Variants of uncertainty in decision-making and their neural correlates

When leaving the tidy world of rules and people start judging probabilities on an intuitive basis, it revealed that they have some intuitions to choose from. One could refer to them as a family of subjective probability concepts or following Kahneman and Tversky, as variants of uncertainty. The authors distinguished between external and internal attributions of uncertainty and could show that the perceived reason of uncertainty determines the selected coping strategy. To investigate whether variants of uncertainty can also be distinguished on the cerebral level, two functional magnetic resonance imaging studies were conducted. Participants had to predict events (abstract visual stimuli) under parametrically varying degrees of (un-)certainty. In the first experiment, uncertainty was induced by the manipulation of event probability (externally attributed uncertainty). In the second experiment, uncertainty depended on participants' knowledge of valid rules of event occurrence, as trained before the experimental session (internally attributed uncertainty). As a result, parametric analyses revealed that activation within the posterior fronto-median cortex, particularly within mesial Brodmann area (BA) 8, increased with increasing uncertainty, no matter for which reason uncertainty emerged. Furthermore, it was found that different variants of uncertainty entailing different coping strategies can be dissociated due to additionally activated networks. Concluding, increasing activation within mesial BA 8 reflects that we are uncertain, additional networks what we do to resolve uncertainty in order to achieve future rewards. Hence, the phenomenological distinction between processes related to externally and internally attributed uncertainty is paralleled on the cerebral level.     

Introducing a mouse model for pre-eclampsia: adoptive transfer of activated Th1 cells leads to pre-eclampsia-like symptoms exclusively in pregnant mice

Pre-eclampsia (PE) is the most severe pregnancy-related disease, leading to high maternal and fetal morbidity/mortality. Immunological imbalances associated with endothelial cell dysfunction have been hypothesized as a cause for the onset and perpetuation of PE. Valid and reliable animal models are urgently required to test this hypothesis and to better understand the mechanisms underlying PE. We developed a novel PE-model by adoptively transferring activated BALB/c Th1-like splenocytes into allogeneically pregnant BALB/c female mice during late gestation; the model mimicked the symptoms of PE, i.e. increased blood pressure and glomerulonephritis accompanied by proteinuria. Interestingly, these PE-like symptoms were not detectable in non-pregnant recipients of activated Th1-like cells. Adoptive cell transfer adversely affected the outcome of pregnancy by increasing fetal rejection, with uterine immune cells showing an inflammatory profile. In conclusion, we have established a valid and reliable PE mouse model, which opens vast opportunities for therapeutic interventions.     

Auditory what, where, and when: a sensory somatotopy in lateral premotor cortex

Recent findings have demonstrated that attention to visual events engages the lateral premotor cortex even in the absence of motor planning. Here, we used functional magnetic resonance imaging to explore acoustically triggered activations within the lateral premotor cortex. Temporal (when), object-related (what), and spatial (where) auditory patterns were to be monitored for violations in a serial prediction task. As a result, we found a modality-dependent modulation for auditory events within the inferior ventrolateral premotor cortex, an area engaged in vocal plans. In addition, however, auditory activations were distributed within the entire premotor cortex depending on which stimulus property was attended to. Attention to where patterns was found to engage fields for gaze and reaching (dorsolateral premotor cortex), what patterns to engage fields for hand movements (superior ventrolateral premotor cortex), and when patterns to engage fields for vocal plans. Together, the findings confirm the idea of a sensory somatotopy in lateral premotor cortex, according to which a perceptual pattern triggers representations within that motor effector which would be most appropriate to generate it as an action effect.     

Glutathione transferase activities in renal carcinomas and adjacent normal renal tissues: factors influencing renal carcinogenesis induced by xenobiotics

In general, the biological activation of nephrocarcinogenic chlorinated hydrocarbons proceeds via conjugation with glutathione. It has mostly been assumed that the main site of initial conjugation is the liver, followed by a mandatory transfer of intermediates to the kidney. It was therefore of interest to study the enzyme activities of subgroups of glutathione transferases (GSTs) in renal cancers and the surrounding normal renal tissues of the same individuals (n = 21). For genotyping the individuals with respect to known polymorphic GST isozymes the following substrates with differential specificity were used: 1-chloro-2,4-dinitrobenzene for overall GST activity (except GST theta); 7-chloro-4-nitrobenzo-2-oxa- 1,3-diazole for GST alpha; 1,2-dichloro-4-nitro-benzene for GST mu; ethacrynic acid and 4-vinylpyridine for GST pi; and methyl chloride for GST theta. In general, the normal tissues were able to metabolize the test substrates. A general decrease in individual GST enzyme activities was apparent in the course of cancerization, and in some (exceptional) cases individual activities, expressed in the normal renal tissue, were lost in the tumour tissue. The GST enzyme activities in tumours were independent of tumour stage, or the age and gender of the patients. There was little influence of known polymorphisms of GSTM1, GSTM3 and GSTP1 upon the activities towards the test substrates, whereas the influence of GSTT1 polymorphism on the activity towads methyl chloride was straightforward. In general, the present findings support the concept that the initial GST-dependent bioactivation step of nephrocarcinogenic chlorinated hydrocarbons may take place in the kidney itself. This should be a consideration in toxicokinetic modelling.     

