Rewarding feedback promotes motor skill consolidation via striatal activity.

Knowledge of performance can activate the striatum, a key region of the reward system and highly relevant for motivated behavior. Using functional magnetic resonance imaging, striatal activity linked to knowledge of performance was measured during the training of a repetitive arc-tracking task. Knowledge of performance was given after a random selection of trials or after good performance. The third group received knowledge of performance after good performance plus a monetary reward. Skill learning was measured from pre- to post- (acquisition) and from post- to 24h posttraining (consolidation). Our results demonstrate an influence of feedback on motor skill learning. Adding a monetary reward after good performance leads to better consolidation and higher ventral striatal activation than knowledge of performance alone. In turn, rewarding strategies that increase ventral striatal response during training of a motor skill may be utilized to improve skill consolidation.

Anatomic features of glioblastoma and their potential impact on survival.

BACKGROUND: Many reports on glioblastoma multiforme discuss the prognostic impact of anatomical features such as cysts, necrotic changes, extent of edema or subependymal spread of tumor cells. In the present study, we examined different growth patterns and their possible relations to patient survival. METHODS: To analyze whether anatomical characteristics are related to prognosis, we reviewed the prospectively collected pre- and postoperative MRIs of 83 patients in the 5-ALA study, provided by the 5-ALA Glioma Study Group. Following a standardized analytic work flow, the tumor volume and site, presence of necrosis or cysts, and perifocal edema were assessed preoperatively. In the same way, postoperative MRI and the MRI at first recurrence were analyzed. In addition, survival time of the patients was documented. RESULTS: Median survival time of all 83 patients was 15.1 months (range 1.5 to 70.1, mean 18). The site or volume of glioblastoma, as well as the presence of intratumoral necrosis or cysts, did not exert a significant effect on survival time; 96.4 % of recurrences occurred within the former resection margin. Tumors with initial contact with the subependymal zone had multifocal or ventricular recurrences significantly more often. In patients with residual tumor on early postoperative MRI, the follow-up images displayed enlargement of the remnants in 91.9 % of these cases. CONCLUSIONS: A merely anatomical analysis of the glioblastoma growth pattern cannot reliably provide prognostic information. The occurrence of most recurrences next to the resection margin and the high percentage of growing residual tumors underline the importance of complete resections.

Tracing toothache intensity in the brain.

Identification of brain regions that differentially respond to pain intensity may improve our understanding of trigeminally mediated nociception. This report analyzed cortical responses to painless and painful electrical stimulation of a right human maxillary canine tooth. Functional magnetic resonance images were obtained during the application of five graded stimulus strengths, from below, at, and above the individually determined pain thresholds. Study participants reported each stimulus on a visual rating scale with respect to evoked sensation. Based on hemodynamic responses of all pooled stimuli, a cerebral network was identified that largely corresponds to the known lateral and medial nociceptive system. Further analysis of the five graded stimulus strengths revealed positive linear correlations for the anterior insula bilaterally, the contralateral (left) anterior mid-cingulate, as well as contralateral (left) pregenual cingulate cortices. Cerebral toothache intensity coding on a group level can thus be attributed to specific subregions within the cortical pain network.

Neuroradiological response criteria for high-grade gliomas.

The recently introduced new response criteria of the response assessment in neuro-oncology (RANO) working group and its clinical implications are the topic of this article. Establishing this working group as a work-in-progress platform and its first report, the RANO criteria represent an important step forward in the accurate assessment of response to therapy in patients with malignant gliomas not only in clinical trials but also in daily practice. Anti-angiogenic therapy and other new treatment modalities have increased the incidence and awareness of novel imaging phenomena, such as pseudoprogression and pseudoresponse not only within clinical trials. The new RANO criteria also take clinical parameters, such as steroid medication and neurological symptoms into account. Neuroradiologists and neuro-oncologists need to be aware of and experienced in applying these new criteria to correctly assess the response to treatment in patients with malignant gliomas. Further research is needed to study new imaging techniques, such as perfusion and diffusion-weighted imaging and to investigate and incorporate these for routine tumor response criteria.

Safety of pramlintide added to mealtime insulin in patients with type 1 or type 2 diabetes: a large observational study.

