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1.  Moving in time: Bayesian causal inference explains movement coordination to auditory beats 
Many everyday skilled actions depend on moving in time with signals that are embedded in complex auditory streams (e.g. musical performance, dancing or simply holding a conversation). Such behaviour is apparently effortless; however, it is not known how humans combine auditory signals to support movement production and coordination. Here, we test how participants synchronize their movements when there are potentially conflicting auditory targets to guide their actions. Participants tapped their fingers in time with two simultaneously presented metronomes of equal tempo, but differing in phase and temporal regularity. Synchronization therefore depended on integrating the two timing cues into a single-event estimate or treating the cues as independent and thereby selecting one signal over the other. We show that a Bayesian inference process explains the situations in which participants choose to integrate or separate signals, and predicts motor timing errors. Simulations of this causal inference process demonstrate that this model provides a better description of the data than other plausible models. Our findings suggest that humans exploit a Bayesian inference process to control movement timing in situations where the origin of auditory signals needs to be resolved.
PMCID: PMC4046422  PMID: 24850915
movement synchronization; Bayesian inference; sensory integration; motor timing
2.  Functional Maturation of the Executive System during Adolescence 
The Journal of Neuroscience  2013;33(41):16249-16261.
Adolescence is characterized by rapid development of executive function. Working memory (WM) is a key element of executive function, but it is not known what brain changes during adolescence allow improved WM performance. Using a fractal n-back fMRI paradigm, we investigated brain responses to WM load in 951 human youths aged 8–22 years. Compared with more limited associations with age, WM performance was robustly associated with both executive network activation and deactivation of the default mode network. Multivariate patterns of brain activation predicted task performance with a high degree of accuracy, and also mediated the observed age-related improvements in WM performance. These results delineate a process of functional maturation of the executive system, and suggest that this process allows for the improvement of cognitive capability seen during adolescence.
PMCID: PMC3792462  PMID: 24107956
3.  Amygdala abnormalities in first-degree relatives of individuals with schizophrenia unmasked by benzodiazepine challenge 
Psychopharmacology  2011;218(3):503-512.
Impaired emotion processing in schizophrenia predicts broader social dysfunction and has been related to negative symptom severity and amygdala dysfunction. Pharmacological modulation of emotion-processing deficits and related neural abnormalities may provide useful phenotypes for pathophysiological investigation.
We used an acute benzodiazepine challenge to identify and modulate potential emotion-processing abnormalities in 20 unaffected first-degree relatives of individuals with schizophrenia, compared to 25 control subjects without a family history of psychosis.
An oral 1mg dose of the short-acting anxiolytic benzodiazepine alprazolam was administered in a balanced crossover placebo-controlled double-blind design, preceding identical 3T fMRI sessions approximately 1 week apart. Primary outcomes included fMRI activity in amygdala and related regions during two facial emotion-processing tasks: emotion identification and emotion memory.
Family members exhibited abnormally strong alprazolam-induced reduction in amygdala and hippocampus activation during emotion identification, compared to equal reduction in both groups for the emotion memory task.
GABAergic modulation with alprazolam produced differential responses in family members vs. controls, perhaps by unmasking underlying amygdalar and/or GABAergic abnormalities. Such pharmacological fMRI paradigms could prove useful for developing drugs targeting specific neural circuits to treat or prevent schizophrenia.
PMCID: PMC3962022  PMID: 21603892
pharmacological fMRI; benzodiazepine; endophenotype; amygdala; facial emotion; GABA; schizophrenia
4.  Oral alprazolam acutely increases nucleus accumbens perfusion 
Molecular psychiatry  2012;18(9):960-961.
Benzodiazepines treat anxiety, but can also produce euphoric effects, contributing to abuse. Using perfusion magnetic resonance imaging, we provide the first direct evidence in humans that alprazolam (Xanax) acutely increases perfusion in the nucleus accumbens, a key reward-processing region linked to addiction.
PMCID: PMC3957329  PMID: 23070072
5.  Comparison of Real-Time Water Proton Spectroscopy and Echo-Planar Imaging Sensitivity to the BOLD Effect at 3 T and at 7 T 
PLoS ONE  2014;9(3):e91620.