Determination of urinary thymidine glycol using affinity chromatography, HPLC and post-column reaction detection: a biomarker of oxidative DNA damage upon kidney transplantation

Reactive oxygen species are generated during ischaemia-reperfusion of tissue. Oxidation of thymidine by hydroxyl radicals (HO) leads to the formation of 5,6-dihydroxy-5,6-dihydrothymidine (thymidine glycol). Thymidine glycol is excreted in urine and can be used as biomarker of oxidative DNA damage. Time dependent changes in urinary excretion rates of thymidine glycol were determined in six patients after kidney transplantation and in six healthy controls. A new analytical method was developed involving affinity chromatography and subsequent reverse-phase high-performance liquid chromatography (RP-HPLC) with a post-column chemical reaction detector and endpoint fluorescence detection. The detection limit of this fluorimetric assay was 1.6 ng thymidine glycol per ml urine, which corresponds to about half of the physiological excretion level in healthy control persons. After kidney transplantation the urinary excretion rate of thymidine glycol increased gradually reaching a maximum around 48 h. The excretion rate remained elevated until the end of the observation period of 10 days. Severe proteinuria with an excretion rate of up to 7.2 g of total protein per mmol creatinine was also observed immediately after transplantation and declined within the first 24 h of allograft function (0.35 ± 0.26 g/mmol creatinine). The protein excretion pattern, based on separation of urinary proteins on sodium dodecyl sulphate-polyacrylamide gel electrophorosis (SDS-PAGE), as well as excretion of individual biomarker proteins, indicated nonselective glomerular and tubular damage. The increased excretion of thymidine glycol after kidney transplantation may be explained by ischaemia-reperfusion induced oxidative DNA damage of the transplanted kidney. Received: 19 May 1999 / Accepted: 4 August 1999     

Quantification of liver iron overload disease with laser ablation inductively coupled plasma mass spectrometry

Background

Hereditary hemochromatosis is the most frequent, identified, genetic disorder in Caucasians affecting about 1 in 1000 people of Northern European ancestry, where the associated genetic defect (homozygosity for the p.Cys282Tyr polymorphism in the HFE gene) has a prevalence of approximately 1:200. The disorder is characterized by excess iron stores in the body. Due to the incomplete disease penetrance of disease-associated genotype, genetic testing and accurate quantification of hepatic iron content by histological grading of stainable iron, quantitative chemical determination of iron, or imaging procedures are important in the evaluation and staging of hereditary hemochromatosis.

Methods

We here established novel laser ablation inductively coupled plasma mass spectrometry protocols for hepatic metal bio-imaging for diagnosis of iron overload.

Results

We demonstrate that these protocols are a significant asset in the diagnosis of iron overload allowing iron measurements and simultaneous determination of various other metals and metalloids with high sensitivity, spatial resolution, and quantification ability.

Conclusions

The simultaneous measurement of various metals and metalloids offers unique opportunities for deeper understanding of metal imbalances. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) is a highly powerful and sensitive technique for the analysis of a variety of solid samples with high spatial resolution. We conclude that this method is an important add-on to routine diagnosis of iron overload and associated hepatic metal dysbalances resulting thereof.

     

A blueprint for target motion: fMRI reveals perceived sequential complexity to modulate premotor cortex

The execution of movements that are guided by an increasingly complex target motion is known to draw on premotor cortices. Whole-brain functional magnetic resonance imaging was used to investigate whether, in the absence of any movement, attending to and predicting increasingly complex target motion also rely on premotor cortices. Complexity was varied as a function of number of sequential elements and amount of dynamic sequential trend in a pulsing target motion. As a result, serial prediction caused activations in premotor and parietal cortices, particularly within the right hemisphere. Parametric analyses revealed that the right ventrolateral premotor cortex and the right anterior intraparietal sulcus were the only areas that, in addition, covaried positively with both behavioral and physical measures of sequential complexity. Further areas that covaried positively with increasing task difficulty reflected influences of both number and trend manipulation. In particular, increasing element number drew on dorsal premotor and corresponding posterior intraparietal regions, whereas increasing trend drew on the visual motion area and area V4. The present findings demonstrate that premotor involvement directly reflects perceptual complexity in attended and predicted target motion. It is suggested that when we try to predict how a target will move, the motor system generates a "blueprint" of the observed motion that allows potential sensorimotor integration. In the absence of any motor requirement, this blueprint appears to be not a by-product of motor planning, but rather the basis for target motion prediction.     

Tuning‐in to the beat: Aesthetic appreciation of musical rhythms correlates with a premotor activity boost

Listening to music can induce us to tune in to its beat. Previous neuroimaging studies have shown that the motor system becomes involved in perceptual rhythm and timing tasks in general, as well as during preference‐related responses to music. However, the role of preferred rhythm and, in particular, of preferred beat frequency (tempo) in driving activity in the motor system remains unknown. The goals of the present functional magnetic resonance imaging (fMRI) study were to determine whether the musical rhythms that are subjectively judged as beautiful boost activity in motor‐related areas and if so, whether this effect is driven by preferred tempo, the underlying pulse people tune in to. On the basis of the subjects' judgments, individual preferences were determined for the different systematically varied constituents of the musical rhythms. Results demonstrate the involvement of premotor and cerebellar areas during preferred compared to not preferred musical rhythms and indicate that activity in the ventral premotor cortex (PMv) is enhanced by preferred tempo. Our findings support the assumption that the premotor activity increase during preferred tempo is the result of enhanced sensorimotor simulation of the beat frequency. This may serve as a mechanism that facilitates the tuning‐in to the beat of appealing music. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.