The objective of this Phase 4, open-label, multicentre, observational study was to fulfil food and drug administration (FDA) postapproval requirement to evaluate in healthcare practices the risk of insulin-induced severe hypoglycaemia following initiation of pramlintide therapy in N = 1297 patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) with inadequate glycaemic control. The duration of the study was approximately 6 months. During the adjustment period (0-3 months), the incidence and event rate of patient-ascertained severe hypoglycaemia (PASH) were 4.8% and 0.33 events/patient-year in patients with T1DM and 2.8% and 0.19 events/patient-year in patients with T2DM. During the maintenance period (>3-6 months), the incidence and event rate of PASH declined in patients with T1DM or T2DM. This study confirms that in healthcare practices, the risk of insulin-induced severe hypoglycaemia following the initiation of pramlintide is low in patients with T1DM or T2DM.

Interindividual differences in the perception of dental stimulation and related brain activity.

For identical diagnoses in the trigeminal innervation territory, individual differences have been clinically observed among the symptoms reported, such as dysesthesia and pain. Different subjective perceptions of unpleasantness and pain intensity may have different cortical substrates. The aim of this study was to identify brain areas in which activation depends on the subjective perception (intensity and unpleasantness) of electric dental stimulation. Electrical stimuli of increasing intensity were applied to maxillary canines in 14 healthy volunteers. Ratings for stimulus intensity and unpleasantness perceived across the stimulation session were reported postscan on 11-point numerical scales. The rating values were then included as covariates in the functional magnetic resonance imaging (fMRI) group analysis. Interindividual differences of intensity ratings were reflected in differential activity of the following brain areas: superior parietal lobule, superior temporal gyrus/anterior insula, inferior and middle temporal gyrus, lingual gyrus, anterior cingulate, and caudate nucleus. Differences related to unpleasantness ratings were reflected in the lingual gyrus. In conclusion, differences of perceived intensity between individuals are reflected in the differential activity of a set of brain areas distinct from those regions, reflecting rating differences of unpleasantness.

Myocardial iron overload in transfusion-dependent pediatric patients with acute leukemia.

For patients who regularly receive blood transfusions, cardiac failure is the major cause of death. This is most alarming because it progresses rapidly and is difficult to manage. We present three pediatric patients with acute leukemia whose therapy-induced anemia was treated with different amounts of red blood cell concentrates (RCC). In all patients, a liver iron overload was measured by super-conducting interference device (SQUID) biosusceptometry and magnetic resonance imaging (MRI). MRI is a rapid, noninvasive, and widely available method of determining early myocardial iron overload caused by multiple blood transfusion due to anemia during polychemotherapy.

Extensive training of elementary finger tapping movements changes the pattern of motor cortex excitability.

There is evidence of a strong capacity for functional and structural reorganization in the human motor system. However, past research has focused mainly on complex movement sequences over rather short training durations. In this study we investigated changes in corticospinal excitability associated with longer training of elementary, maximum-speed tapping movements. All participating subjects were consistent right-handers and were trained using either the right (experiment 1) or the left thumb (experiment 2). Transcranial magnetic stimulation was applied to obtain motor evoked potentials (MEPs) from the abductor pollicis brevis (APB) muscle of the right and the left hand before and after training. As a result of training, a significant increase was observed in tapping speed accompanied by increased MEPs, recorded from the trained APB muscle, following contralateral M1 stimulation. In the case of subdominant-hand training we additionally demonstrate increased MEP amplitudes evoked at the right APB (untrained hand) in the first training week. Enhanced corticospinal excitability associated with practice of elementary movements may constitute a necessary precursor for inducing plastic changes within the motor system. The involvement of the ipsilateral left M1 likely reflects the predominant role of the left M1 in the general control (modification) of simple motor parameters in right-handed subjects.

Asymmetry of cortical activation during maximum and convenient tapping speed.

An effect of finger tapping rate on the hemodynamic response in primary motor cortex and the cerebellum has been well established over the last years (the rate effect). The present study compares the magnitude of this effect when either the dominant or subdominant hand is used by right and left handers. In contrast to previous studies maximum and convenient tapping rate for both hands are used as tapping tasks. The results confirm "rate effects" for the primary motor cortex and the cerebellum. In addition, a "rate effect" was found for the cingulate motor area. A novel finding is that the cortical and cerebellar "rate effects" are similar for the subdominant and for the dominant hand even though tapping rates are lower for the subdominant hand. This result demonstrates that the subdominant motor cortex and neurally connected cerebellar areas operate at suboptimal control levels although maximum neurophysiological activation has been reached during the maximum tapping task.