Gradient-echo echo-planar imaging (GE EPI) is the most commonly used approach to assess localized blood oxygen level dependent (BOLD) signal changes in real-time. Alternatively, real-time spin-echo single-voxel spectroscopy (SE SVS) has recently been introduced for spatially specific BOLD neurofeedback at 3 T and at 7 T. However, currently it is not known how neurofeedback based on real-time SE SVS compares to real-time GE EPI-based. We therefore compared both methods at high (3 T) and at ultra-high (7 T) magnetic field strengths. We evaluated standard quality measures of both methods for signals originating from the motor cortex, the visual cortex, and for a neurofeedback condition. At 3 T, the data quality of the real-time SE SVS and GE EPI R2* estimates were comparable. At 7 T, the data quality of the real-time GE EPI acquisitions was superior compared to those of the real-time SE SVS. Despite the somehow lower data quality of real-time SE SVS compared to GE EPI at 7 T, SE SVS acquisitions might still be an interesting alternative. Real-time SE SVS allows for a direct and subject-specific T2* estimation and thus for a physiologically more plausible neurofeedback signal.
PMCID: PMC3948886  PMID: 24614912
6.  Climate-Related Hazards: A Method for Global Assessment of Urban and Rural Population Exposure to Cyclones, Droughts, and Floods 
Global climate change (GCC) has led to increased focus on the occurrence of, and preparation for, climate-related extremes and hazards. Population exposure, the relative likelihood that a person in a given location was exposed to a given hazard event(s) in a given period of time, was the outcome for this analysis. Our objectives were to develop a method for estimating the population exposure at the country level to the climate-related hazards cyclone, drought, and flood; develop a method that readily allows the addition of better datasets to an automated model; differentiate population exposure of urban and rural populations; and calculate and present the results of exposure scores and ranking of countries based on the country-wide, urban, and rural population exposures to cyclone, drought, and flood. Gridded global datasets on cyclone, drought and flood occurrence as well as population density were combined and analysis was carried out using ArcGIS. Results presented include global maps of ranked country-level population exposure to cyclone, drought, flood and multiple hazards. Analyses by geography and human development index (HDI) are also included. The results and analyses of this exposure assessment have implications for country-level adaptation. It can also be used to help prioritize aid decisions and allocation of adaptation resources between countries and within a country. This model is designed to allow flexibility in applying cyclone, drought and flood exposure to a range of outcomes and adaptation measures.
PMCID: PMC3945591  PMID: 24566046
climate change; hazard events; exposure; ArcGIS; urban; rural; cyclone; drought; flood
7.  Single Voxel Proton Spectroscopy for Neurofeedback at 7 Tesla 
Materials  2011;4(9):10.3390/ma4091548.
Echo-planar imaging (EPI) in fMRI is regularly used to reveal BOLD activation in presubscribed regions of interest (ROI). The response is mediated by relative changes in T2* which appear as changes in the image pixel intensities. We have proposed an application of functional single-voxel proton spectroscopy (fSVPS) for real-time studies at ultra-high MR field which can be comparable to the EPI BOLD fMRI technique. A spin-echo SVPS protocol without water suppression was acquired with 310 repetitions on a 7T Siemens MR scanner (TE/TR = 20/1000 ms, flip angle α = 90°, voxel size 10 × 10 × 10 mm3). Transmitter reference voltage was optimized for the voxel location. Spectral processing of the water signal free induction decay (FID) using log-linear regression was used to estimate the T2* change between rest and activation of a functional task. The FID spectrum was filtered with a Gaussian window around the water peak, and log-linear regression was optimized for the particular ROI by adoption of the linearization length. The spectroscopic voxel was positioned on an ROI defined from a real-time fMRI EPI BOLD localizer. Additional online signal processing algorithms performed signal drift removal (exponential moving average), despiking and low-pass filtering (modified Kalman filter) and, finally, the dynamic feedback signal normalization. Two functional tasks were used to estimate the sensitivity of the SVPS method compared to BOLD signal changes, namely the primary motor cortex (PMC, left hand finger tapping) and visual cortex (VC, blinking checkerboard). Four healthy volunteers performed these tasks and an additional session using real-time signal feedback modulating their activation level of the PMC. Results show that single voxel spectroscopy is able to provide a good and reliable estimation of the BOLD signal changes. Small data size and FID signal processing instead of processing entire brain volumes as well as more information revealed from the acquired total water spectrum, i.e., direct estimation of the T2* values and B0 changes, make SVPS proton spectroscopy suitable and advantageous for real-time neurofeedback studies. Particular challenges of ultra-high field spectroscopy due to the non-linearity in the spectral information, e.g., poor main magnetic field homogeneity and the absence of motion correction for the SVPS sequence may lead to the special artifacts in the control signal which still need to be addressed. The contrast to noise ratio (CNR), experimental statistic (t-values) and percent signal change were used as quality parameters to estimate the method performance. The potential and challenges of the spectroscopic approach for fMRI studies needs to be further investigated.
