Ins, and phosphocholine were clearly reversed after intervention with methadone or clonidine. Our study highlights the potential of metabolic profiling to enhance our understanding of metabolite alteration and neurobiological actions associated with morphine addiction and withdrawal therapy in primates., (Copyright © 2012 Wiley Periodicals, Inc.)

Metabolic consequences of morphine dependence and withdrawal intervention have not been well explored. In the present study, the metabolic changes in brain hippocampus, nucleus accumbens (NAc), prefrontal cortex (PFC) and striatum of rats with morphine dependence and withdrawal intervention were explored by using ¹H nuclear magnetic resonance coupled with principal component analysis, partial least squares and orthogonal signal correction analysis. We found that the concentrations of neurotransmitters including glutamate, glutamine and gamma-aminobutyric acid changed differentially in hippocampus, NAc, PFC and striatum after repeated morphine treatment. Significant changes were also found in a number of cerebral metabolites including N-acetyl aspartate (NAA), lactic acid, creatine, myo-inositol and taurine. These findings indicate the profound disturbances of energy metabolism, amino acid metabolism and neurotransmitters caused by chronic morphine treatment. Interestingly, morphine-induced changes in lactic acid, creatine and NAA were clearly reversed by intervention of methadone or clonidine. Our study provides a comprehensive understanding of the metabolic alteration associated with morphine addiction and withdrawal therapy, which may help to develop new pharmacotherapies., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Solanum tuberosum lectin (STL) conjugated poly (DL-lactic-co- glycolic acid) (PLGA) nanoparticle (STL-NP) was constructed in this paper as a novel biodegradable nose-to-brain drug delivery system. The in vitro uptake study showed markedly enhanced endocytosis of STL-NP compared to unmodified PLGA nanoparticles (NP) in Calu-3 cells and significant inhibition of uptake in the presence of inhibitor sugar (chitin hydrolysate). Following intranasal administration, coumarin-6 carried by STL-NP was rapidly absorbed into blood and brain. The AUC((0→12 h)) of coumarin-6 in blood, olfactory bulb, cerebrum and cerebellum were about 0.77-, 1.48-, 1.89- and 1.45-fold of those of NP, respectively (p < 0.05). STL-NP demonstrated 1.89-2.45 times (p < 0.01) higher brain targeting efficiency in different brain tissues than unmodified NP. Enhanced accumulation of STL-NP in the brain was also observed by near infrared fluorescence probe image following intranasal administration. The fluorescence signal of STL-NP appeared in olfactory bulb, cerebrum and brainstem early at 0.25 h. The signal in olfactory bulb decreased gradually after 2 h, while the obvious signal in brainstem, cerebrum and cerebellum lasted for more than 8 h. The STL-NP safety experiments showed mild cytotoxicity and negligible cilia irritation. These intriguing in vitro and in vivo results suggest that STL-NP might serve as a promising brain drug delivery system.

A novel conotoxin, qc16a, was identified from the venom of vermivorous Conus quercinus. qc16a has only 11 amino acid residues, DCQPCGHNVCC, with a unique cysteine pattern. Its disulfide connectivity was determined to be I-IV, II-III. The NMR structure shows that qc16a adopts a ribbon conformation with a simple beta-turn motif formed by residues Gly6, His7 and Asn8. qc16a causes depression symptom in mice when injected intracranially. Point mutation results showed that Asp1, His7 and Asn8 are all essential for the activity of qc16a. Electrophysiologically, qc16a has no strong effect on the whole-cell currents of neurons and the currents of Drosophila Shaker channels, human BK channels and Na(V)1.7 channels. Its specific target still remains to be identified., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The study of endocrine disruption is being increasingly conducted at the mRNA level of genes, as this approach might yield insight into the modes of action and mechanisms of toxicity. In this study, the transcriptional responses of a set of functionally relevant genes associated with the pathways of the hypothalamic-pituitary-gonadal (HPG; or HPG[L]-liver) axis of Japanese ricefish were examined after treatment with two model anti-estrogens, letrozole (LET) and tamoxifen (TAM), at three concentrations (30, 100 and 300μg/L) for 72h. The results showed that LET and TAM produced distinct expression profiles in a complex tissue- and gender-specific manner, confirming that they exert their anti-estrogenic effects via different molecular mechanisms. For example, the transcriptional levels of hepatic vitellogenin were significantly downregulated in females exposed to either LET or TAM, while they were significantly upregulated in TAM-exposed males and did not exhibit any change in LET-treated males. The expression of genes involved in steroidogenesis was also modulated by these two anti-estrogens in a way that corresponded with their anticipated mode of action. Overall, the data not only provide mechanistic information of anti-estrogenic chemicals but also demonstrate the potential of investigation of gene expression in the HPG(L) axis of model fish for diagnostic and predictive assessments of the risks associated with chemical exposure., (2011 Elsevier Inc. All rights reserved.)

