Patients with schizophrenia improve episodic memory accuracy when given organizational strategies through levels-of-processing paradigms. This study tested if improvement is accompanied by normalized frontotemporal function.
Event-related blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI) was used to measure activation during shallow (perceptual) and deep (semantic) word encoding and recognition in 14 patients with schizophrenia and 14 healthy comparison subjects.
Despite slower and less accurate overall word classification, the patients showed normal levels-of-processing effects, with faster and more accurate recognition of deeply processed words. These effects were accompanied by left ventrolateral prefrontal activation during encoding in both groups, although the thalamus, hippocampus, and lingual gyrus were overactivated in the patients. During word recognition, the patients showed overactivation in the left frontal pole and had a less robust right prefrontal response.
Evidence of normal levels-of-processing effects and left prefrontal activation suggests that patients with schizophrenia can form and maintain semantic representations when they are provided with organizational cues and can improve their word encoding and retrieval. Areas of overactivation suggest residual inefficiencies. Nevertheless, the effect of teaching organizational strategies on episodic memory and brain function is a worthwhile topic for future interventional studies.
Neuropsychological studies have demonstrated verbal episodic memory deficits in schizophrenia during word encoding and retrieval. This study examined neural substrates of memory in an analysis that controlled for successful retrieval.
Event-related blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to measure brain activation during word encoding and recognition in 14 patients with schizophrenia and 15 healthy comparison subjects. An unbiased multiple linear regression procedure was used to model the BOLD response, and task effects were detected by contrasting the signal before and after stimulus onset.
Patients attended during encoding and had unimpaired reaction times and normal response biases during recognition, but they had lower recognition discriminability scores, compared with the healthy subjects. Analysis of contrasts was restricted to correct items. Previous findings of a deficit in bilateral prefrontal cortex activation during encoding in patients were reproduced, but patients showed greater parahippocampal activation rather than deficits in temporal lobe activation. During recognition, left dorsolateral pre-frontal cortex activation was lower in the patients and right anterior prefrontal cortex activation was preserved, as in the authors’ previous study using positron emission tomography. Successful retrieval was associated with greater right dorsolateral prefrontal cortex activation in the comparison subjects, whereas orbitofrontal, superior frontal, mesial temporal, middle temporal, and inferior parietal regions were more active in the patients during successful retrieval.
The pattern of prefrontal cortex underactivation and parahippocampal overactivation in the patients suggests that functional connectivity of dorsolateral prefrontal and temporal-limbic structures is disrupted by schizophrenia. This disruption may be reflected in the memory strategies of patients with schizophrenia, which include reliance on rote rehearsal rather than associative semantic processing.
Safe drinking water and sanitation are important determinants of human health and wellbeing and have recently been declared human rights by the international community. Increased access to both were included in the Millennium Development Goals under a single dedicated target for 2015. This target was reached in 2010 for water but sanitation will fall short; however, there is an important difference in the benchmarks used for assessing global access. For drinking water the benchmark is community-level access whilst for sanitation it is household-level access, so a pit latrine shared between households does not count toward the Millennium Development Goal (MDG) target. We estimated global progress for water and sanitation under two scenarios: with equivalent household- and community-level benchmarks. Our results demonstrate that the “sanitation deficit” is apparent only when household-level sanitation access is contrasted with community-level water access. When equivalent benchmarks are used for water and sanitation, the global deficit is as great for water as it is for sanitation, and sanitation progress in the MDG-period (1990–2015) outstrips that in water. As both drinking water and sanitation access yield greater benefits at the household-level than at the community-level, we conclude that any post–2015 goals should consider a household-level benchmark for both.
Several independent studies have demonstrated that small amounts of in-scanner motion systematically bias estimates of resting-state functional connectivity. This confound is of particular importance for studies of neurodevelopment in youth because motion is strongly related to subject age during this period. Critically, the effects of motion on connectivity mimic major findings in neurodevelopmental research, specifically an age-related strengthening of distant connections and weakening of short-range connections. Here, in a sample of 780 subjects ages 8–22, we re-evaluate patterns of change in functional connectivity during adolescent development after rigorously controlling for the confounding influences of motion at both the subject and group level. We find that motion artifact inflates both overall estimates of age-related change as well as specific distance-related changes in connectivity. When motion is more fully accounted for, the prevalence of age-related change as well as the strength of distance-related effects is substantially reduced. However, age-related changes remain highly significant. In contrast, motion artifact tends to obscure age-related changes in connectivity associated with segregation of functional brain modules; improved preprocessing techniques allow greater sensitivity to detect increased within-module connectivity occurring with development. Finally, we show that subject’s age can still be accurately estimated from the multivariate pattern of functional connectivity even while controlling for motion. Taken together, these results indicate that while motion artifact has a marked and heterogeneous impact on estimates of connectivity change during adolescence, functional connectivity remains a valuable phenotype for the study of neurodevelopment.
