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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  ICA model order selection of task co-activation networks 
Independent component analysis (ICA) has become a widely used method for extracting functional networks in the brain during rest and task. Historically, preferred ICA dimensionality has widely varied within the neuroimaging community, but typically varies between 20 and 100 components. This can be problematic when comparing results across multiple studies because of the impact ICA dimensionality has on the topology of its resultant components. Recent studies have demonstrated that ICA can be applied to peak activation coordinates archived in a large neuroimaging database (i.e., BrainMap Database) to yield whole-brain task-based co-activation networks. A strength of applying ICA to BrainMap data is that the vast amount of metadata in BrainMap can be used to quantitatively assess tasks and cognitive processes contributing to each component. In this study, we investigated the effect of model order on the distribution of functional properties across networks as a method for identifying the most informative decompositions of BrainMap-based ICA components. Our findings suggest dimensionality of 20 for low model order ICA to examine large-scale brain networks, and dimensionality of 70 to provide insight into how large-scale networks fractionate into sub-networks. We also provide a functional and organizational assessment of visual, motor, emotion, and interoceptive task co-activation networks as they fractionate from low to high model-orders.
doi:10.3389/fnins.2013.00237
PMCID: PMC3857551  PMID: 24339802
meta-analysis; co-activations; BrainMap; intrinsic connectivity networks; functional brain networks; functional connectivity; resting state networks; independent component analysis
15.  Modulation of Neuronal Voltage-Activated Calcium and Sodium Channels by Polyamines and pH 
Channels (Austin, Tex.)  2007;1(4):281-290.
The endogenous polyamines spermine, spermidine and putrescine are present at high concentrations inside neurons and can be released into the extracellular space where they have been shown to modulate ion channels. Here, we have examined polyamine modulation of voltage-activated Ca2+ channels (VACCs) and voltage-activated Na+ channels (VANCs) in rat superior cervical ganglion neurons using whole-cell voltage-clamp at physiological divalent concentrations. Polyamines inhibited VACCs in a concentration-dependent manner with IC50s for spermine, spermidine, and putrescine of 4.7 ± 0.7, 11.2 ± 1.4 and 90 ± 36 mM, respectively. Polyamines caused inhibition by shifting the VACC half-activation voltage (V0.5) to depolarized potentials and by reducing total VACC permeability. The shift was described by Gouy-Chapman-Stern theory with a surface charge density of 0.120 ± 0.005 e− nm−2 and a surface potential of −19 mV. Attenuation of spermidine and spermine inhibition of VACC at decreased pH was explained by H+ titration of surface charge. Polyamine-mediated effects also decreased at elevated pH due to the inhibitors having lower valence and being less effective at screening surface charge. Polyamines affected VANC currents indirectly by reducing TTX inhibition of VANCs at high pH. This may reflect surface charge induced decreases in the local TTX concentration or polyamine-TTX interactions. In conclusion, polyamines inhibit neuronal VACCs via complex interactions with extracellular H+ and Ca. Many of the observed effects can be explained by a model incorporating polyamine binding, H+ binding and surface charge screening.
PMCID: PMC2561315  PMID: 18708745
polyamine; spermine; spermidine; putrescine; surface charge screening; surface potential; Gouy-Chapman; voltage-activated calcium channel; VACC; voltage-activated Na+ channels; VANC; superior cervical ganglion; neuron
16.  A Bayesian model of shape and appearance for subcortical brain segmentation 
NeuroImage  2011;56(3):907-922.
