Topographic non-invasive near infrared spectroscopy (NIRS) has become a well-established tool for functional brain imaging. Applying up to 100 optodes over the head of a subject, allows achieving a ...spatial resolution in the centimeter range. This resolution is poor compared to other functional imaging tools.
However, recently it was shown that diffuse optical tomography (DOT) as an extension of NIRS based on high-density (HD) probe arrays and supplemented by an advanced image reconstruction procedure allows describing activation patterns with a spatial resolution in the millimeter range. Building on these findings, we hypothesize that HD-DOT may render very focal activations accessible which would be missed by the traditionally used sparse arrays.
We examined activation patterns in the primary somatosensory cortex, since its somatotopic organization is very fine-grained. We performed a vibrotactile stimulation study of the first and fifth finger in eight human subjects, using a 900-channel continuous-wave DOT imaging system for achieving a higher resolution than conventional topographic NIRS. To compare the results to a well-established high-resolution imaging technique, the same paradigm was investigated in the same subjects by means of functional magnetic resonance imaging (fMRI).
In this work, we tested the advantage of ultrahigh-density probe arrays and show that highly focal activations would be missed by classical next-nearest neighbor NIRS approach, but also by DOT, when using a sparse probe array. Distinct activation patterns for both fingers correlated well with the expected neuroanatomy in five of eight subjects. Additionally we show that activation for different fingers is projected to different tissue depths in the DOT image. Comparison to the fMRI data yielded similar activation foci in seven out of ten finger representations in these five subjects when comparing the lateral localization of DOT and fMRI results.
► Ultrahigh-density DOT can resolve cortical activation in the millimeter range. ► Highly focal activations can be missed by classical NIRS and conventional DOT. ► Ultrahigh-density DOT and fMRI have comparable acces to cortical activation.
BACKGROUND: Prediction of poststroke outcome using the degree of subacute deficit or magnetic resonance imaging is well studied in humans. While mice are the most commonly used animals in preclinical ...stroke research, systematic analysis of outcome predictors is lacking. METHODS: We intended to incorporate heterogeneity into our retrospective study to broaden the applicability of our findings and prediction tools. We therefore analyzed the effect of 30, 45, and 60 minutes of arterial occlusion on the variance of stroke volumes. Next, we built a heterogeneous cohort of 215 mice using data from 15 studies that included 45 minutes of middle cerebral artery occlusion and various genotypes. Motor function was measured using a modified protocol for the staircase test of skilled reaching. Phases of subacute and residual deficit were defined. Magnetic resonance images of stroke lesions were coregistered on the Allen Mouse Brain Atlas to characterize stroke topology. Different random forest prediction models that either used motor-functional deficit or imaging parameters were generated for the subacute and residual deficits. RESULTS: Variance of stroke volumes was increased by 45 minutes of arterial occlusion compared with 60 minutes. The inclusion of various genotypes enhanced heterogeneity further. We detected both a subacute and residual motor-functional deficit after stroke in mice and different recovery trajectories could be observed. In mice with small cortical lesions, lesion volume was the best predictor of the subacute deficit. The residual deficit could be predicted most accurately by the degree of the subacute deficit. When using imaging parameters for the prediction of the residual deficit, including information about the lesion topology increased prediction accuracy. A subset of anatomic regions within the ischemic lesion had particular impact on the prediction of long-term outcomes. Prediction accuracy depended on the degree of functional impairment. CONCLUSIONS: For the first time, we developed and validated a robust tool for the prediction of functional outcomes after experimental stroke in mice using a large and genetically heterogeneous cohort. These results are discussed in light of study design and imaging limitations. In the future, using outcome prediction can improve the design of preclinical studies and guide intervention decisions.
Summary: Systematic analysis of stroke outcome predictors in mice is lacking. We developed a tool to predict late pellet reaching performance based on early stroke localization in a diverse cohort of 215 mice.
A prompt behavioral response to a stimulus depends both on the salience of the stimulus as well as the subject's preparedness. Thus, both stimulus properties and cognitive factors, such as attention, ...may determine the strength of neuronal synchronization in the gamma range. For a comprehensive investigation of stimulus-response processing through noninvasive imaging, it is, however, a crucial issue whether both kinds of gamma modulation elicit a hemodynamic response. Here, we show that, in the human visual cortex, stimulus strength and internal state modulate sustained gamma activity and hemodynamic response in close correspondence. When participants reported velocity changes of gratings varying in contrast, gamma activity (35-70 Hz) increased systematically with contrast. For stimuli of constant contrast, the amplitude of gamma activity before the behaviorally relevant velocity change was inversely correlated to the behavioral response latency. This indicates that gamma activity also reflects an overall attentive state. For both sources of variance, gamma activity was tightly coupled to the hemodynamic response measured through optical topography. Because of the close relationship between high-frequency neuronal activity and the hemodynamic signal, we conclude that both stimulus-induced and state-dependent gamma activity trigger a metabolic demand and are amenable to vascular-based imaging.
