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1.  Evaluation of slice accelerations using multiband echo planar imaging at 3 Tesla 
NeuroImage  2013;83:10.1016/j.neuroimage.2013.07.055.
We evaluate residual aliasing among simultaneously excited and acquired slices in slice accelerated multiband (MB) echo planar imaging (EPI). No in-plane accelerations were used in order to maximize and evaluate achievable slice acceleration factors at 3 Tesla. We propose a novel leakage (L-) factor to quantify the effects of signal leakage between simultaneously acquired slices. With a standard 32-channel receiver coil at 3 Tesla, we demonstrate that slice acceleration factors of up to eight (MB = 8) with blipped controlled aliasing in parallel imaging (CAIPI), in the absence of in-plane accelerations, can be used routinely with acceptable image quality and integrity for whole brain imaging. Spectral analyses of single-shot fMRI time series demonstrate that temporal fluctuations due to both neuronal and physiological sources were distinguishable and comparable up to slice-acceleration factors of nine (MB = 9). The increased temporal efficiency could be employed to achieve, within a given acquisition period, higher spatial resolution, increased fMRI statistical power, multiple TEs, faster sampling of temporal events in a resting state fMRI time series, increased sampling of q-space in diffusion imaging, or more quiet time during a scan.
doi:10.1016/j.neuroimage.2013.07.055
PMCID: PMC3815955  PMID: 23899722
lipped CAIPI; leakage (L-) factor; g-factor; residual aliasing; spectral analysis; single-shot fMRI time series
2.  Functional connectomics from resting-state fMRI 
Trends in cognitive sciences  2013;17(12):666-682.
Spontaneous fluctuations in activity in different parts of the brain can be used to study functional brain networks. We review the use of resting-state functional MRI for the purpose of mapping the macroscopic functional connectome. After describing MRI acquisition and image processing methods commonly used to generate data in a form amenable to connectomics network analysis, we discuss different approaches for estimating network structure from that data. Finally, we describe new possibilities resulting from the high-quality rfMRI data being generated by the Human Connectome Project, and highlight some upcoming challenges in functional connectomics.
doi:10.1016/j.tics.2013.09.016
PMCID: PMC4004765  PMID: 24238796
connectomics; resting-state fMRI; network modelling
3.  An anatomically comprehensive atlas of the adult human brain transcriptome 
Nature  2012;489(7416):391-399.
Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of ~900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography— the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function.
doi:10.1038/nature11405
PMCID: PMC4243026  PMID: 22996553
Neuroscience; Genetics; Genomics; Databases
4.  First steps in using machine learning on fMRI data to predict intrusive memories of traumatic film footage 
After psychological trauma, why do some only some parts of the traumatic event return as intrusive memories while others do not? Intrusive memories are key to cognitive behavioural treatment for post-traumatic stress disorder, and an aetiological understanding is warranted. We present here analyses using multivariate pattern analysis (MVPA) and a machine learning classifier to investigate whether peri-traumatic brain activation was able to predict later intrusive memories (i.e. before they had happened). To provide a methodological basis for understanding the context of the current results, we first show how functional magnetic resonance imaging (fMRI) during an experimental analogue of trauma (a trauma film) via a prospective event-related design was able to capture an individual's later intrusive memories. Results showed widespread increases in brain activation at encoding when viewing a scene in the scanner that would later return as an intrusive memory in the real world. These fMRI results were replicated in a second study. While traditional mass univariate regression analysis highlighted an association between brain processing and symptomatology, this is not the same as prediction. Using MVPA and a machine learning classifier, it was possible to predict later intrusive memories across participants with 68% accuracy, and within a participant with 97% accuracy; i.e. the classifier could identify out of multiple scenes those that would later return as an intrusive memory. We also report here brain networks key in intrusive memory prediction. MVPA opens the possibility of decoding brain activity to reconstruct idiosyncratic cognitive events with relevance to understanding and predicting mental health symptoms.