motion artifact; fMRI; connectivity; development; adolescence; network; connectome; resting-state
Increased small airway resistance and decreased lung elasticity contribute to the airflow limitation in chronic obstructive pulmonary disease (COPD). The lesion that corresponds to loss of lung elasticity is emphysema; the small airway obstruction is due to inflammatory narrowing and obliteration. Despite their convergence in altered physiology, different mechanisms contribute to these processes. The relationships between gene expression and these specific phenotypes may be more revealing than comparison with lung function.
We measured the ratio of alveolar surface area to lung volume (SA/V) in lung tissue from 43 smokers. Two samples from 21 subjects, in which SA/V differed by >49 cm2/mL were profiled to select genes whose expression correlated with SA/V. Significant genes were tested for replication in the 22 remaining subjects.
The level of expression of 181 transcripts was related to SA/V ( p < 0.05). When these genes were tested in the 22 remaining subjects as a replication, thirty of the 181 genes remained significantly associated with SA/V (P < 0.05) and the direction of association was the same in 164/181. Pathway and network analysis revealed enrichment of genes involved in protein ubiquitination, and western blotting showed altered expression of genes involved in protein ubiquitination in obstructed individuals.
This study implicates modified protein ubiquitination and degradation as a potentially important pathway in the pathogenesis of emphysema.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2466-14-187) contains supplementary material, which is available to authorized users.
Pulmonary emphysema; Surface area to lung volume ratio; Gene expression; Transcriptional analysis; mRNA; Cigarette smoking; Protein ubquitination
Synchronization of spatially distributed neural assemblies at frequencies in the range 30–70 Hz (the “gamma” band) may be instrumental in grouping stimulus features. In agreement with this we have shown that detection reaction times to a grouping target stimulus are expedited when the stimulus is preceded by repeated presentation of a priming stimulus, presented below detection thresholds in a matrix that flickers at particular frequencies in the 27–68 Hz range. This dynamic priming effect can be partly explained as a function of the return phase of the priming stimulus relative to the premask matrix, indicating one of the primary consequences of repeating stimulation is pre-activation of a priming response relative to prime-stimulus presentation. However, this cannot entirely explain the relationship that develops between the timing of stimulus events (in this instance the time of target relative to priming-stimulus presentations) and response. By varying the frequency and phase of priming-stimulus and target presentations we discovered that given a particular relationship between the phase of target presentation relative to the return phase of the prime, target coding is expedited by a prime that achieves its maximum activation at a phase that would precede priming-stimulus presentation by several tens of milliseconds. However, and in addition, the cognition concerned is flexible enough to be able to achieve an identical prime retroactively, that is to say at a phase during or subsequent to priming-stimulus presentation. This occurs because of a different relationship between the phase of target presentation (defined relative to prime frequency) and the frequency of premask-matrix presentation. On this basis, it can be concluded that by virtue of the relationship between its dynamics and the timing of stimulus events, microstructural cognition functions in a temporal context that can shift from past to future states. Consequently and at the lowest level of psychological function, the conventional, one-dimensional model of time flow—from future to past states does not fully explain how cognition can function. In fact depending upon the interaction in phase between different coding frequencies, the same form of cognition can anticipate or retroactively code events. Consequently, and in so far as our cognition at this level provides a content structure for consciousness, our psychological lives may be fundamentally based upon the ability of our cognitive states to travel backwards and forwards across very short intervals of time.
oscillatory synchronization; gamma band; pro- and retroactive microcognition; protention; visual-event coding
Glutamate (Glu) is the most abundant excitatory neurotransmitter in the brain and spinal cord. The concentration of Glu is altered in a range of neurologic disorders that affect the spinal cord including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and spinal cord injury. Currently available magnetic resonance spectroscopy (MRS) methods for measuring Glu are limited to low spatial resolution, which makes it difficult to measure differences in gray and white matter glutamate. Recently, it has been shown that Glu exhibits a concentration dependent chemical exchange saturation transfer (CEST) effect between its amine (−NH2) and bulk water protons (GluCEST). Here, we demonstrate the feasibility of imaging glutamate in the spinal cord at 7T using the GluCEST technique. Results from healthy human volunteers (N=7) showed a significantly higher (p<0.001) GluCESTasym from gray matter (6.6 ± 0.3%) compared to white matter (4.8 ± 0.4%). Potential overlap of CEST signals from other spinal cord metabolites with the observed GluCESTasym is discussed. This noninvasive approach potentially opens the way to image Glu in vivo in the spinal cord and to monitor its alteration in many disease conditions.