In detoxified alcohol‐dependent patients, alcohol‐related stimuli can promote relapse. However, to date, the mechanisms by which contextual stimuli promote relapse have not been elucidated in detail. ...One hypothesis is that such contextual stimuli directly stimulate the motivation to drink via associated brain regions like the ventral striatum and thus promote alcohol seeking, intake and relapse. Pavlovian‐to‐Instrumental‐Transfer (PIT) may be one of those behavioral phenomena contributing to relapse, capturing how Pavlovian conditioned (contextual) cues determine instrumental behavior (e.g. alcohol seeking and intake). We used a PIT paradigm during functional magnetic resonance imaging to examine the effects of classically conditioned Pavlovian stimuli on instrumental choices in n = 31 detoxified patients diagnosed with alcohol dependence and n = 24 healthy controls matched for age and gender. Patients were followed up over a period of 3 months. We observed that (1) there was a significant behavioral PIT effect for all participants, which was significantly more pronounced in alcohol‐dependent patients; (2) PIT was significantly associated with blood oxygen level‐dependent (BOLD) signals in the nucleus accumbens (NAcc) in subsequent relapsers only; and (3) PIT‐related NAcc activation was associated with, and predictive of, critical outcomes (amount of alcohol intake and relapse during a 3 months follow‐up period) in alcohol‐dependent patients. These observations show for the first time that PIT‐related BOLD signals, as a measure of the influence of Pavlovian cues on instrumental behavior, predict alcohol intake and relapse in alcohol dependence.
To date mechanisms by which contextual stimuli promote relapse in detoxified alcohol‐dependent patients have not been elucidated. One hypothesis is that contextual stimuli stimulate the motivation to drink (Pavlovian‐to‐Instrumental‐Transfer; PIT) via associated brain regions like the ventral striatum and thus promote relapse. Using a PIT paradigm during fMRI, we observed that PIT‐related Nucleus Accumbens activation was associated with and predictive of relapse during a three months follow up period in detoxified alcohol‐dependent patients.
Paracrine cerebral Interleukin 6 (Il6) is relevant for stroke recovery, but systemic Il6 elevation may worsen outcome. Hence, paracrine Il6 response modulation within the neurovascular unit has ...emerged as an attractive therapeutic approach. Lithium modulates Il6 responses and improves stroke outcome. However, lithium may cause serious adverse effects. Here, we report that Zincfinger protein 580 (Zfp580) mediates the effects of lithium on Il6 signaling. In contrast to lithium, Zfp580 inactivation had no neurotoxic effects, and Zfp580 knock out mice showed no phenotypic changes in cognitive and motor function behavioral tests. We discovered that lithium and hypoxia disinhibited Il6 via Zfp580 suppression and post-translational modification by small ubiquitin-like modifier (SUMO). After transient middle cerebral artery occlusion, loss of Zfp580 reduced paracrine Il6 and increased Il6 trans-signaling. Aside from modulating Il6 signaling, Zfp580 loss improved endothelial resilience to ischemia, was highly neuroprotective resulting in smaller infarcts and enhanced use-dependent neuroplasticity, all of which led to improved functional outcome. In conclusion, inactivation of Zfp580 exerts positive effects on multiple key mechanisms without exhibiting relevant adverse side effects, making it potentially a more specific and effective treatment target for stroke recovery than lithium. To fully assess its potential, Zfp580 inhibitors must be developed.
Tile drainage is a widespread practice in agriculturally dominated lowlands with naturally high groundwater tables. A realistic estimation of the stream flow composition including tile drainage is an ...essential precondition for identifying major flow sources of nutrients. In this study, the Soil Water Assessment Tool (SWAT) was applied to the partially tile-drained Warnow catchment in north-eastern Germany to evaluate the effect of tile drainage systems on stream flow composition on a subbasin scale. In addition, model performance was tested after excluding tile drainages from the calibrated model setup. A sensitivity analysis revealed the highest sensitivities for parameters concerning evapotranspiration, soil characteristics, and groundwater flow, with a large variability in sensitivity ranks among the subbasins. Nash-Suttcliffe-Efficiencies (NSE) varied strongly among the subbasins for the tile-drained model setup ranging from 0.22 to 0.81 for the calibration and from −0.81 to 0.66 for the validation period. The percentage of tile flow varied between 0.3 and 31.9 %, and reflected statistically significantly (p < 0.05) the spatial extent of tile-drained areas within the subbasins. Excluding tile drainages from the model setup led to a strong decrease in model quality and to a changed stream flow constitution dominated by groundwater. The results of our study indicate that the SWAT model realistically represented the actual fractions of tile flow on discharge on the subbasin scale within the Warnow catchment. Therefore, we conclude that the incorporation of tile drainage systems is essential to calculate flow components accurately.