Highlights
•Why only some moments within a trauma intrude while others do not is unclear.•Neuroimaging may provide further clues as to why this is the case.•Multivariate pattern analysis, a recent neuroimaging analysis tool, was able to predict intrusive memories.•Those brain networks involved in intrusive memory prediction are presented.•Multivariate pattern analysis may inform future innovation in mental health.
doi:10.1016/j.brat.2014.07.010
PMCID: PMC4222599  PMID: 25151915
Intrusive memories; Trauma; Flashback; MVPA; Machine learning; Functional magnetic resonance imaging; Mental imagery
5.  Fast transient networks in spontaneous human brain activity 
eLife  2014;3:e01867.
To provide an effective substrate for cognitive processes, functional brain networks should be able to reorganize and coordinate on a sub-second temporal scale. We used magnetoencephalography recordings of spontaneous activity to characterize whole-brain functional connectivity dynamics at high temporal resolution. Using a novel approach that identifies the points in time at which unique patterns of activity recur, we reveal transient (100–200 ms) brain states with spatial topographies similar to those of well-known resting state networks. By assessing temporal changes in the occurrence of these states, we demonstrate that within-network functional connectivity is underpinned by coordinated neuronal dynamics that fluctuate much more rapidly than has previously been shown. We further evaluate cross-network interactions, and show that anticorrelation between the default mode network and parietal regions of the dorsal attention network is consistent with an inability of the system to transition directly between two transient brain states.
DOI: http://dx.doi.org/10.7554/eLife.01867.001
eLife digest
When subjects lie motionless inside scanners without any particular task to perform, their brains show stereotyped patterns of activity across regions known as resting state networks. Each network consists of areas with a common function, such as the ‘motor’ network or the ‘visual’ network. The role of resting state networks is unclear, but these spontaneous activity patterns are altered in disorders including autism, schizophrenia, and Alzheimer’s disease.
One puzzling feature of resting state networks is that they seem to last for relatively long times. However, the majority of studies into resting state networks have used fMRI brain scans, in which changes in the level of oxygen in the blood are used as a proxy for the activity of a given brain region. Since changes in blood oxygen occur relatively slowly, the ability of fMRI to detect rapid changes in activity is limited: it is thus possible that the long-lived nature of resting state networks is an artefact of the use of fMRI.
Now, Baker et al. have used a different type of brain scan known as an MEG scan to show that the activity of resting state networks is shorter lived than previously thought. MEG scanners measure changes in the magnetic fields generated by electrical currents in the brain, which means that they can detect alterations in brain activity much more rapidly than fMRI.
MEG recordings from the brains of nine healthy subjects revealed that individual resting state networks were typically stable for only 100 ms to 200 ms. Moreover, transitions between different networks did not occur randomly; instead, certain networks were much more likely to become active after others. The work of Baker et al. suggests that the resting brain is constantly changing between different patterns of activity, which enables it to respond quickly to any given situation.
DOI: http://dx.doi.org/10.7554/eLife.01867.002
doi:10.7554/eLife.01867
PMCID: PMC3965210  PMID: 24668169
magnetoencephalography; resting state; connectivity; non-stationary; hidden Markov model; microstates; human
6.  Pushing spatial and temporal resolution for functional and diffusion MRI in the Human Connectome Project 
NeuroImage  2013;80:80-104.
The human connectome project (HCP) relies primarily on three complementary magnetic resonance (MR) methods. These are: 1) resting state functional MR imaging (rfMRI) which uses correlations in the temporal fluctuations in an fMRI time series to deduce ‘functional connectivity’; 2) diffusion imaging (dMRI), which provides the input for tractography algorithms used for the reconstruction of the complex axonal fiber architecture; and 3) task based fMRI (tfMRI), which is employed to identify functional parcellation in the human brain in order to assist analyses of data obtained with the first two methods. We describe technical improvements and optimization of these methods as well as instrumental choices that impact speed of acquisition of fMRI and dMRI images at 3 Tesla, leading to whole brain coverage with 2 mm isotropic resolution in 0.7 second for fMRI, and 1.25 mm isotropic resolution dMRI data for tractography analysis with three-fold reduction in total data acquisition time. Ongoing technical developments and optimization for acquisition of similar data at 7 Tesla magnetic field are also presented, targeting higher resolution, specificity of functional imaging signals, mitigation of the inhomogeneous radio frequency (RF) fields and power deposition. Results demonstrate that overall, these approaches represent a significant advance in MR imaging of the human brain to investigate brain function and structure.
doi:10.1016/j.neuroimage.2013.05.012
PMCID: PMC3740184  PMID: 23702417
7.  The WU-Minn Human Connectome Project: An Overview 
NeuroImage  2013;80:62-79.