PMCID: PMC3886242  PMID: 24416473
neurofeedback; signal processing; spectroscopy; imaging
8.  White matter organization and neurocognitive performance variability in schizophrenia 
Schizophrenia research  2012;143(1):172-178.
White matter alterations in schizophrenia are associated with deficits in neurocognitive performance. Recently, across task within-individual variability (WIV) has emerged as a useful construct for assessing the profile in cognitive performance in schizophrenia. However, the neural basis of WIV has not been studied in patients with schizophrenia.
Twenty-five patients with schizophrenia (SZ) and 27 healthy comparison subjects (HC) performed a computerized neurocognitive battery (CNB) and underwent diffusion tensor imaging (DTI). WIV for performance accuracy and speed on the CNB was calculated across-tasks. Voxel-wise group comparisons of white matter fractional anisotropy (FA) were performed using tract-based spatial statistics (TBSS). The relationship between accuracy and speed WIV on the CNB and white matter FA was examined within the regions that differentiated patients and healthy comparison subjects.
SZ had higher WIV for performance accuracy and speed as compared to HC. FA in SZ compared to HC was reduced in bilateral frontal, temporal and occipital white matter including a large portion of the corpus callosum. In white matter regions that differed between patients and comparison subjects, higher FA in the left cingulum bundle and left fronto-occipital fasciculus were associated with lower CNB speed WIV for HC, but not SZ. Accuracy WIV was not associated with differences in white matter FA between SZ and HC.
We provide evidence that WIV is greater in patients with SZ and that this greater within-individual variability in performance in patients is associated with disruptions of WM integrity in specific brain regions.
PMCID: PMC3540127  PMID: 23148898
diffusion tensor imaging; intraindividual variability; cognition; white matter
9.  An Improved Framework for Confound Regression and Filtering for Control of Motion Artifact in the Preprocessing of Resting-State Functional Connectivity Data 
NeuroImage  2012;64:10.1016/j.neuroimage.2012.08.052.
Several recent reports in large, independent samples have demonstrated the influence of motion artifact on resting-state functional connectivity MRI (rsfc-MRI). Standard rsfc-MRI preprocessing typically includes regression of confounding signals and band-pass filtering. However, substantial heterogeneity exists in how these techniques are implemented across studies, and no prior study has examined the effect of differing approaches for the control of motion-induced artifacts. To better understand how in-scanner head motion affects rsfc-MRI data, we describe the spatial, temporal, and spectral characteristics of motion artifacts in a sample of 348 adolescents. Analyses utilize a novel approach for describing head motion on a voxelwise basis. Next, we systematically evaluate the efficacy of a range of confound regression and filtering techniques for the control of motion-induced artifacts. Results reveal that the effectiveness of preprocessing procedures on the control of motion is heterogeneous, and that improved preprocessing provides a substantial benefit beyond typical procedures. These results demonstrate that the effect of motion on rsfc-MRI can be substantially attenuated through improved preprocessing procedures, but not completely removed.
PMCID: PMC3811142  PMID: 22926292
motion; artifact; fMRI; connectivity; development; adolescence; network; connectome; resting-state
10.  The Impact of Gabapentin Administration on Brain GABA and Glutamate Concentrations: A 7T 1H-MRS Study 
Neuropsychopharmacology  2012;37(13):2764-2771.
