Average Time Course Research Articles

In Silico Modeling of the Antiplatelet Pharmacodynamics of Low-dose Aspirin in Health and Disease.

The influence of platelet turnover on cyclooxygenase (COX-1) inhibition by low-dose aspirin remains largely uncharacterized due to limited feasibility of studying aspirin pharmacodynamics in bone marrow precursors. We developed an in silico compartmental model describing the aspirin effects on COX-1 activity in a population of megakaryocytes (MK) and in peripheral platelets. Model parameters were inferred from the literature and calibrated using measurements of serum thromboxane B2 (sTXB2 ), as proxy of COX-1 activity in peripheral platelets, in 17 healthy subjects and 24 patients with essential thrombocythemia (ET). The model reproduced well the average time-course of sTXB2 inhibition in healthy (accuracy = 10.4%), the reduced inhibition of sTXB2 observed in ET, and the effect of different dosing regimens. In conclusion, the in silico model accurately describes COX-1 inactivation by low-dose aspirin in MK and platelets in different clinical settings, and might help personalize aspirin regimens in conditions of altered megakaryopoiesis.

Developing a Drawing Task to Differentiate Group Average Time Course vs. Dynamics in the Individual

Teaching and theorizing in psychology has long been torn between targeting general underlying principles by observing dynamics in the individual or focusing on average behavior. As dealing with gro...

P154 Probing the sensitivity of a novel MR head coil array for TMS/fMRI studies of the motor cortex

Question The typical setup used in online TMS/fMRI experiments presents some limitations, most importantly the poor sensitivity of the MR coil (Fig. 1a) Download : Download high-res image (262KB) Download : Download full-size image . In addition, new imaging techniques like parallel imaging and multiband excitation are not available. To get over these limitations, a dedicated MR coil array (Fig. 1b) for combining TMS with fMRI was developed (Navarro de et al., 2015) . We present results of an online TMS/fMRI experiment over the motor cortex to show the advantages of the new setup. Methods The experiment was performed at 3T (Siemens, Germany). The TMS system included a MagProX100 stimulator and an MRi-B91 MR-compatible TMS coil (MagVenture, Denmark). Six healthy subjects participated in the study. Functional images were acquired using a multiband EPI sequence (TR/TE = 1000/33 ms), 14 slices, 1.5 × 1.5 × 3 mm3. Slices were aligned parallel to the TMS coil and covered primary motor cortex. The stimulation protocol comprised 20 stimulation blocks, with five blocks of each of the following stimulation intensities: 80, 90, 100 and 110% of the individual’s motor threshold distributed randomly over the experiment. A finger tapping task was also conducted. Data analysis was performed using SPM12. The design matrix comprised four task regressors representing the 4 stimulation amplitudes. For each subject, two regions were defined based on fMRI activation maps: (i) the global maximum, and (ii) the maximum within M1. Results Fig. 2a,b Download : Download high-res image (632KB) Download : Download full-size image shows group results as the mean of the BOLD signal intensity change in percent for the two voxels defined above with indicator of statistical significance. In addition, averaged time courses were calculated for global maximum (2c) and the M1 maximum (2d). Conclusions In both regions, a monotonic ascending relationship of signal change amplitude with TMS intensity was observed. While activations at the global maxima were statistically significant for all intensities, results on the M1 maximum are only significant for the 100% and 110% intensities. These results on M1 are consistent with results obtained before (Bestmann et al., 2004) . Contrary to the standard setup, the new one didn’t suffer of any artefacts under the TMS coil, where the global maximal activation was always found. The obtained time courses demonstrated the efficiency of the new setup to acquire the signal with high accuracy.

Comparison of large-scale human brain functional and anatomical networks in schizophrenia.