The Human Connectome Project consortium led by Washington University, University of Minnesota, and Oxford University is undertaking a systematic effort to map macroscopic human brain circuits and their relationship to behavior in a large population of healthy adults. This overview article focuses on progress made during the first half of the 5-year project in refining the methods for data acquisition and analysis. Preliminary analyses based on a finalized set of acquisition and preprocessing protocols demonstrate the exceptionally high quality of the data from each modality. The first quarterly release of imaging and behavioral data via the ConnectomeDB database demonstrates the commitment to making HCP datasets freely accessible. Altogether, the progress to date provides grounds for optimism that the HCP datasets and associated methods and software will become increasingly valuable resources for characterizing human brain connectivity and function, their relationship to behavior, and their heritability and genetic underpinnings.
doi:10.1016/j.neuroimage.2013.05.041
PMCID: PMC3724347  PMID: 23684880
8.  Resting-state fMRI in the Human Connectome Project 
NeuroImage  2013;80:144-168.
Resting-state functional magnetic resonance imaging (rfMRI) allows one to study functional connectivity in the brain by acquiring fMRI data while subjects lie inactive in the MRI scanner, and taking advantage of the fact that functionally related brain regions spontaneously co-activate. rfMRI is one of the two primary data modalities being acquired for the Human Connectome Project (the other being diffusion MRI). A key objective is to generate a detailed in vivo mapping of functional connectivity in a large cohort of healthy adults (over 1,000 subjects), and to make these datasets freely available for use by the neuroimaging community. In each subject we acquire a total of one hour of whole-brain rfMRI data at 3 Tesla, with a spatial resolution of 2×2×2mm and a temporal resolution of 0.7s, capitalizing on recent developments in slice-accelerated echo-planar imaging. We will also scan a subset of the cohort at higher field strength and resolution. In this paper we outline the work behind, and rationale for, decisions taken regarding the rfMRI data acquisition protocol and pre-processing pipelines, and present some initial results showing data quality and example functional connectivity analyses.
doi:10.1016/j.neuroimage.2013.05.039
PMCID: PMC3720828  PMID: 23702415
9.  Spatially constrained hierarchical parcellation of the brain with resting-state fMRI 
NeuroImage  2013;76:313-324.
We propose a novel computational strategy to partition the cerebral cortex into disjoint, spatially contiguous and functionally homogeneous parcels. The approach exploits spatial dependency in the fluctuations observed with functional Magnetic Resonance Imaging (fMRI) during rest. Single subject parcellations are derived in a two stage procedure in which a set of (~1000 to 5000) stable seeds is grown into an initial detailed parcellation. This parcellation is then further clustered using a hierarchical approach that enforces spatial contiguity of the parcels.
A major challenge is the objective evaluation and comparison of different parcellation strategies; here, we use a range of different measures. Our single subject approach allows a subject-specific parcellation of the cortex, which shows high scan-to-scan reproducibility and whose borders delineate clear changes in functional connectivity. Another important measure, on which our approach performs well, is the overlap of parcels with task fMRI derived clusters. Connectivity-derived parcellation borders are less well matched to borders derived from cortical myelination and from cytoarchitectonic atlases, but this may reflect inherent differences in the data.
doi:10.1016/j.neuroimage.2013.03.024
PMCID: PMC3758955  PMID: 23523803
Resting state fMRI; Cortical parcellation; Connectomics
10.  Calcium regulation of spontaneous and asynchronous neurotransmitter release 
Cell calcium  2012;52(3-4):226-233.