Gamma-aminobutyric acid (GABA) and glutamate are implicated in numerous neuropsychiatric and substance abuse conditions, but their spectral overlap with other resonances makes them a challenge to quantify in humans. Gabapentin, marketed for the treatment of seizures and neuropathic pain, has been shown to increase in vivo GABA concentration in the brain of both rodents and humans. Gabapentin effects on glutamate are not known. We conducted a gabapentin (900 mg) challenge in healthy human subjects to confirm and explore its effects on GABA and glutamate concentrations, respectively, and to test the ability of single voxel localized proton magnetic resonance spectroscopy (1H-MRS) to reliably measure GABA and glutamate in the visual cortex at the ultra-high magnetic field of 7 Tesla. Reproducibility of GABA and glutamate measurements was determined in a comparison group without drug twice within day and 2 weeks apart. Although GABA concentration changes were small both within day (average 5.6%) and between day (average 4.8%), gabapentin administration was associated with an average increase in GABA concentration of 55.7% (6.9–91.0%). Importantly, drug-induced change in GABA levels was inversely correlated to the individual's baseline GABA level (R2=0.72). Mean glutamate concentrations did not change significantly with or without drug administration. In conclusion, localized 1H-MRS at 7 Tesla can be successfully applied to the measurement of GABA concentration and is sensitive to acute drug-induced changes in cortical GABA. Whether baseline GABA concentrations predict clinical efficacy of gabapentin is an area worthy of exploration.
PMCID: PMC3499716  PMID: 22871916
gabapentin; 7 Tesla; γ-aminobutyric acid; GABA; glutamate; Glu; 1H-MRS; GABA; gabapentin; glutamate; imaging; clinical or preclinical; magnetic resonance spectroscopy; psychopharmacology; visual cortex
11.  3-Chloro-1-lithiopropene, a Functional Organolithium Reagent, and Its Reactions with Alkylboronates To Give 3-Alkylprop-1-en-3-ols 
The Journal of Organic Chemistry  2013;78(18):9526-9531.
The reagent 3-chloro-1-lithiopropene (4) can be generated by treating 1-bromo-3-chloropropene with t-BuLi. It is unstable but if generated at low temperature in the presence of alkylboronic esters, such as 3, is trapped in situ to give rearrangement products 2, which on oxidation give 3-alkylprop-1-en-3-ols in good yields. The reaction works for primary, secondary, benzylic, and even tertiary alkylboronic esters, providing allylic alcohols bearing almost any alkyl group available using organoborane chemistry and incorporating all features of such groups.
PMCID: PMC3806150  PMID: 24020427
12.  PET imaging to non-invasively study immune activation leading to antitumor responses with a 4-1BB agonistic antibody 
Molecular imaging with positron emission tomography (PET) may allow the non-invasive study of the pharmacodynamic effects of agonistic monoclonal antibodies (mAb) to 4-1BB (CD137). 4-1BB is a member of the tumor necrosis factor family expressed on activated T cells and other immune cells, and activating 4-1BB antibodies are being tested for the treatment of patients with advanced cancers.
We studied the antitumor activity of 4-1BB mAb therapy using [18 F]-labeled fluoro-2-deoxy-2-D-glucose ([18 F]FDG) microPET scanning in a mouse model of colon cancer. Results of microPET imaging were correlated with morphological changes in tumors, draining lymph nodes as well as cell subset uptake of the metabolic PET tracer in vitro.
The administration of 4-1BB mAb to Balb/c mice induced reproducible CT26 tumor regressions and improved survival; complete tumor shrinkage was achieved in the majority of mice. There was markedly increased [18 F]FDG signal at the tumor site and draining lymph nodes. In a metabolic probe in vitro uptake assay, there was an 8-fold increase in uptake of [3H]DDG in leukocytes extracted from tumors and draining lymph nodes of mice treated with 4-1BB mAb compared to untreated mice, supporting the in vivo PET data.
Increased uptake of [18 F]FDG by PET scans visualizes 4-1BB agonistic antibody-induced antitumor immune responses and can be used as a pharmacodynamic readout to guide the development of this class of antibodies in the clinic.