Schizophrenia is a disease with disruptions in thought, emotion, and behavior. The dysconnectivity hypothesis suggests these disruptions are due to aberrant brain connectivity. Many studies have identified connectivity differences but few have been able to unify gray and white matter findings into one model. Here we develop an extension of the Network-Based Statistic (NBS) called NBSm (Multimodal Network-based statistic) to compare functional and anatomical networks in schizophrenia. Structural, resting functional, and diffusion magnetic resonance imaging data were collected from 29 chronic patients with schizophrenia and 29 healthy controls. Images were preprocessed, and average time courses were extracted for 90 regions of interest (ROI). Functional connectivity matrices were estimated by pairwise correlations between wavelet coefficients of ROI time series. Following diffusion tractography, anatomical connectivity matrices were estimated by white matter streamline counts between each pair of ROIs. Global and regional strength were calculated for each modality. NBSm was used to find significant overlap between functional and anatomical components that distinguished health from schizophrenia. Global strength was decreased in patients in both functional and anatomical networks. Regional strength was decreased in all regions in functional networks and only one region in anatomical networks. NBSm identified a distinguishing functional component consisting of 46 nodes with 113 links (p < 0.001), a distinguishing anatomical component with 47 nodes and 50 links (p = 0.002), and a distinguishing intermodal component with 26 nodes (p < 0.001). NBSm is a powerful technique for understanding network-based group differences present in both anatomical and functional data. In light of the dysconnectivity hypothesis, these results provide compelling evidence for the presence of significant overlapping anatomical and functional disruption in people with schizophrenia.

Multi-contrast T2⁎-relaxometry upon visual stimulation at 3 T and 7 T

This study aims to quantify the mean change of the effective transverse relaxation time T2⁎ in active brain regions of human volunteers at field strengths of B0=3T and 7T. Besides the mono-exponential signal decay model an extended model is tested that considers mesoscopic field gradients across imaging voxels. Both models are checked for cross-talk and correlations between the parameters. A visual checkerboard-stimulation experiment with pause and stimulation periods of 50s and six repetitions was performed on healthy volunteers. Eleven contrasts were acquired in about 1.47s/1.43s at 3T/7T using a segmented multi-contrast echo-planar imaging (EPI) sequence. Average BOLD-signal time courses were calculated in a multi-step (non-)linear least-squares process. Baseline T2⁎ values of 37.72ms/24.99ms (47.34ms/33.71ms) with stimulus-correlated changes ∆T2⁎of 1.32ms/0.74ms (1.99ms/1.43ms) resulted from the mono-exponential (extended) model for 3T/7T. A dependence of those values on the initial intensity S0 was observed. Stimulus-correlated changes of S0 in the order of 1% were measured at both field strengths. The mono-exponential model was found to be less prone to instabilities in the regression of both parameters. Signal alterations due to inflow were observed. Measured relaxation times agree with values from literature using repetitive stimulation. A strong dependence of the measured relaxation times on the inflow-related model parameter was found for both models. The extended model is applicable to dynamic neurofunctional measurements, but is currently limited due to the low number of contrasts acquired.

Psoriasis in elderly patients in the Côte d'Ivoire: socio-demographic, clinical, and therapeutic aspects, and follow-up.

Psoriasis is a chronic, inflammatory, and recurrent dermatological disease. In the Côte d'Ivoire, it is about 0.75% of dermatology cases. Psoriasis care is challenging in elderly patients. We aimed to show its specificities related to the sociodemographic, clinical, and therapeutic aspects, and follow-up in geriatric patients. Cross-sectional and descriptive study over a period of 10 years (January 2004-December 2013). The prevalence of patients 60 years of age and older was about 0.1% (47 of 46,623 cases). The average age was 67 ± 1 years ranging from 60 to 85 years. The sex ratio was 1 : 9 in favor of men. The average time course of psoriasis was 25 ± 2 months. Comorbidity was found in 27 cases (57.5%). The most observed type of psoriasis in our study was chronic plaque psoriasis in 51.1% of cases. We found severe cases of psoriasis in 25.5% of cases. More than 10% of the body surface area was affected in 27.6% of cases. We used topical treatments in the majority of cases (83%). The course of psoriasis under treatment was good in 63.8% of cases, and only 6.4% of cases were worsening. Topical agents could be the first-line treatment in geriatric patients in poor countries. If necessary, systemic agents should be used by taking into account the severity of psoriasis, presence of comorbidity factors, immune system level, and lifestyle.

Relationship between adaptation and cardiovascular response to tonic cold and heat pain Adaptability to tonic pain and cardiovascular responses.

