Whole brain functional connectivity using phase locking measures of resting state magnetoencephalography

The analysis of spontaneous functional connectivity (sFC) reveals the statistical connections between regions of the brain consistent with underlying functional communication networks within the brain. In this work, we describe the implementation of a complete all-to-all network analysis of resting state neuronal activity from magnetoencephalography (MEG). Using graph theory to define networks at the dipole level, we established functionally defined regions by k-means clustering cortical surface locations using Eigenvector centrality (EVC) scores from the all-to-all adjacency model. Permutation testing was used to estimate regions with statistically significant connections compared to empty room data, which adjusts for spatial dependencies introduced by the MEG inverse problem. In order to test this model, we performed a series of numerical simulations investigating the effects of the MEG reconstruction on connectivity estimates. We subsequently applied the approach to subject data to investigate the effectiveness of our method in obtaining whole brain networks. Our findings indicated that our model provides statistically robust estimates of functional region networks. Application of our phase locking network methodology to real data produced networks with similar connectivity to previously published findings, specifically, we found connections between contralateral areas of the arcuate fasciculus that have been previously investigated. The use of data-driven methods for neuroscientific investigations provides a new tool for researchers in identifying and characterizing whole brain functional connectivity networks. © 2014 Schmidt, Ghuman and Huppert

Laboratory observations of double-diffusive convection using high-frequency broadband acoustics

Author Posting. © The Author(s), 2008. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Experiments in Fluids 46 (2009): 355-364, doi:10.1007/s00348-008-0570-9.High-frequency broadband (200-300 kHz) acoustic scattering techniques have been used to observe the diffusive regime of double-diffusive convection in the laboratory. Pulse compression signal processing techniques allow 1) centimetre-scale interface thickness to be rapidly, remotely, and continuously measured, 2) the evolution, and ultimate merging, of multiple interfaces to be observed at high-resolution, and 3) convection cells within the surrounding mixed layers to be observed. The acoustically measured interface thickness, combined with knowledge of the slowly-varying temperatures within the surrounding layers, in turn allows the direct estimation of double-diffusive heat and buoyancy fluxes. The acoustically derived interface thickness, interfacial fluxes and migration rates are shown to support established theory. Acoustic techniques complement traditional laboratory sampling methods and provide enhanced capabilities for observing the diffusive regime of double-diffusion in the ocean.Funding for this project was provided by the Ocean Acoustics program at the Office of Naval Research, and by the WHOI Cecil and Ida Greene Technology Award

Age-related changes in global motion coherence: conflicting haemodynamic and perceptual responses

Our aim was to use both behavioural and neuroimaging data to identify indicators of perceptual decline in motion processing. We employed a global motion coherence task and functional Near Infrared Spectroscopy (fNIRS). Healthy adults (n = 72, 18-85) were recruited into the following groups: young (n = 28, mean age = 28), middle-aged (n = 22, mean age = 50), and older adults (n = 23, mean age = 70). Participants were assessed on their motion coherence thresholds at 3 different speeds using a psychophysical design. As expected, we report age group differences in motion processing as demonstrated by higher motion coherence thresholds in older adults. Crucially, we add correlational data showing that global motion perception declines linearly as a function of age. The associated fNIRS recordings provide a clear physiological correlate of global motion perception. The crux of this study lies in the robust linear correlation between age and haemodynamic response for both measures of oxygenation. We hypothesise that there is an increase in neural recruitment, necessitating an increase in metabolic need and blood flow, which presents as a higher oxygenated haemoglobin response. We report age-related changes in motion perception with poorer behavioural performance (high motion coherence thresholds) associated with an increased haemodynamic response

Functional imaging of cognition in an old-old population: A case for portable functional near-infrared spectroscopy

In this study, functional near-infrared spectroscopy (fNIRS) was used to record brain activa- tion during cognitive testing in older individuals (88±6yo; N = 19) living in residential care communities. This population, which is often associated with loss of personal independence due to physical or cognitive decline associated with aging, is also often under-represented in neuroscience research because of a limited means to participate in studies which often take place in large urban or university centers. In this study, we demonstrate the feasibility and initial results using a portable 8-source by 4-detector fNIRS system to measure brain activity from participants within residential care community centers. Using fNIRS, brain sig- nals were recorded during a series of computerized cognitive tests, including a Symbol Digit Coding test (SDC), Stroop Test (ST), and Shifting Attention Test (SAT). The SDC and SAT elicited greater activity in the left middle frontal region of interest. Three components of the ST produced increases in the right middle frontal and superior frontal, and left superior frontal regions. An association between advanced age and increased activation in the right middle frontal region was observed during the incongruent ST. Although none of the partici- pants had clinical dementia based on the short portable mental status questionnaire, the group performance was slightly below age-normed values on these cognitive tests. These results demonstrate the capability for obtaining functional neuroimaging measures in resi- dential settings, which ultimately may aid in prognosis and care related to dementia in older adults