Summary
The molecular machinery underlying action potential-evoked, synchronous neurotransmitter release, has been intensely studied. It was presumed that two other forms of exocytosis- delayed (asynchronous) and spontaneous transmission, were mediated by the same voltage-activated Ca2+ channels (VACCs), intracellular Ca2+ sensors and vesicle pools. However, a recent explosion in the study of spontaneous and asynchronous release has shown these presumptions to be incorrect. Furthermore, the finding that different forms of synaptic transmission may mediate distinct physiological functions emphasizes the importance of identifying the mechanisms by which Ca2+ regulates spontaneous and asynchronous release. In this article we will briefly summarize new and published data on the role of Ca2+ in regulating spontaneous and asynchronous release at a number of different synapses. We will discuss how an increase of extracellular [Ca2+] increases spontaneous and asynchronous release, show that VACCs are involved at only some synapses, and identify regulatory roles for other ion channels and G protein-coupled receptors. In particular, we will focus on two novel pathways that play important roles in the regulation of non-synchronous release at two exemplary synapses: one modulated by the Ca2+-sensing receptor and the other by transient receptor potential cation channel sub-family V member 1.
doi:10.1016/j.ceca.2012.06.001
PMCID: PMC3433637  PMID: 22748761
11.  Study protocol: the Whitehall II imaging sub-study 
BMC Psychiatry  2014;14:159.
Background
The Whitehall II (WHII) study of British civil servants provides a unique source of longitudinal data to investigate key factors hypothesized to affect brain health and cognitive ageing. This paper introduces the multi-modal magnetic resonance imaging (MRI) protocol and cognitive assessment designed to investigate brain health in a random sample of 800 members of the WHII study.
Methods/design
A total of 6035 civil servants participated in the WHII Phase 11 clinical examination in 2012–2013. A random sample of these participants was included in a sub-study comprising an MRI brain scan, a detailed clinical and cognitive assessment, and collection of blood and buccal mucosal samples for the characterisation of immune function and associated measures. Data collection for this sub-study started in 2012 and will be completed by 2016. The participants, for whom social and health records have been collected since 1985, were between 60–85 years of age at the time the MRI study started. Here, we describe the pre-specified clinical and cognitive assessment protocols, the state-of-the-art MRI sequences and latest pipelines for analyses of this sub-study.
Discussion
The integration of cutting-edge MRI techniques, clinical and cognitive tests in combination with retrospective data on social, behavioural and biological variables during the preceding 25 years from a well-established longitudinal epidemiological study (WHII cohort) will provide a unique opportunity to examine brain structure and function in relation to age-related diseases and the modifiable and non-modifiable factors affecting resilience against and vulnerability to adverse brain changes.
doi:10.1186/1471-244X-14-159
PMCID: PMC4048583  PMID: 24885374
Epidemiology; Magnetic resonance imaging; Diffusion tensor imaging; White matter; Functional MRI; Connectome; Resting state brain networks; Neuropsychology; Dementia; Affective disorders
12.  Permutation inference for the general linear model 
Neuroimage  2014;92(100):381-397.
Permutation methods can provide exact control of false positives and allow the use of non-standard statistics, making only weak assumptions about the data. With the availability of fast and inexpensive computing, their main limitation would be some lack of flexibility to work with arbitrary experimental designs. In this paper we report on results on approximate permutation methods that are more flexible with respect to the experimental design and nuisance variables, and conduct detailed simulations to identify the best method for settings that are typical for imaging research scenarios. We present a generic framework for permutation inference for complex general linear models (glms) when the errors are exchangeable and/or have a symmetric distribution, and show that, even in the presence of nuisance effects, these permutation inferences are powerful while providing excellent control of false positives in a wide range of common and relevant imaging research scenarios. We also demonstrate how the inference on glm parameters, originally intended for independent data, can be used in certain special but useful cases in which independence is violated. Detailed examples of common neuroimaging applications are provided, as well as a complete algorithm – the “randomise” algorithm – for permutation inference with the glm.