The mechanisms of adaptation to tonic pain are not elucidated. We hypothesized that the adaptability to tonic pain is related to the cardiovascular system. Twenty-six subjects received over two sessions in a random order: tonic cold (7±0.2°C) and heat pain (47.5±0.5°C) on the hand for 5min. Pain intensity, blood pressure (BP), and heart rate (HR) were continuously monitored. Pain experience during the heat (HIT) and cold (CIT) immersion tests exhibited different average time courses, being approximated with a linear and cubic function, respectively. In each test, two groups of participants could be identified based on the time course of their tonic thermal pain: one-third of participants were pain adaptive and two-thirds non adaptive. The adaptive group exhibited higher initial pain, lower last pain, and shorter latency to peak pain than the non-adaptive one. Interestingly, some participants were adaptive to both pain stimuli, most were not. HIT as well as CIT produced a stable elevation of BP. However, BP was higher during CIT than HIT (p=0.034). HR was also increased during CIT and HIT, but the two tests differed with respect to the time course of responses. Finally, the intensity and time course of pain rating to both HIT and CIT correlated with neither BP nor HR responses. These results suggest that individual sensitivity and adaptability to tonic thermal pain is related to the intensity of initial pain rating and the latency to peak pain but not to cardiovascular responses.

Perturbed Hippocampal Synaptic Inhibition and γ-Oscillations in a Neuroligin-4 Knockout Mouse Model of Autism.

SummaryLoss-of-function mutations in the synaptic adhesion protein Neuroligin-4 are among the most common genetic abnormalities associated with autism spectrum disorders, but little is known about the function of Neuroligin-4 and the consequences of its loss. We assessed synaptic and network characteristics in Neuroligin-4 knockout mice, focusing on the hippocampus as a model brain region with a critical role in cognition and memory, and found that Neuroligin-4 deletion causes subtle defects of the protein composition and function of GABAergic synapses in the hippocampal CA3 region. Interestingly, these subtle synaptic changes are accompanied by pronounced perturbations of γ-oscillatory network activity, which has been implicated in cognitive function and is altered in multiple psychiatric and neurodevelopmental disorders. Our data provide important insights into the mechanisms by which Neuroligin-4-dependent GABAergic synapses may contribute to autism phenotypes and indicate new strategies for therapeutic approaches.

Abnormally reduced anti-correlation between resting-state default mode and fronto-parietal networks is associated with memory impairment in MCI

Impaired deactivations of the Default Mode Network (DMN) during tasks have been associated with cognitive impairment in Alzheimer's disease. However, it remains unclear whether the functional connectivity (FC) between brain networks is also altered at rest. Here, we examined whether the FC between the task-negative DMN and the task-positive frontoparietal attention network (FPAN) is altered at rest and whether that predicts cognitive performance in non-demented elderlies with Mild Cognitive Impairment (MCI). We examined 93 subjects with MCI, recruited at our memory clinic in Munich. For cross-validation, 78 MCI subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were used. Subjects underwent resting-state fMRI and episodic memory testing using standard neuropsychological tests (word list learning). Via Independent Component Analysis, we identified 4 networks of interest (NOI): an anterior and posterior DMN component (a-DMN, p-DMN) and a left and right lateralized FPAN component (l-FPAN, r-FPAN). The average time course was extracted for each NOI and the between-NOI functional connectivity (FC) was computed via pair-wise Pearson moment correlations. Linear regression analyses were conducted, with between-NOI FC values as a regressor of memory scores, controlling for age, gender, and cognitive reserve. The between-NOI FC values ranged from -0.41 to +0.80 in the Munich sample, and from -0.44 to +0.78 in the ADNI sample. More positive between-NOI FC between a-DMN and l-FPAN predicted lower word list learning scores in both the Munich (β=-0.24, p=0.008) and the ADNI sample (β=-0.28, p=0.009). More positive between-NOI FC between a-DMN and r-FPAN predicted lower verbal learning scores (β=-0.18, p=0.046) in the Munich sample (for an example, see figure 1). The between NOI FC is plotted against the word list learning raw score. The fitted regression line plus β-weight and p-value are indicated. Our results indicate, that weaker inverse correlations between the DMN and FPAN are associated with memory impairment in MCI. This suggests, that impaired anti-correlation of task-activated and task-deactivated networks even when assessed during rest might be predictive of memory impairment in MCI.

Broadcasting of cortical activity to the olfactory bulb.