Chemical Exchange Saturation Transfer; Glutamate; Spinal Cord; MRI
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.
movement synchronization; Bayesian inference; sensory integration; motor timing
Although small, rural water supplies may present elevated microbial risks to consumers in some settings, characterizing exposures through representative point-of-consumption sampling is logistically challenging. In order to evaluate the usefulness of consumer self-reported data in predicting measured water quality and risk factors for contamination, we compared matched consumer interview data with point-of-survey, household water quality and pressure data for 910 households served by 14 small water systems in rural Alabama. Participating households completed one survey that included detailed feedback on two key areas of water service conditions: delivery conditions (intermittent service and low water pressure) and general aesthetic characteristics (taste, odor and color), providing five condition values. Microbial water samples were taken at the point-of-use (from kitchen faucets) and as-delivered from the distribution network (from outside flame-sterilized taps, if available), where pressure was also measured. Water samples were analyzed for free and total chlorine, pH, turbidity, and presence of total coliforms and Escherichia coli. Of the 910 households surveyed, 35% of participants reported experiencing low water pressure, 15% reported intermittent service, and almost 20% reported aesthetic problems (taste, odor or color). Consumer-reported low pressure was associated with lower gauge-measured pressure at taps. While total coliforms (TC) were detected in 17% of outside tap samples and 12% of samples from kitchen faucets, no reported water service conditions or aesthetic characteristics were associated with presence of TC. We conclude that consumer-reported data were of limited utility in predicting potential microbial risks associated with small water supplies in this setting, although consumer feedback on low pressure—a risk factor for contamination—may be relatively reliable and therefore useful in future monitoring efforts.
small water supply; rural; water quality; perceived service; drinking water quality; infrastructure; environmental health
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.
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.
pharmacological fMRI; benzodiazepine; endophenotype; amygdala; facial emotion; GABA; schizophrenia
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.
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.
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.
climate change; hazard events; exposure; ArcGIS; urban; rural; cyclone; drought; flood
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.
neurofeedback; signal processing; spectroscopy; imaging
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.
diffusion tensor imaging; intraindividual variability; cognition; white matter
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.
motion; artifact; fMRI; connectivity; development; adolescence; network; connectome; resting-state
Humans can synchronize movements with auditory beats or rhythms without apparent effort. This ability to entrain to the beat is considered automatic, such that any perturbations are corrected for, even if the perturbation was not consciously noted. Temporal correction of upper limb (e.g., finger tapping) and lower limb (e.g., stepping) movements to a phase perturbed auditory beat usually results in individuals being back in phase after just a few beats. When a metronome is presented in more than one sensory modality, a multisensory advantage is observed, with reduced temporal variability in finger tapping movements compared to unimodal conditions. Here, we investigate synchronization of lower limb movements (stepping in place) to auditory, visual and combined auditory-visual (AV) metronome cues. In addition, we compare movement corrections to phase advance and phase delay perturbations in the metronome for the three sensory modality conditions. We hypothesized that, as with upper limb movements, there would be a multisensory advantage, with stepping variability being lowest in the bimodal condition. As such, we further expected correction to the phase perturbation to be quickest in the bimodal condition. Our results revealed lower variability in the asynchronies between foot strikes and the metronome beats in the bimodal condition, compared to unimodal conditions. However, while participants corrected substantially quicker to perturbations in auditory compared to visual metronomes, there was no multisensory advantage in the phase correction task—correction under the bimodal condition was almost identical to the auditory-only (AO) condition. On the whole, we noted that corrections in the stepping task were smaller than those previously reported for finger tapping studies. We conclude that temporal corrections are not only affected by the reliability of the sensory information, but also the complexity of the movement itself.
sensorimotor synchronization; multisensory integration; movement synchronization; modality effects; timing; phase correction; stepping; gait
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.
gabapentin; 7 Tesla; γ-aminobutyric acid; GABA; glutamate; Glu; 1H-MRS; GABA; gabapentin; glutamate; imaging; clinical or preclinical; magnetic resonance spectroscopy; psychopharmacology; visual cortex
The reagent 3-chloro-1-lithiopropene
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.
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.
4-1BB; CD137; Immune activating antibodies; PET imaging; Colon cancer
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.
fMRI; connectivity; network; independent component analysis; fALFF; development; adolescent
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 .
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.
Ventral striatum; working memory; adolescence; reward; motivation