Highlights
•Permutation for the GLM in the presence of nuisance or non-independence.•A generalised statistic that performs well even under heteroscedasticity.•Permutation and/or sign-flipping, exchangeability blocks and variance groups.•The “randomise” algorithm, as well as various practical examples.
doi:10.1016/j.neuroimage.2014.01.060
PMCID: PMC4010955  PMID: 24530839
Permutation inference; Multiple regression; General linear model; Randomise
13.  Co-activation of multiple tightly-coupled calcium channels triggers spontaneous release of GABA 
Nature neuroscience  2012;15(9):1195-1197.
Voltage-activated Ca2+ channels (VACCs) mediate Ca2+ influx to trigger action potential-evoked neurotransmitter release but the mechanism by which Ca2+ regulates spontaneous transmission is unclear. Here we show VACCs are the major physiological triggers for spontaneous release at murine neocortical inhibitory synapses. Moreover, despite the absence of a synchronizing action potential, we find that spontaneous fusion of a GABA-containing vesicle requires the activation of multiple tightly-coupled VACCs of variable type.
doi:10.1038/nn.3162
PMCID: PMC3431448  PMID: 22842148
14.  Local GABA concentration is related to network-level resting functional connectivity 
eLife  2014;3:e01465.
Anatomically plausible networks of functionally inter-connected regions have been reliably demonstrated at rest, although the neurochemical basis of these ‘resting state networks’ is not well understood. In this study, we combined magnetic resonance spectroscopy (MRS) and resting state fMRI and demonstrated an inverse relationship between levels of the inhibitory neurotransmitter GABA within the primary motor cortex (M1) and the strength of functional connectivity across the resting motor network. This relationship was both neurochemically and anatomically specific. We then went on to show that anodal transcranial direct current stimulation (tDCS), an intervention previously shown to decrease GABA levels within M1, increased resting motor network connectivity. We therefore suggest that network-level functional connectivity within the motor system is related to the degree of inhibition in M1, a major node within the motor network, a finding in line with converging evidence from both simulation and empirical studies.
DOI: http://dx.doi.org/10.7554/eLife.01465.001
eLife digest
Even when your body is at rest, your brain remains active. Subjects lying in brain scanners without any specific task to perform show coordinated and reproducible patterns of brain activity. Areas of the brain with similar functions, such as those involved in vision or in movement, tend to increase or decrease their activity in sync, and these coordinated patterns are referred to as resting state networks.
The functions of these networks are unclear—they may support introspection, memory recall or planning for the future, or they may help to strengthen newly acquired skills by enabling the brain to replay previous learning episodes. There is evidence that resting state networks are altered in disorders such as Alzheimer’s disease, autism and schizophrenia, but little is known about how these changes arise or what they might mean.
Now, Stagg et al. have used a type of brain scan called magnetic resonance spectroscopy to gain insights into the mechanisms by which one particular network—the resting motor network—is generated. This network consists of areas involved in planning, monitoring and executing movements, and includes the primary motor cortex, which initiates movements by sending instructions to the spinal cord.
The levels of a chemical called GABA—a neurotransmitter molecule that tends to inhibit the activity of nerve cells—were measured in the primary motor cortex of young healthy volunteers as they lay idle in a scanner. GABA levels were negatively correlated with the amount of coordinated activity within the resting motor network. By contrast, no relation was seen between coordinated activity and the levels of the neurotransmitter glutamate, which tends to increase the activity of nerve cells. Furthermore, when a weak electric current was applied through the subjects’ scalp to their primary motor cortex—a technique previously shown to lower levels of GABA in the region—the resting motor network became stronger.
In addition to providing new information on how the rhythmic patterns of activity seen in the resting brain arise, the work of Stagg et al. contributes to the more general effort to understand the complex patterns of connections within the human brain.
DOI: http://dx.doi.org/10.7554/eLife.01465.002
doi:10.7554/eLife.01465
PMCID: PMC3964822  PMID: 24668166
magnetic resonance spectroscopy; GABA; resting state fMRI; human
15.  Change in Internalized Stigma and Social Functioning among Persons Diagnosed with Severe Mental Illness 
Psychiatry research  2012;200(2-3):1032-1034.