Odor representations are initially formed in the olfactory bulb, which contains a topographic glomerular map of odor molecular features. The bulb transmits sensory information directly to piriform cortex, where it is encoded by distributed ensembles of pyramidal cells without spatial order. Intriguingly, piriform cortex pyramidal cells project back to the bulb, but the information contained in this feedback projection is unknown. Here, we use imaging in awake mice to directly monitor activity in the presynaptic boutons of cortical feedback fibers. We show that the cortex provides the bulb with a rich array of information for any individual odor and that cortical feedback isdependent on brain state. In contrast to the stereotyped, spatial arrangement of olfactory bulb glomeruli, cortical inputs tuned to different odors commingle and indiscriminately target individual glomerular channels. Thus, the cortex modulates early odor representations by broadcasting sensory information diffusely onto spatially ordered bulbar circuits.

Local and long-range phase-amplitude coupling in a cortical spiking network model

Phase-amplitude coupling (PAC) between neural oscillations in different frequency bands has been observed in population recordings of the hippocampus and neocortex [1,2]. Specifically, bursts of gamma (>30 Hz) oscillations are often found to be phase-locked to a slower oscillation in the theta range (4-8 Hz), raising questions about the mechanisms and computational consequences of this pattern. Recently, inter-areal gamma synchronization was also found to be systematically modulated by theta rhythms [3]. We study mechanisms for these experimental findings and their potential role in long-range inter-areal coupling using spiking neuron network models. Using dynamical systems theory, bursting has previously been analyzed in detail for single neuron dynamics [4], requiring interaction of fast and slow adapting variables, driving the neuron through alternations of active (limit cycle) and resting (stable equilibrium) periods. On the population level, bursting can be studied within the same framework, treating average synaptic activity and time courses as slow/fast variables. Our model (Panel A) is based on observations of dynamically distinct interneuron populations in the cortex, namely fast-spiking, non-adapting (FS) and adapting interneurons (low-threshold spiking, LTS) exhibiting fast and slow synaptic time courses [5]. Coupled with a population of principal cells (regular spiking, RS), this network displays spontaneous phase-amplitude coupling as sparsely synchronized population bursts. Feed-forward connections between populations of this type lead to theta modulated gamma synchronization (Panel B and C). We study in detail the parameter range/bifurcations of this model. Considering that in-vivo neural circuits are generally only sparsely synchronized, we contrast oscillatory patterns on the population level with stochastic firing of single neurons. Figure 1 Local and long-range phase-amplitude coupling in a cortical spiking network model A) Schematic showing two populations of 1,000 spiking neurons and connections on the population level. Intra-/inter-areal connections are shown in black/blue respectively. ...

Monitor corneal epithelial healing under bandage contact lens using ultrahigh-resolution optical coherence tomography after pterygium surgery.

To monitor corneal epithelial healing under bandage contact lens (BCL) using ultrahigh-resolution optical coherence tomography (UHR-OCT) after pterygium surgery. Thirty-nine eyes of 39 patients undergoing pterygium excision and conjunctival autografting were randomly allocated into 2 groups: 20 eyes were covered with silicone hydrogel BCLs at the end of surgery and 19 eyes served as a control. Ultrahigh-resolution optical coherence tomography scans of the cornea were performed sequentially at 1, 2, and 3 days, and then every other day until the end of re-epithelialization after surgery. Complete epithelial healing was verified with fluorescein staining examination after removal of BCLs. Postsurgery pain was evaluated using the visual analog scale. All BCLs were successfully fit without any contact lens-related complications. Ultrahigh-resolution optical coherence images clearly revealed the architectural features of postoperative cornea with BCL in situ and showed epithelial healing process. Ultrahigh-resolution optical coherence tomography imaging agreed with the fluorescein staining examinations in detecting corneal epithelial defect. Based on the assessment by UHR-OCT, the average time course of re-epithelialization in the BCL group was 3.9±1.2 days, whereas in the control group, it was 5.7±1.8 days (P=0.001). Visual analog scale scoring showed lower pain levels in the BCL group comparing with the control group at each point of time (all P<0.05). Ultrahigh-resolution optical coherence tomography is an excellent tool in monitoring corneal epithelial healing under BCLs and determining the appropriate time for lens removal. Silicone hydrogel BCL is recommended as an adjuvant therapy after pterygium surgery for its efficacy in improving re-epithelialization and postoperative comfort.