PMCID: PMC4019904  PMID: 24829750
4-1BB; CD137; Immune activating antibodies; PET imaging; Colon cancer
13.  Impact of In-Scanner Head Motion on Multiple Measures of Functional Connectivity: Relevance for Studies of Neurodevelopment in Youth 
NeuroImage  2012;60(1):623-632.
It has recently been reported (Van Dijk et al., 2011) that in-scanner head motion can have a substantial impact on MRI measurements of resting-state functional connectivity. This finding may be of particular relevance for studies of neurodevelopment in youth, confounding analyses to the extent that motion and subject age are related. Furthermore, while Van Dijk et al. demonstrated the effect of motion on seed-based connectivity analyses, it is not known how motion impacts other common measures of connectivity. Here we expand on the findings of Van Dijk et al. by examining the effect of motion on multiple types of resting-state connectivity analyses in a large sample of children and adolescents (n=456). Following replication of the effect of motion on seed-based analyses, we examine the influence of motion on graphical measures of network modularity, dual-regression of independent component analysis, as well as the amplitude and fractional amplitude of low frequency fluctuation. In the entire sample, subject age was highly related to motion. Using a subsample where age and motion were unrelated, we demonstrate that motion has marked effects on connectivity in every analysis examined. While subject age was associated with increased within-network connectivity even when motion was accounted for, controlling for motion substantially attenuated the strength of this relationship. The results demonstrate the pervasive influence of motion on multiple types functional connectivity analysis, and underline the importance of accounting for motion in studies of neurodevelopment.
PMCID: PMC3746318  PMID: 22233733
fMRI; connectivity; network; independent component analysis; fALFF; development; adolescent
14.  (E)-2-(1,1-Di­cyclo­hexyl-3-phenyl­all­yl)-5,5-dimethyl-1,3,2-dioxaborinane 
The crystal structure of the title compound, C26H39BO2, which contains no strong hydrogen bond donors, displays only long C—H⋯O contacts between inversion-related pairs of mol­ecules. The structure contains layers rich in oxygen and boron parallel to the ac plane. The dioxaborinane ring adopts an envelope conformation with the C atom attached to the two methyl groups as the flap .
PMCID: PMC3884414  PMID: 24427041
15.  Being Right Is Its Own Reward: Load and Performance Related Ventral Striatum Activation to Correct Responses During a Working Memory Task in Youth 
Neuroimage  2012;61(3):723-729.
The ventral striatum (VS) is a critical brain region for reinforcement learning and motivation. Intrinsically motivated subjects performing challenging cognitive tasks engage reinforcement circuitry including VS even in the absence of external feedback or incentives. However, little is known about how such VS responses develop with age, relate to task performance, and are influenced by task difficulty. Here we used fMRI to examine VS activation to correct and incorrect responses during a standard n-back working memory task in a large sample (n= 304) of healthy children, adolescents and young adults aged 8–22. We found that bilateral VS activates more strongly to correct than incorrect responses, and that the VS response scales with the difficulty of the working memory task. Furthermore, VS response was correlated with discrimination performance during the task, and the magnitude of VS response peaked in mid-adolescence. These findings provide evidence for scalable intrinsic reinforcement signals during standard cognitive tasks, and suggest a novel link between motivation and cognition during adolescent development.
PMCID: PMC3358426  PMID: 22484308
Ventral striatum; working memory; adolescence; reward; motivation
16.  On Disturbed Time Continuity in Schizophrenia: An Elementary Impairment in Visual Perception? 
Schizophrenia is associated with a series of visual perception impairments, which might impact on the patients’ every day life and be related to clinical symptoms. However, the heterogeneity of the visual disorders make it a challenge to understand both the mechanisms and the consequences of these impairments, i.e., the way patients experience the outer world. Based on earlier psychiatry literature, we argue that issues regarding time might shed a new light on the disorders observed in patients with schizophrenia. We will briefly review the mechanisms involved in the sense of time continuity and clinical evidence that they are impaired in patients with schizophrenia. We will then summarize a recent experimental approach regarding the coding of time-event structure in time, namely the ability to discriminate between simultaneous and asynchronous events. The use of an original method of analysis allowed us to distinguish between explicit and implicit judgments of synchrony. We showed that for SOAs below 20 ms neither patients nor controls fuse events in time. On the contrary subjects distinguish events at an implicit level even when judging them as synchronous. In addition, the implicit responses of patients and controls differ qualitatively. It is as if controls always put more weight on the last occurred event, whereas patients have a difficulty to follow events in time at an implicit level. In patients, there is a clear dissociation between results at short and large asynchronies, that suggest selective mechanisms for the implicit coding of time-event structure. These results might explain the disruption of the sense of time continuity in patients. We argue that this line of research might also help us to better understand the mechanisms of the visual impairments in patients and how they see their environment.