This study examined the relationship between change in internalized stigma and social functioning over time. Thirty-nine individuals with severe mental illness completed measures of self-stigma, social functioning and symptoms at baseline, 4-months, and 7-months. Change in self-stigma was significantly negatively related to change in social functioning, controlling for negative symptoms.
doi:10.1016/j.psychres.2012.06.017
PMCID: PMC3477502  PMID: 22763091
Self-stigma; social functioning; negative symptoms
16.  Correction: Multiplexed Echo Planar Imaging for Sub-Second Whole Brain FMRI and Fast Diffusion Imaging 
PLoS ONE  2011;6(9):10.1371/annotation/d9496d01-8c5d-4d24-8287-94449ada5064.
doi:10.1371/annotation/d9496d01-8c5d-4d24-8287-94449ada5064
PMCID: PMC3182862
17.  Spontaneous glutamate release is independent of calcium influx and tonically activated by the calcium-sensing receptor 
Spontaneous release of glutamate is important for maintaining synaptic strength and controlling spike timing in the brain. Mechanisms regulating spontaneous exocytosis remain poorly understood. Extracellular calcium concentration ([Ca2+]o) regulates Ca2+ entry through voltage-activated calcium channels (VACCs) and consequently is a pivotal determinant of action potential-evoked vesicle fusion. Extracellular Ca2+ also enhances spontaneous release, but via unknown mechanisms. Here we report that external Ca2+ triggers spontaneous glutamate release more weakly than evoked release in mouse neocortical neurons. Blockade of VACCs has no effect on the spontaneous release rate or its dependence on [Ca2+]o. Intracellular [Ca2+] slowly increases in a minority of neurons following increases in [Ca2+]o. Furthermore, the enhancement of spontaneous release by extracellular calcium is insensitive to chelation of intracellular calcium by BAPTA. Activation of the calcium-sensing receptor (CaSR), a G-protein coupled receptor present in nerve terminals, by several specific agonists increased spontaneous glutamate release. The frequency of spontaneous synaptic transmission was decreased in CaSR mutant neurons. The concentration effect relationship for extracellular calcium regulation of spontaneous release was well described by a combination of CaSR-dependent and CaSR-independent mechanisms. Overall these results indicate that extracellular Ca2+ does not trigger spontaneous glutamate release by simply increasing calcium influx but stimulates CaSR and thereby promotes resting spontaneous glutamate release.
doi:10.1523/JNEUROSCI.6398-10.2011
PMCID: PMC3097128  PMID: 21430159
18.  Correction: Multiplexed Echo Planar Imaging for Sub-Second Whole Brain FMRI and Fast Diffusion Imaging 
PLoS ONE  2011;6(9):10.1371/annotation/5e4082fd-6d86-441f-b946-a6e87a22ea57.
doi:10.1371/annotation/5e4082fd-6d86-441f-b946-a6e87a22ea57
PMCID: PMC3182257
19.  Group-Based Treatment for Internalized Stigma among Persons with Severe Mental Illness: Findings from a Randomized Controlled Trial 
Psychological services  2012;9(3):248-258.
Elevated internalized stigma is common and is linked to subjective and objective outcomes for severe mental illness. The authors developed a manualized group-based intervention (Narrative Enhancement/Cognitive Therapy; NECT) to address internalized stigma in severe mental illness. The purpose of the present study was to evaluate the feasibility and effectiveness of NECT. 144 individuals were screened at two sites to evaluate if they met criteria for “elevated” internalized stigma; 39 and were eligible were randomized to NECT or to treatment as usual (TAU) and were assessed at baseline, post-treatment, and 3-month follow-up. Fifteen of the 21 individuals assigned to NECT were classified as “exposed” to treatment. Intent-to-treat analyses found no significant difference between the NECT and TAU groups. A comparison of exposed vs. unexposed participants noted trends for exposed participants to have improved more in two aspects of self-stigma as well as insight. We conclude that NECT is feasible and tolerable, but findings did not support the hypothesis that NECT was more effective than TAU, although small sample size and significant dropout may have restricted the ability to detect an effect.
doi:10.1037/a0028048
PMCID: PMC3413784  PMID: 22545821
Self-stigma; severe mental illness; narrative
20.  Calcium-sensing receptor: a high-affinity presynaptic target for aminoglycoside-induced weakness 
Neuropharmacology  2009;57(5-6):502-505.