Noncontrast mapping of arterial delay and functional connectivity using resting‐state functional MRI: A study in Moyamoya patients

To investigate if delays in resting-state spontaneous fluctuations of the BOLD (sfBOLD) signal can be used to create maps similar to time-to-maximum of the residue function (Tmax) in Moyamoya patients and to determine whether sfBOLD delays affect the results of brain connectivity mapping. Ten patients were scanned at 3 Tesla using a gradient-echo echo planar imaging sequence for sfBOLD imaging. Cross correlation analysis was performed between each brain voxel signal and a reference signal comprised of either the superior sagittal sinus (SSS) or whole brain (WB) average time course. sfBOLD delay maps were created based on the time shift necessary to maximize the correlation coefficient, and compared with dynamic susceptibility contrast Tmax maps. Standard and time-shifted resting-state BOLD connectivity analyses of the default mode network were compared. Good linear correlations were found between sfBOLD delays and Tmax using the SSS as reference (r(2) = 0.8, slope = 1.4, intercept = -4.6) or WB (r(2) = 0.7, slope = 0.8, intercept = -3.2). New nodes of connectivity were found in delayed regions when accounting for delays in the analysis. Resting-state sfBOLD imaging can create delay maps similar to Tmax maps without the use of contrast agents in Moyamoya patients. Accounting for these delays may affect the results of functional connectivity maps.

DataHigh: graphical user interface for visualizing and interacting with high-dimensional neural activity

Objective. Analyzing and interpreting the activity of a heterogeneous population of neurons can be challenging, especially as the number of neurons, experimental trials, and experimental conditions increases. One approach is to extract a set of latent variables that succinctly captures the prominent co-fluctuation patterns across the neural population. A key problem is that the number of latent variables needed to adequately describe the population activity is often greater than 3, thereby preventing direct visualization of the latent space. By visualizing a small number of 2-d projections of the latent space or each latent variable individually, it is easy to miss salient features of the population activity. Approach. To address this limitation, we developed a Matlab graphical user interface (called DataHigh) that allows the user to quickly and smoothly navigate through a continuum of different 2-d projections of the latent space. We also implemented a suite of additional visualization tools (including playing out population activity timecourses as a movie and displaying summary statistics, such as covariance ellipses and average timecourses) and an optional tool for performing dimensionality reduction. Main results. To demonstrate the utility and versatility of DataHigh, we used it to analyze single-trial spike count and single-trial timecourse population activity recorded using a multi-electrode array, as well as trial-averaged population activity recorded using single electrodes. Significance. DataHigh was developed to fulfil a need for visualization in exploratory neural data analysis, which can provide intuition that is critical for building scientific hypotheses and models of population activity.

A Deconvolution-Based Method with High Sensitivity and Temporal Resolution for Detection of Spontaneous Synaptic Currents In Vitro and In Vivo

Spontaneous postsynaptic currents (PSCs) provide key information about the mechanisms of synaptic transmission and the activity modes of neuronal networks. However, detecting spontaneous PSCs in vitro and in vivo has been challenging, because of the small amplitude, the variable kinetics, and the undefined time of generation of these events. Here, we describe a, to our knowledge, new method for detecting spontaneous synaptic events by deconvolution, using a template that approximates the average time course of spontaneous PSCs. A recorded PSC trace is deconvolved from the template, resulting in a series of delta-like functions. The maxima of these delta-like events are reliably detected, revealing the precise onset times of the spontaneous PSCs. Among all detection methods, the deconvolution-based method has a unique temporal resolution, allowing the detection of individual events in high-frequency bursts. Furthermore, the deconvolution-based method has a high amplitude resolution, because deconvolution can substantially increase the signal/noise ratio. When tested against previously published methods using experimental data, the deconvolution-based method was superior for spontaneous PSCs recorded in vivo. Using the high-resolution deconvolution-based detection algorithm, we show that the frequency of spontaneous excitatory postsynaptic currents in dentate gyrus granule cells is 4.5 times higher in vivo than in vitro.