PMCID: PMC3664782  PMID: 23755027
schizophrenia; time; anticipation; synchrony; attention; implicit processing; Simon effect
17.  The oscillatory entrainment of virtual pitch perception 
Evidence suggests that synchronized brain oscillations in the low gamma range (around 33 Hz) are involved in the perceptual integration of harmonic complex tones. This process involves the binding of harmonic components into “harmonic templates” – neural structures responsible for pitch coding in the brain. We investigated the hypothesis that oscillatory harmonic binding promotes a change in pitch perception style from spectral (frequency) to virtual (relational). Using oscillatory priming we asked 24 participants to judge as rapidly as possible, the direction of an ambiguous target with ascending spectral and descending virtual contour. They made significantly more virtual responses when primed at 29, 31, and 33 Hz and when the first target tone was harmonically related to the prime, suggesting that neural synchronization in the low gamma range could facilitate a shift toward virtual pitch processing.
PMCID: PMC3635022  PMID: 23630515
gamma-band; virtual pitch; pitch perception; pitch coding; harmonic templates; oscillatory priming
18.  Structural Imbalance Promotes Behavior Analogous to Aesthetic Preference in Domestic Chicks 
PLoS ONE  2012;7(8):e43029.
Visual images may be judged ‘aesthetic’ when their positioning appears imbalanced. An apparent imbalance may signify an as yet incomplete action or event requiring more detailed processing. As such it may refer to phylogenetically ancient stimulus-response mechanisms such as those mediating attentional deployment.
Methodology/Principal Findings
We studied preferences for structural balance or imbalance in week-old domestic chicks (Gallus gallus), using a conditioning procedure to reinforce pecking at either “aligned” (balanced) or “misaligned” (imbalanced) training stimuli. A testing phase with novel balanced and imbalanced stimuli established whether chicks would retain their conditioned behavior or revert to chance responding. Whereas those trained on aligned stimuli were equally likely to choose aligned or misaligned stimuli, chicks trained on misaligned stimuli maintained the trained preference.
Our results are consistent with the idea that the coding of structural imbalance is primary and even overrides classical conditioning. Generalized to the humans, these results suggest aesthetic judgments based upon structural imbalance may be based on evolutionarily ancient mechanisms, which are shared by different vertebrate species.
PMCID: PMC3419233  PMID: 22905198
19.  Opposing Amygdala and Ventral Striatum Connectivity During Emotion Identification 
Brain and cognition  2011;76(3):353-363.
Lesion and electrophysiological studies in animals provide evidence of opposing functions for subcortical nuclei such as the amygdala and ventral striatum, but the implications of these findings for emotion identification in humans remain poorly described. Here we report a high-resolution fMRI study in a sample of 39 healthy subjects who performed a well-characterized emotion identification task. As expected, the amygdala responded to THREAT (angry or fearful) faces more than NON-THREAT (sad or happy) faces. A functional connectivity analysis of the time series from an anatomically defined amygdala seed revealed a strong anti-correlation between the amygdala and the ventral striatum /ventral pallidum, consistent with an opposing role for these regions in during emotion identification. A second functional connectivity analysis (psychophysiological interaction) investigating relative connectivity on THREAT vs. NON-THREAT trials demonstrated that the amygdala had increased connectivity with the orbitofrontal cortex during THREAT trials, whereas the ventral striatum demonstrated increased connectivity with the posterior hippocampus on NON-THREAT trials. These results indicate that activity in the amygdala and ventral striatum may be inversely related, and that both regions may provide opposing affective bias signals during emotion identification.