Automatic segmentation of subcortical structures in human brain MR images is an important but difficult task due to poor and variable intensity contrast. Clear, well-defined intensity features are absent in many places along typical structure boundaries and so extra information is required to achieve successful segmentation. A method is proposed here that uses manually labelled image data to provide anatomical training information. It utilises the principles of the Active Shape and Appearance Models but places them within a Bayesian framework, allowing probabilistic relationships between shape and intensity to be fully exploited. The model is trained for 15 different subcortical structures using 336 manually-labelled T1-weighted MR images. Using the Bayesian approach, conditional probabilities can be calculated easily and efficiently, avoiding technical problems of ill-conditioned covariance matrices, even with weak priors, and eliminating the need for fitting extra empirical scaling parameters, as is required in standard Active Appearance Models. Furthermore, differences in boundary vertex locations provide a direct, purely local measure of geometric change in structure between groups that, unlike voxel-based morphometry, is not dependent on tissue classification methods or arbitrary smoothing. In this paper the fully-automated segmentation method is presented and assessed both quantitatively, using Leave-One-Out testing on the 336 training images, and qualitatively, using an independent clinical dataset involving Alzheimer’s disease. Median Dice overlaps between 0.7 and 0.9 are obtained with this method, which is comparable or better than other automated methods. An implementation of this method, called FIRST, is currently distributed with the freely-available FSL package.
doi:10.1016/j.neuroimage.2011.02.046
PMCID: PMC3417233  PMID: 21352927
Segmentation; Classification; Bayesian; Subcortical structures; Shape model
17.  Crystal Structure and Characterization of Particulate Methane Monooxygenase from Methylocystis species Strain M 
Biochemistry  2011;50(47):10231-10240.
Particulate methane monooxygenase (pMMO) is an integral membrane metalloenzyme that oxidizes methane to methanol in methanotrophic bacteria. Previous biochemical and structural studies of pMMO have focused on preparations from Methylococcus capsulatus (Bath) and Methylosinus trichosporium OB3b. A pMMO from a third organism, Methylocystis species strain M, has been isolated and characterized. Both membrane-bound and solubilized Methylocystis sp. strain M pMMO contain ~2 copper ions per 100 kDa protomer and exhibit copper-dependent propylene epoxidation activity. Spectroscopic data indicate that Methylocystis sp. strain M pMMO contains a mixture of CuI and CuII, of which the latter exhibits two distinct type 2 CuII electron paramagnetic resonance (EPR) signals. Extended X-ray absorption fine structure (EXAFS) data are best fit with a mixture of Cu–O/N and Cu–Cu ligand environments with a Cu–Cu interaction at 2.52–2.64 Å. The crystal structure of Methylocystis sp. strain M pMMO was determined to 2.68 Å resolution and is the best quality pMMO structure obtained to date. It provides a revised model for the pmoA and pmoC subunits and has led to an improved model of M. capsulatus (Bath) pMMO. In these new structures, the intramembrane zinc/copper binding site has a different coordination environment from that in previous models.
doi:10.1021/bi200801z
PMCID: PMC3364217  PMID: 22013879
18.  Metal Reconstitution of Particulate Methane Monooxygenase and Heterologous Expression of the pmoB Subunit 
Methods in Enzymology  2011;495:195-210.
Particulate methane monooxygenase (pMMO) is a multisubunit metalloenzyme complex used by methanotrophic bacteria to oxidize methane in the first step of carbon assimilation and energy production. In this chapter, we detail methods to prepare metal free (apo) membrane-bound pMMO and to reconstitute apo pMMO with metal ions. We also describe protocols to clone, express, and refold metal-loaded soluble domain constructs of the pmoB subunit. These approaches were used to address fundamental questions concerning the metal content and location of the pMMO active site.
doi:10.1016/B978-0-12-386905-0.00013-9
PMCID: PMC3361753  PMID: 21419923
19.  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
20.  Coping, Productive Time Use, and Negative Mood among Adults with Severe Mental Illness: A Daily Diary Study 
Schizophrenia research  2010;124(1-3):54-59.
Most studies on coping among persons with severe mental illness have relied on retrospective self-report methods; a limitation of this methodology is susceptibility to recall bias. The purpose of the present investigation was to expand the current understanding of the impact of coping among persons with severe mental illness by examining coping strategies, mood, and social functioning (operationalized as productive time use) using a daily process design. Twenty-seven adults diagnosed with severe mental illness completed baseline clinical interviews and up to 20 days of nightly telephone interviews addressing coping and daily life. A total of 198 coping efforts were reported for 387 days. Mixed-effects regression analyses examined the association between type of daily coping strategy (problem-centered, neutral, or avoidant) and both daily proportion of time participants spent in productive activity and daily negative mood, controlling for demographic and clinical variables. The results indicated that productive time use was significantly lower on days when avoidant strategies were used, in contrast with days when problem-centered strategies and neutral strategies were used. There was not a significant main effect of coping on negative mood, although there was a trend in the expected direction. Findings support the hypothesis that the types of coping strategies adults with severe mental illness use are related to better social functioning on a daily level.