High‐dose isotretinoin in acne vulgaris: improved treatment outcomes and quality of life

Isotretinoin, for acne treatment, is associated with high rates of permanent remission. However, at recommended doses of 0.5-1.0 mg/kg/day for 5-6 months [average cumulative dose: 120-150 mg/kg], more than 20% of patients experience a relapse within two years that requires further medical management. To examine outcomes of high-dose isotretinoin in a cohort with cystic acne, as well as measuring its impact on quality of life (QOL). A single dermatologist, single institution investigation within an academic tertiary care center in Bronx, NY. Eighty patients with nodulocystic acne, maintained on oral isotretinoin at a dose of 1.3 mg/kg/day or greater, were studied from 2006-2009 while additionally participating in a QOL survey. Main outcome measures included documented events, acne clearance, presence of relapse, and quality of life parameters. The mean daily dose of isotretinoin was 1.6 mg/kg/day for an average time course of 178 days [cumulative dose: 290 mg/kg]. No side effects or laboratory abnormalities led to discontinuation of treatment. There were no psychiatric symptoms. One-hundred percent (100%) of patients were disease-free upon completion of treatment. During the three-year study period, 10 patients (12.5%) developed a relapse that required an additional course of isotretinoin. Analysis of QOL domains (self-perception, role-social, symptoms) revealed significant improvement following isotretinoin therapy (p = 0.0124, p = 0.0066, p = 0.0265, respectively). Isotretinoin prescribed at 1.5 mg/kg/day or greater for 5-6 months [cumulative total dose of 290 mg/kg] is safe and effective compared to current standard dosing practices. We propose the use of high-dose isotretinoin (>1.3 mg/kg/day) as a treatment option in severe nodulocystic acne and encourage larger, prospective, multicenter studies into this therapeutic approach.

Requirement of neuronal connexin36 in pathways mediating presynaptic inhibition of primary afferents in functionally mature mouse spinal cord

Electrical synapses formed by gap junctions containing connexin36 (Cx36) promote synchronous activity of interneurones in many regions of mammalian brain; however, there is limited information on the role of electrical synapses in spinal neuronal networks. Here we show that Cx36 is widely distributed in the spinal cord and is involved in mechanisms that govern presynaptic inhibition of primary afferent terminals. Electrophysiological recordings were made in spinal cord preparations from 8- to 11-day-old wild-type and Cx36 knockout mice. Several features associated with presynaptic inhibition evoked by conditioning stimulation of low threshold hindlimb afferents were substantially compromised in Cx36 knockout mice. Dorsal root potentials (DRPs) evoked by low intensity stimulation of sensory afferents were reduced in amplitude by 79% and in duration by 67% in Cx36 knockouts. DRPs were similarly affected in wild-types by bath application of gap junction blockers. Consistent with presynaptic inhibition of group Ia muscle spindle afferent terminals on motoneurones described in adult cats, conditioning stimulation of an adjacent dorsal root evoked a long duration inhibition of monosynaptic reflexes recorded from the ventral root in wild-type mice, and this inhibition was antagonized by bicuculline. The same conditioning stimulation failed to inhibit monosynaptic reflexes in Cx36 knockout mice. Immunofluorescence labelling for Cx36 was found throughout the dorsal and ventral horns of the spinal cord of juvenile mice and persisted in mature animals. In deep dorsal horn laminae, where interneurones involved in presynaptic inhibition of large diameter muscle afferents are located, cells were extensively dye-coupled following intracellular neurobiotin injection. Coupled cells displayed Cx36-positive puncta along their processes. Our results indicate that gap junctions formed by Cx36 in spinal cord are required for maintenance of presynaptic inhibition, including the regulation of transmission from Ia muscle spindle afferents. In addition to a role in presynaptic inhibition in juvenile animals, the persistence of Cx36 expression among spinal neuronal populations in the adult mouse suggests that the contribution of electrical synapses to integrative processes in fully mature spinal cord may be as diverse as that found in other areas of the CNS.