PMCID: PMC3147143  PMID: 21600684
emotion; amygdala; ventral striatum; fMRI; faces; connectivity
20.  A botulinum toxin–derived targeted secretion inhibitor downregulates the GH/IGF1 axis 
The Journal of Clinical Investigation  2012;122(9):3295-3306.
Botulinum neurotoxins (BoNTs) are zinc endopeptidases that block release of the neurotransmitter acetylcholine in neuromuscular synapses through cleavage of soluble N-ethylmaleimide-sensitive fusion (NSF) attachment protein receptor (SNARE) proteins, which promote fusion of synaptic vesicles to the plasma membrane. We designed and tested a BoNT-derived targeted secretion inhibitor (TSI) targeting pituitary somatotroph cells to suppress growth hormone (GH) secretion and treat acromegaly. This recombinant protein, called SXN101742, contains a modified GH-releasing hormone (GHRH) domain and the endopeptidase domain of botulinum toxin serotype D (GHRH-LHN/D, where HN/D indicates endopeptidase and translocation domain type D). In vitro, SXN101742 targeted the GHRH receptor and depleted a SNARE protein involved in GH exocytosis, vesicle-associated membrane protein 2 (VAMP2). In vivo, administering SXN101742 to growing rats produced a dose-dependent inhibition of GH synthesis, storage, and secretion. Consequently, hepatic IGF1 production and resultant circulating IGF1 levels were reduced. Accordingly, body weight, body length, organ weight, and bone mass acquisition were all decreased, reflecting the biological impact of SXN101742 on the GH/IGF1 axis. An inactivating 2–amino acid substitution within the zinc coordination site of the endopeptidase domain completely abolished SXN101742 inhibitory actions on GH and IGF1. Thus, genetically reengineered BoNTs can be targeted to nonneural cells to selectively inhibit hormone secretion, representing a new approach to treating hormonal excess.
PMCID: PMC3428092  PMID: 22850878
21.  Predicting active school travel: The role of planned behavior and habit strength 
Despite strong support for predictive validity of the theory of planned behavior (TPB) substantial variance in both intention and behavior is unaccounted for by the model’s predictors. The present study tested the extent to which habit strength augments the predictive validity of the TPB in relation to a currently under-researched behavior that has important health implications, namely children’s active school travel.
Participants (N = 126 children aged 8–9 years; 59 % males) were sampled from five elementary schools in the west of Scotland and completed questionnaire measures of all TPB constructs in relation to walking to school and both walking and car/bus use habit. Over the subsequent week, commuting steps on school journeys were measured objectively using an accelerometer. Hierarchical multiple regressions were used to test the predictive utility of the TPB and habit strength in relation to both intention and subsequent behavior.
The TPB accounted for 41 % and 10 % of the variance in intention and objectively measured behavior, respectively. Together, walking habit and car/bus habit significantly increased the proportion of explained variance in both intention and behavior by 6 %. Perceived behavioral control and both walking and car/bus habit independently predicted intention. Intention and car/bus habit independently predicted behavior.
The TPB significantly predicts children’s active school travel. However, habit strength augments the predictive validity of the model. The results indicate that school travel is controlled by both intentional and habitual processes. In practice, interventions could usefully decrease the habitual use of motorized transport for travel to school and increase children’s intention to walk (via increases in perceived behavioral control and walking habit, and decreases in car/bus habit). Further research is needed to identify effective strategies for changing these antecedents of children’s active school travel.
PMCID: PMC3419676  PMID: 22647194
Theory of planned behavior; Habit; Active school travel; Walking; Children
22.  A Summary Catalogue of Microbial Drinking Water Tests for Low and Medium Resource Settings 
Microbial drinking-water quality testing plays an essential role in measures to protect public health. However, such testing remains a significant challenge where resources are limited. With a wide variety of tests available, researchers and practitioners have expressed difficulties in selecting the most appropriate test(s) for a particular budget, application and setting. To assist the selection process we identified the characteristics associated with low and medium resource settings and we specified the basic information that is needed for different forms of water quality monitoring. We then searched for available faecal indicator bacteria tests and collated this information. In total 44 tests have been identified, 18 of which yield a presence/absence result and 26 of which provide enumeration of bacterial concentration. The suitability of each test is assessed for use in the three settings. The cost per test was found to vary from $0.60 to $5.00 for a presence/absence test and from $0.50 to $7.50 for a quantitative format, though it is likely to be only a small component of the overall costs of testing. This article presents the first comprehensive catalogue of the characteristics of available and emerging low-cost tests for faecal indicator bacteria. It will be of value to organizations responsible for monitoring national water quality, water service providers, researchers and policy makers in selecting water quality tests appropriate for a given setting and application.