Core Ideas
Severe rainfall events cause increased phosphorus release from soils.
The proportion of DRP increases with increasing rainfall duration.
Digestate application causes a 400‐fold increase in ...pore water P concentrations.
The DRP fraction is clearly dominant immediately after fertilization.
Digestate application facilitates a flux regime shift with preferential flow pathways.
The application of fertilizers to soils may impair the quality of both surface and subsurface waters. Severe rainfall events that follow fertilizer application can increase P release from soils. In this study, suction plates were installed in a loamy soil with the aim of determining the P transport patterns and processes in the soil before and after the application of biogas digestate. Prior to the application of biogas digestate, the pore water concentrations of dissolved reactive P (DRP) were significantly lower than the total P (TP) concentrations, with DRP/TP ratios increasing from 0.03 to 0.89. After fertilizer application, the TP and DRP pore water concentrations increased 400‐fold. The DRP/TP ratio remained almost constant at 0.83. After 220 mm of precipitation, 4.5% of the P mass applied was leached to below the 50‐cm soil depth, indicating the general mobility of P in soils during high‐intensity rainfall. Brilliant Blue dye tracing experiments revealed that organic‐matter‐rich biogas digestate obviously changes the flow and transport patterns in soils from being homogenous to moderately heterogeneous, including preferential flow. Although the P loading across the flux plane had been equilibrated prior to treatment, after the application it was found to be concentrated in preferred transport regions. The emerging conclusion is that the risk of ground and subsequent surface water pollution with P after fertilization with biogas digestate originates not only from the applied P mass but also from the shift in the flow and transport regime caused by the organic‐matter‐rich slurry.
Learning accounts of addiction and obesity emphasize the persistent power of Pavlovian reward cues to trigger craving and increase relapse risk. While extinction can reduce conditioned responding, ...Pavlovian relapse phenomena-the return of conditioned responding following successful extinction-challenge the long-term success of extinction-based treatments. Translational laboratory models of Pavlovian relapse could therefore represent a valuable tool to investigate the mechanisms mediating relapse, although so far human research has mostly focused on return of fear phenomena. To this end we developed an appetitive conditioning paradigm with liquid food rewards in combination with a 3-day design to investigate the return of appetitive Pavlovian responses and the involved neural structures in healthy subjects. Pavlovian conditioning (day 1) was assessed in 62 participants, and a subsample (n = 33) further completed extinction (day 2) and a reinstatement test (day 3). Conditioned responding was assessed on explicit (pleasantness ratings) and implicit measures (reaction time, skin conductance, heart rate, startle response) and reinstatement effects were further evaluated using fMRI. We observed a return of conditioned responding during the reinstatement test, evident by enhanced skin conductance responses, accompanied by enhanced BOLD responses in the amygdala. On an individual level, psychophysiological reinstatement intensity was significantly anticorrelated with ventromedial prefrontal cortex (vmPFC) activation, and marginally anticorrelated with enhanced amygdala-vmPFC connectivity during late reinstatement. Our results extend evidence from return of fear phenomena to the appetitive domain, and highlight the role of the vmPFC and its functional connection with the amygdala in regulating appetitive Pavlovian relapse.
Placental hypoperfusion and hypoxia are key drivers in complications during fetal development such as fetal growth restriction and preeclampsia. In order to study the mechanisms of disease in mouse ...models, the development of quantitative biomarkers of placental hypoxia is a prerequisite. The goal of this exploratory study was to establish a technique to noninvasively characterize placental partial pressure of oxygen (PO2) in vivo in the Lgals1 (lectin, galactoside-binding, soluble, 1) deficient mouse model of preeclampsia using fluorine magnetic resonance imaging. We hypothesized a decrease in placental oxygenation in knockout mice. Wildtype and knockout animals received fluorescently labeled perfluoro-5-crown-15-ether nanoemulsion i.v. on day E14-15 during pregnancy. Placental PO2 was assessed via calibrated 19F MRI saturation recovery T1 mapping. A gas challenge with varying levels of oxygen in breathing air (30%, 60% and 100% O2) was used to validate that changes in oxygenation can be detected in freely breathing, anesthetized animals. At the end of the experiment, fluorophore-coupled lectin was injected i.v. to label the vasculature for histology. Differences in PO2 between breathing conditions and genotype were statistically analyzed with linear mixed-effects modeling. As expected, a significant increase in PO2 with increasing oxygen in breathing air was found. PO2 in Lgals1 knockout animals was decreased but this effect was only present at 30% oxygen in breathing air, not at 60% and 100%. Histological examinations showed crossing of the perfluorocarbon nanoemulsion to the fetal blood pool but the dominating contribution of 19F MR signal is estimated at > 70% from maternal plasma based on volume fraction measurements of previous studies. These results show for the first time that 19F MRI can characterize oxygenation in mouse models of placental malfunction.
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