Patterns of altered functional connectivity in mesial temporal lobe epilepsy

In mesial temporal lobe epilepsy (MTLE) the epileptogenic area is confined to the mesial temporal lobe, but other cortical and subcortical areas are also affected and cognitive and psychiatric impairments are usually documented. Functional connectivity methods are based on the correlation of the blood oxygen level dependent (BOLD) signal between brain regions, which exhibit consistent and reproducible functional networks from resting state data. The aim of this study is to compare functional connectivity of patients with MTLE during the interictal period with healthy subjects. We hypothesize that patients show reduced functional connectivity compared to controls, the interest being to determine which regions show this reduction. We selected electroencephalography-functional magnetic resonance imaging (EEG-fMRI) resting state data without EEG spikes from 16 patients with right and 7 patients with left MTLE. EEG-fMRI resting state data of 23 healthy subjects matched for age, sex, and manual preference were selected as controls. Four volumes of interest in the left and right amygdalae and hippocampi (LA, RA, LH, and RH) were manually segmented in the anatomic MRI of each subject. The averaged BOLD time course within each volume of interest was used to detect brain regions with BOLD signal correlated with it. Group differences between patients and controls were estimated. In patients with right MTLE, group difference functional connectivity maps (RMTLE - controls) showed for RA and RH decreased connectivity with the brain areas of the default mode network (DMN), the ventromesial limbic prefrontal regions, and contralateral mesial temporal structures; and for LA and LH, decreased connectivity with DMN and contralateral hippocampus. Additional decreased connectivity was found between LA and pons and between LH and ventromesial limbic prefrontal structures. In patients with left MTLE, functional connectivity maps (LMTLE - controls) showed for LA and LH decreased connectivity with DMN, contralateral hippocampus, and bilateral ventromesial limbic prefrontal regions; no change in connectivity was detected for RA; and for RH, there was decreased connectivity with DMN, bilateral ventromesial limbic prefrontal regions, and contralateral amygdala and hippocampus. In unilateral MTLE, amygdala and hippocampus on the affected and to a lesser extent on the healthy side are less connected, and are also less connected with the dopaminergic mesolimbic and the DMNs. Changes in functional connectivity between mesial temporal lobe structures and these structures may explain cognitive and psychiatric impairments often found in patients with MTLE.

The Acute Haemodynamic Effect of Nebulised Frusemide in Stable, Advanced Heart Failure

To assess the acute haemodynamic effects of nebulised frusemide in a stable advanced heart failure population. In this randomised, double blind, placebo controlled trial, people with stable, advanced heart failure undergoing right heart catheterisation were randomised to receive either 40 mg (4 ml) of nebulised frusemide or 4 ml of normal saline. Following inhalation of the study medication, subjects' pulmonary pressures were recorded every 15 min for 1 h. There were no significant changes in the weighted average time course data of the subjects (n=32) in either group over the study period, in particular no differences were observed in haemodynamic parameters between the two groups. Weighted average pulmonary capillary wedge pressure after 60 min in the frusemide group was 22.5 (SD 6.5) mmHg (n=14) compared to the placebo group's 24.0 (SD 7.3) mmHg (n=18), p=0.55. The frusemide group had a significantly greater change in the median volume of urine in the bladder over the study period (186 ml IQR 137.8-260.8) compared to the placebo group (76 ml IQR 39.0-148.0) p=0.02. This study showed that nebulised frusemide had no significant clinical effect on the haemodynamic characteristics of the subjects.

Visualization of Subunit-Specific Delivery of Glutamate Receptors to Postsynaptic Membrane during Hippocampal Long-Term Potentiation

An increase in the number of AMPA-type glutamate receptors (AMPARs) is critical for long-term potentiation (LTP), synaptic plasticity regarded as a basal mechanism of learning and memory. However, when and how each type of AMPAR reaches the postsynaptic membrane remain unclear. We have developed experimental methods to form postsynaptic-like membrane (PSLM) on a glass surface to precisely visualize the location and movement of receptors. We observed fluorescence-labeled AMPAR subunits (GluA1-3) around PSLM with total internal reflection fluorescence microscopy. The increases of GluA1, 2, and 3 in PSLM showed different time courses after LTP induction. GluA1 increased first, and was exocytosed to the periphery of PSLM soon after LTP induction. GluA2 and GluA3 initially decreased, and then increased. Exocytosis of GluA2 and GluA3 occurred primarily in non-PSLM, and later than exocytosis of GluA1. Thus, GluA1-3 appear to increase in the postsynaptic membrane through distinct pathways during LTP.