doi:10.1016/j.schres.2010.08.020
PMCID: PMC2981651  PMID: 20817412
Coping; severe mental illness; time use; negative mood; social functioning
21.  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
22.  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
23.  Prevalence of Internalized Stigma among Persons with Severe Mental Illness 
Stigma research and action  2011;1(1):3-10.
Purpose
There is evidence that internalized stigma significantly impacts the lives of people with severe mental illness. Nevertheless, there is little data on the prevalence of clinically significant internalized stigma. This study investigated the current prevalence and demographic correlates of significantly elevated levels of internalized stigma in two samples of people with severe mental illness living in the community.
Method
A total of 144 people (79.9% males, 20.1% females) participated, completing a demographic form and the Internalized Stigma of Mental Illness scale.
Results
Overall, 36% of the sample had elevated internalized stigma scores using a cutoff criterion. Participants in the middle of the age distribution had the highest scores, and there was a site difference. No other demographic variables studied were related to overall internalized stigma.
Conclusions
We conclude that internalized stigma affects a relatively high percentage of people with severe mental illness.
doi:10.5463/sra.v1i1.9
PMCID: PMC3144559  PMID: 21804951
internalized stigma; self-stigma; severe mental illness; prevalence; Internalized Stigma of Mental Illness Scale
24.  Diffusion imaging of whole, post-mortem human brains on a clinical MRI scanner 
Neuroimage  2011;57(1-4):167-181.
Diffusion imaging of post mortem brains has great potential both as a reference for brain specimens that undergo sectioning, and as a link between in vivo diffusion studies and “gold standard” histology/dissection. While there is a relatively mature literature on post mortem diffusion imaging of animals, human brains have proven more challenging due to their incompatibility with high-performance scanners. This study presents a method for post mortem diffusion imaging of whole, human brains using a clinical 3-Tesla scanner with a 3D segmented EPI spin-echo sequence. Results in eleven brains at 0.94 × 0.94 × 0.94 mm resolution are presented, and in a single brain at 0.73 × 0.73 × 0.73 mm resolution. Region-of-interest analysis of diffusion tensor parameters indicate that these properties are altered compared to in vivo (reduced diffusivity and anisotropy), with significant dependence on post mortem interval (time from death to fixation). Despite these alterations, diffusion tractography of several major tracts is successfully demonstrated at both resolutions. We also report novel findings of cortical anisotropy and partial volume effects.
Research highlights
► Acquisition and processing protocols for diffusion MRI of post-mortem human brains. ► Effect of post-mortem and scan intervals on diffusion indices. ► Tractography in post-mortem human brains. ► Radial diffusion anisotropy in cortical gray matter.
doi:10.1016/j.neuroimage.2011.03.070
PMCID: PMC3115068  PMID: 21473920
Diffusion tensor imaging; Tractography; Post mortem; Human; Brain
25.  Integrity of white matter in the corpus callosum correlates with bimanual co-ordination skills 
NeuroImage  2007;36(Suppl 2):T16-T21.
Variation in brain structure may reflect variation in functional properties of specific brain systems. Structural variation may therefore reflect variation in behavioural performance. Here, we use diffusion-weighted magnetic resonance imaging to show that variation in white matter integrity in a specific region in the body of the corpus callosum is associated with variation in performance of a bimanual co-ordination task. When the callosal region showing this association is used as a seed for probabilistic tractography, inter-hemispheric pathways are generated to the supplementary motor area and caudal cingulate motor area. This provides further evidence for the role of medial wall motor areas in bimanual co-ordination and supports the idea that variation in brain structure reflects inter-individual differences in skilled performance.
doi:10.1016/j.neuroimage.2007.03.041
PMCID: PMC3119816  PMID: 17499163

Results 1-25 (51)