Administration of aminoglycoside antibiotics can precipitate sudden, profound bouts of weakness that have been attributed to block of presynaptic voltage-activated calcium channels (VACC) and failure of neuromuscular transmission. This serious adverse drug reaction is more likely in neuromuscular diseases such as myasthenia gravis. The relatively low affinity of VACC for aminoglycosides prompted us to explore alternative mechanisms. We hypothesized that the presynaptic Ca2+-sensing receptor (CaSR) may contribute to aminoglycoside-induced weakness due to its role in modulating synaptic transmission and its sensitivity to aminoglycosides in heterologous expression systems. We have previously shown that presynaptic CaSR controls a non-specific cation channel (NSCC) that regulates nerve terminal excitability and transmitter release. Using direct, electrophysiological recording, we report that neuronal VACCs are inhibited by neomycin (IC50 830 ± 110 μM) at a much lower affinity than CaSR-modulated NSCC currents recorded from acutely isolated presynaptic terminals (synaptosomes; IC50 20 ± 1 μM). Thus, at clinically relevant concentrations, aminoglycoside-induced weakness is likely precipitated by enhanced CaSR activation and subsequent decrease in terminal excitability rather than through direct inhibition of VACCs themselves.
doi:10.1016/j.neuropharm.2009.07.031
PMCID: PMC2836903  PMID: 19646457
21.  Behavioral Interpretations of Intrinsic Connectivity Networks 
Journal of cognitive neuroscience  2011;23(12):4022-4037.
An increasingly large number of neuroimaging studies have investigated functionally connected networks during rest, providing insight into human brain architecture. Assessment of the functional qualities of resting state networks has been limited by the task-independent state, which results in an inability to relate these networks to specific mental functions. However, it was recently demonstrated that similar brain networks can be extracted from resting state data and data extracted from thousands of task-based neuroimaging experiments archived in the BrainMap database. Here, we present a full functional explication of these intrinsic connectivity networks at a standard low order decomposition using a neuroinformatics approach based on the BrainMap behavioral taxonomy as well as a stratified, data-driven ordering of cognitive processes. Our results serve as a resource for functional interpretations of brain networks in resting state studies and future investigations into mental operations and the tasks that drive them.
doi:10.1162/jocn_a_00077
PMCID: PMC3690655  PMID: 21671731
22.  Spatial vs. Temporal Features in ICA of Resting-State fMRI – A Quantitative and Qualitative Investigation in the Context of Response Inhibition 
PLoS ONE  2013;8(6):e66572.
Independent component analysis (ICA) can identify covarying functional networks in the resting brain. Despite its relatively widespread use, the potential of the temporal information (unlike spatial information) obtained by ICA from resting state fMRI (RS-fMRI) data is not always fully utilized. In this study, we systematically investigated which features in ICA of resting-state fMRI relate to behaviour, with stop signal reaction time (SSRT) in a stop-signal task taken as a test case. We did this by correlating SSRT with the following three kinds of measure obtained from RS-fMRI data: (1) the amplitude of each resting state network (RSN) (evaluated by the standard deviation of the RSN timeseries), (2) the temporal correlation between every pair of RSN timeseries, and (3) the spatial map of each RSN. For multiple networks, we found significant correlations not only between SSRT and spatial maps, but also between SSRT and network activity amplitude. Most of these correlations are of functional interpretability. The temporal correlations between RSN pairs were of functional significance, but these correlations did not appear to be very sensitive to finding SSRT correlations. In addition, we also investigated the effects of the decomposition dimension, spatial smoothing and Z-transformation of the spatial maps, as well as the techniques for evaluating the temporal correlation between RSN timeseries. Overall, the temporal information acquired by ICA enabled us to investigate brain function from a complementary perspective to the information provided by spatial maps.