Prefrontal cortex activation and young driver behaviour: a fNIRS study

Road traffic accidents consistently show a significant over-representation for young, novice and particularly male drivers. This research examines the prefrontal cortex activation of young drivers and the changes in activation associated with manipulations of mental workload and inhibitory control. It also considers the explanation that a lack of prefrontal cortex maturation is a contributing factor to the higher accident risk in this young driver population. The prefrontal cortex is associated with a number of factors including mental workload and inhibitory control, both of which are also related to road traffic accidents. This experiment used functional near infrared spectroscopy to measure prefrontal cortex activity during five simulated driving tasks: one following task and four overtaking tasks at varying traffic densities which aimed to dissociate workload and inhibitory control. Age, experience and gender were controlled for throughout the experiment. The results showed that younger drivers had reduced prefrontal cortex activity compared to older drivers. When both mental workload and inhibitory control increased prefrontal cortex activity also increased, however when inhibitory control alone increased there were no changes in activity. Along with an increase in activity during overtaking manoeuvres, these results suggest that prefrontal cortex activation is more indicative of workload in the current task. There were no differences in the number of overtakes completed by younger and older drivers but males overtook significantly more than females. We conclude that prefrontal cortex activity is associated with the mental workload required for overtaking. We additionally suggest that the reduced activation in younger drivers may be related to a lack of prefrontal maturation which could contribute to the increased crash risk seen in this population

The NIRS Analysis Package: Noise Reduction and Statistical Inference

Near infrared spectroscopy (NIRS) is a non-invasive optical imaging technique that can be used to measure cortical hemodynamic responses to specific stimuli or tasks. While analyses of NIRS data are normally adapted from established fMRI techniques, there are nevertheless substantial differences between the two modalities. Here, we investigate the impact of NIRS-specific noise; e.g., systemic (physiological), motion-related artifacts, and serial autocorrelations, upon the validity of statistical inference within the framework of the general linear model. We present a comprehensive framework for noise reduction and statistical inference, which is custom-tailored to the noise characteristics of NIRS. These methods have been implemented in a public domain Matlab toolbox, the NIRS Analysis Package (NAP). Finally, we validate NAP using both simulated and actual data, showing marked improvement in the detection power and reliability of NIRS

Dendrimer-Based Fluorescent Indicators: In Vitro and In Vivo Applications

BACKGROUND: The development of fluorescent proteins and synthetic molecules whose fluorescence properties are controlled by the environment makes it possible to monitor physiological and pathological events in living systems with minimal perturbation. A large number of small organic dyes are available and routinely used to measure biologically relevant parameters. Unfortunately their application is hindered by a number of limitations stemming from the use of these small molecules in the biological environment. PRINCIPAL FINDINGS: We present a novel dendrimer-based architecture leading to multifunctional sensing elements that can overcome many of these problems. Applications in vitro, in living cells and in vivo are reported. In particular, we image for the first time extracellular pH in the brain in a mouse epilepsy model. CONCLUSION: We believe that the proposed architecture can represent a useful and novel tool in fluorescence imaging that can be widely applied in conjunction with a broad range of sensing dyes and experimental setups

Small-molecule-induced DNA damage identifies alternative DNA structures in human genes.

Guanine-rich DNA sequences that can adopt non-Watson-Crick structures in vitro are prevalent in the human genome. Whether such structures normally exist in mammalian cells has, however, been the subject of active research for decades. Here we show that the G-quadruplex-interacting drug pyridostatin promotes growth arrest in human cancer cells by inducing replication- and transcription-dependent DNA damage. A chromatin immunoprecipitation sequencing analysis of the DNA damage marker γH2AX provided the genome-wide distribution of pyridostatin-induced sites of damage and revealed that pyridostatin targets gene bodies containing clusters of sequences with a propensity for G-quadruplex formation. As a result, pyridostatin modulated the expression of these genes, including the proto-oncogene SRC. We observed that pyridostatin reduced SRC protein abundance and SRC-dependent cellular motility in human breast cancer cells, validating SRC as a target of this drug. Our unbiased approach to define genomic sites of action for a drug establishes a framework for discovering functional DNA-drug interactions

G-quadruplex structures mark human regulatory chromatin

G-quadruplex (G4) structural motifs have been linked to transcription, replication and genome instability and are implicated in cancer and other diseases. However, it is crucial to demonstrate the bona fide formation of G4 structures within an endogenous chromatin context. Herein we address this through the development of G4 ChIP-seq, an antibody-based G4 chromatin immunoprecipitation and high-throughput sequencing approach. We find ∼10,000 G4 structures in human chromatin, predominantly in regulatory, nucleosome-depleted regions. G4 structures are enriched in the promoters and 5' UTRs of highly transcribed genes, particularly in genes related to cancer and in somatic copy number amplifications, such as $\textit{MYC}$. Strikingly, $\textit{de novo}$ and enhanced G4 formation are associated with increased transcriptional activity, as shown by HDAC inhibitor-induced chromatin relaxation and observed in immortalized as compared to normal cellular states. Our findings show that regulatory, nucleosome-depleted chromatin and elevated transcription shape the endogenous human G4 DNA landscape.European Molecular Biology Organization (EMBO Long-Term Fellowship), University of Cambridge, Cancer Research UK (Grant ID: C14303/A17197), Wellcome Trust (Grant ID: 099232/z/12/z