Biodegradable polymer-based nanoparticles have been widely studied to deliver therapeutic agents to the brain after intranasal administration. However, knowledge as to the side effects of nanoparticle delivery system to the brain is limited. The aim of this study was to investigate the in vivo toxicity and immunogenicity of wheat germ agglutinin (WGA) conjugated poly(ethylene glycol)-poly(lactic acid) nanoparticles (WGA-NP) after intranasal instillation. Sprague-Dawley rats were intranasally given WGA-NP for 7 continuous days. Amino acid neurotransmitters, lactate dehydrogenase (LDH) activity, reduced glutathione (GSH), acetylcholine, acetylcholinesterase activity, tumor necrosis factor α (TNF-α) and interleukin-8 (IL-8) in rat olfactory bulb (OB) and brain were measured to estimate the in vivo toxicity of WGA-NP. Balb/C mice were intranasally immunized by WGA-NP and then WGA-specific antibodies in serum and nasal wash were detected by indirect ELISA. WGA-NP showed slight toxicity to brain tissue, as evidenced by increased glutamate level in rat brain and enhanced LDH activity in rat OB. No significant changes in acetylcholine level, acetylcholinesterase activity, GSH level, TNF-α level and IL-8 level were observed in rat OB and brain for the WGA-NP group. WGA-specific antibodies in mice serum and nasal wash were not increased after two intranasal immunizations of WGA-NP. These results demonstrate that WGA-NP is a safe carrier system for intranasal delivery of therapeutic agents to the brain., (© 2010 Elsevier Inc. All rights reserved.)

Amplitude integrated electroencephalogram (aEEG), also known as cerebral function monitor (CFM), is a non-invasive detection of brain function, having good accuracy in early diagnosis and prognosis evaluation of neonatal brain damage. Today, doctors classify amplitude integrated electroencephalogram mainly based on its waveform and amplitude, then they make correct diagnosis of brain function of neonates. However, in some cases, the amplitude and waveform of aEEG are not very clearly shown, the only way is relying on doctors' experience to give out judgement, which has some subjective factors, so doctors can not present accurate diagnostic information. To solve this problem by the use of non-linear dynamics, we calculate and analyze the correlation dimension, Lyapunov exponent and approximate entropy of the aEEG for neonates with convulsions and for normal neonates; then we take these three characters as a three-dimensional vector; finally, the aEEG of neonates with convulsions and the aEEG of normal neonates are distributed into two parts in threedimensional space, thus the correlation dimension, Lyapunov exponent and approximate entropy of the aEEG can reflect the internal information of neonatal brain function. Therefore, it can be used as a new method for studying neonatal aEEG.

In this paper is proposed a new method for functional connectivity detection using regression analysis. First, the resting state functional magnetic resonance imaging (fMRI) data from each voxel is passed through a bandpass filter to obtain frequencies between 0.01 Hz and 0.1 Hz. Then, the region of interest (ROI) is defined and the mean time course of all voxels in ROI is used as a regressor. Finally, the linear relationship between the time course of other voxels and the regressor in the resting brain is estimated. By the application of this new method in simulation data and fMRI data, the relevant validity and reliability are demonstrated.

Cognitive functions are often studied by recording electric potentials from the brain over repeated presentations of a sensory stimulus or repeated performance of a motor action. Each repetition is called a trial. Recent work has demonstrated that contrary to the traditional view, the event-related potential (ERP) can vary from trial to trial and the background ongoing activity often contains rich information about the cognitive state of the brain. Based on such a variable signal plus ongoing activity model, an iterative parameter estimation method is proposed in which both the single-trial parameters of the ERP and the autoregressive representation of the ongoing activity are obtained simultaneously. This technique, referred to as the analysis of single-trial ERP and ongoing activities method, is first tested on simulation examples, and then applied to the local field potential recordings from monkeys performing a visuomotor task.

The N-[(11)C]methylpiperidinyl esters are used as radiopharmaceuticals for measuring brain cholinesterase activity. We have synthesized a series of N-methylpiperidinemethyl (1), N-methylpyrrolidinyl (2) and N-methylpyrrolidinemethyl (3) esters and examined the effects of sterric constraint and stereochemistry on cholinesterase-mediated cleavage. Acetylcholinesterase exhibited a preference for primary esters 1 and for the R-isomers of both 1 and 2. Biological data for (S)-N-[(11)C]methyl-2-piperidinemethyl acetate (1a) were similar to [(11)C]AMP. These data better define the structure-activity relationships for cholinesterase radiotracers and provide lead compounds for (18)F- labeling.