doi:10.1371/journal.pone.0066572
PMCID: PMC3688987  PMID: 23825545
23.  Tools of the trade: psychophysiological interactions and functional connectivity 
Psychophysiological interactions (PPIs) analysis is a method for investigating task-specific changes in the relationship between activity in different brain areas, using functional magnetic resonance imaging (fMRI) data. Specifically, PPI analyses identify voxels in which activity is more related to activity in a seed region of interest (seed ROI) in a given psychological context, such as during attention or in the presence of emotive stimuli. In this tutorial, we aim to give a simple conceptual explanation of how PPI analysis works, in order to assist readers in planning and interpreting their own PPI experiments.
doi:10.1093/scan/nss055
PMCID: PMC3375893  PMID: 22569188
psychophysiological interactions; PPI; functional connectivity; resting state
24.  Synaptic vesicle endocytosis: fast and slow modes of membrane retrieval 
Trends in neurosciences  2008;31(11):559-568.
Several modes of synaptic vesicle release, retrieval and recycling have been identified. In a well-established mode of exocytosis, termed ‘full-collapse fusion’, vesicles empty their neurotransmitter content fully into the synaptic cleft by flattening out and becoming part of the presynaptic membrane. The fused vesicle membrane is then reinternalized via a slow and clathrin-dependent mode of compensatory endocytosis that takes several seconds. A more fleeting mode of vesicle fusion, termed ‘kiss-and-run’ exocytosis or ‘flicker-fusion’, indicates that during synaptic transmission some vesicles are only briefly connected to the presynaptic membrane by a transient fusion pore. Finally, a mode that retrieves a large amount of membrane, equivalent to that of several fused vesicles, termed ‘bulk endocytosis’, has been found after prolonged exocytosis. We are of the opinion that both fast and slow modes of endocytosis co-exist at central nervous system nerve terminals and that one mode can predominate depending on stimulus strength, temperature and synaptic maturation.
doi:10.1016/j.tins.2008.08.005
PMCID: PMC3626563  PMID: 18817990
25.  Calcium-sensing receptor activation depresses synaptic transmission 
At excitatory synapses, decreases in cleft [Ca] arising from activity-dependent transmembrane Ca flux reduce the probability of subsequent transmitter release. Intense neural activity, induced by physiological and pathological stimuli, disturb the external microenvironment reducing extracellular [Ca] ([Ca]o) and thus may impair neurotransmission. Increases in [Ca]o activate the extracellular calcium sensing receptor (CaSR) which in turn inhibits non-selective cation channels (NSCC) at the majority of cortical nerve terminals. This pathway may modulate synaptic transmission by attenuating the impact of decreases in [Ca]o on synaptic transmission. Using patch-clamp recording from isolated cortical terminals, cortical neuronal pairs and isolated neuronal soma we examined the modulation of synaptic transmission by CaSR. Excitatory postsynaptic currents were increased on average by 88% in reduced affinity CaSR-mutant (CaSR−/−) neurons compared to wild-type. Variance-mean analysis indicates that the enhanced synaptic transmission was due largely to an increase in average probability of release (0.27 vs 0.46 for wild-type vs CaSR−/− pairs) with little change in quantal size (23 ± 4 pA vs 22 ± 4 pA) or number of release sites (11 vs 13). In addition, the CaSR agonist spermidine reduced synaptic transmission and increased paired-pulse depression at physiological [Ca]o. Spermidine did not affect quantal size, consistent with a presynaptic mechanism of action, nor did it affect voltage-activated Ca channel currents. In summary, reduced CaSR function enhanced synaptic transmission and CaSR stimulation had the opposite effect. Thus CaSR provides a mechanism that may compensate for the fall in release probability that accompanies decreases in [Ca]o .
doi:10.1523/JNEUROSCI.4134-08.2008
PMCID: PMC2761683  PMID: 19005071
calcium; GPCR; Depression; Synaptic plasticity; synaptic transmission; Synaptic vesicle release; Synaptosome; Extracellular; Receptor

Results 1-25 (59)