PMCID: PMC3386575  PMID: 22754460
drinking-water quality; safe water; microbial water testing; faecal indicator bacteria; Escherichia coli; coliform test; H2S test
23.  Enhanced Visual Temporal Resolution in Autism Spectrum Disorders 
PLoS ONE  2012;7(3):e32774.
Cognitive functions that rely on accurate sequencing of events, such as action planning and execution, verbal and nonverbal communication, and social interaction rely on well-tuned coding of temporal event-structure. Visual temporal event-structure coding was tested in 17 high-functioning adolescents and adults with autism spectrum disorder (ASD) and mental- and chronological-age matched typically-developing (TD) individuals using a perceptual simultaneity paradigm. Visual simultaneity thresholds were lower in individuals with ASD compared to TD individuals, suggesting that autism may be characterised by increased parsing of temporal event-structure, with a decreased capability for integration over time. Lower perceptual simultaneity thresholds in ASD were also related to increased developmental communication difficulties. These results are linked to detail-focussed and local processing bias.
PMCID: PMC3309999  PMID: 22470425
24.  The Dynamics of Visual Experience, an EEG Study of Subjective Pattern Formation 
PLoS ONE  2012;7(1):e30830.
Since the origin of psychological science a number of studies have reported visual pattern formation in the absence of either physiological stimulation or direct visual-spatial references. Subjective patterns range from simple phosphenes to complex patterns but are highly specific and reported reliably across studies.
Methodology/Principal Findings
Using independent-component analysis (ICA) we report a reduction in amplitude variance consistent with subjective-pattern formation in ventral posterior areas of the electroencephalogram (EEG). The EEG exhibits significantly increased power at delta/theta and gamma-frequencies (point and circle patterns) or a series of high-frequency harmonics of a delta oscillation (spiral patterns).
Subjective-pattern formation may be described in a way entirely consistent with identical pattern formation in fluids or granular flows. In this manner, we propose subjective-pattern structure to be represented within a spatio-temporal lattice of harmonic oscillations which bind topographically organized visual-neuronal assemblies by virtue of low frequency modulation.
PMCID: PMC3266910  PMID: 22292053
25.  Ventrolateral prefrontal cortex and the effects of task demand context on facial affect appraisal in schizophrenia 
Schizophrenia patients display impaired performance and brain activity during facial affect recognition. These impairments may reflect stimulus-driven perceptual decrements and evaluative processing abnormalities. We differentiated these two processes by contrasting responses to identical stimuli presented under different contexts. Seventeen healthy controls and 16 schizophrenia patients performed an fMRI facial affect detection task. Subjects identified an affective target presented amongst foils of differing emotions. We hypothesized that targeting affiliative emotions (happiness, sadness) would create a task demand context distinct from that generated when targeting threat emotions (anger, fear). We compared affiliative foil stimuli within a congruent affiliative context with identical stimuli presented in an incongruent threat context. Threat foils were analysed in the same manner. Controls activated right orbitofrontal cortex (OFC)/ventrolateral prefrontal cortex (VLPFC) more to affiliative foils in threat contexts than to identical stimuli within affiliative contexts. Patients displayed reduced OFC/VLPFC activation to all foils, and no activation modulation by context. This lack of context modulation coincided with a 2-fold decrement in foil detection efficiency. Task demands produce contextual effects during facial affective processing in regions activated during affect evaluation. In schizophrenia, reduced modulation of OFC/VLPFC by context coupled with reduced behavioural efficiency suggests impaired ventral prefrontal control mechanisms that optimize affective appraisal.
PMCID: PMC3023083  PMID: 20212004
schizophrenia; social cognition; face; emotion; amygdala; ventrolateral prefrontal cortex (VLPFC); orbitofrontal cortex (OFC); fMRI

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