Cortical activation resulting from painless vibrotactile dental stimulation measured by functional magnetic resonance imaging (FMRI).

There have been few investigations on hemodynamic responses in the human cortex resulting from dental stimulation. Identification of cortical areas involved in stimulus perception may offer new targets for pain treatment. This initial study aimed at establishing a cortical map of dental representation, based on non-invasive fMRI measurements. Five right-handed subjects were studied. Eight maxillary and 8 mandibular teeth were stimulated after the vibratory perception threshold was determined for each tooth. Suprathreshold stimulation was repeated thrice per session, in a total of three sessions performed on three consecutive days. Statistical inference on cluster level identified increased blood-oxygen-level-dependent signal during vibratory dental stimulation, primarily in the insular cortex bilaterally and in the supplementary motor cortex. No significant brain activation was observed in the somatosensory cortex with this stimulation protocol. These results agree with previous findings obtained from invasive direct electrical cortical stimulation of the human insula.

Lack of conservation of editing sites in mRNAs that encode subunits of the NAD(P)H dehydrogenase complex in plastids and mitochondria of Arabidopsis thaliana.

RNA editing in the plastids and mitochondria of higher plants involves C to U conversion of specific nucleotides in the mRNA. This leads to the synthesis of proteins that are different from those predicted by the DNA sequence. Editing appears to have arisen at about the same time in both plastids and mitochondria, suggesting a common evolutionary origin. The problem we address here is whether or not there has been co-evolution of the editing systems in the two organelles. Our test system was editing of the Arabidopsis thaliana mRNAs for ndhB and nad2, and for ndhD and nad4, which encode homologous subunits of the plastid and mitochondrial NAD(P)H dehydrogenases, respectively. The editing sites in the Arabidopsis nad2 and nad4 mRNAs have previously been determined and we report here 19 editing sites in eight mRNAs in Arabidopsis plastids. Out of these, eight sites are localized in the ndhB mRNA. In its mitochondrial counterpart, nad2, 31 editing sites are present, none of which are shared with the ndhB gene. The Arabidopsis ndhD mRNA is edited at four positions, only one of which is shared by its mitochondrial homologue, nad4, which contains 32 editing sites. These findings suggest that, although editing in the two organelles may have derived from a single system, there is no significant conservation of editing sites in cognate mRNAs in plastids and mitochondria.

Focused and nonfocused attention in verbal and emotional dichotic listening: an FMRI study.

Functional magnetic resonance imaging (fMRI) was used to identify cortical regions which are involved in two dichotic listening tasks. During one task the subjects were required to allocate attention to both ears and to detect a specific target word (phonetic task), while during a second task the subjects were required to detect a specific emotional tone (emotional task). During three attentional conditions of each task, the subjects were required to focus attention to the right (FR) or left ear (FL), while during a third condition subjects were required to allocate attention to both ears simultaneously. In 11 right-handed male subjects, these dichotic listening tasks evoked strong activations in a temporofrontal network involving auditory cortices located in the temporal lobe and prefrontal brain regions. Hemodynamic responses were measured in the following regions of interest: Heschl's gyrus (HG), the planum polare (PP), the planum temporale (PT), the anterior superior temporal sulcus (aSTS), the posterior superior temporal sulcus (pSTS), and the inferior frontal gyrus region (IFG) of both hemispheres. The following findings were obtained: (1) the degree of activation in HG and PP depends on the direction of attention. In particular it was found that selectively attending to right-ear input led to increased activity specifically in the left HG and PP and attention to left ear input increased right-sided activity in these structures; (2) hemodynamic responses in the PT, aSTS, pSTS, and IFG were not modulated by the different focused-attention conditions; (3) hemodynamic responses in HG and PP in the nonforced conditions were the sum activation of the forced conditions; (4) there was no general difference between the phonetic and emotion tasks in terms of hemodynamic responses; (5) hemodynamic responses in the PT and pSTS were strongly left-lateralized, reflecting the specialization of these brain regions for language processing. These findings are discussed in the context of current theories of hemispheric specialization.

Efficient elimination of selectable marker genes from the plastid genome by the CRE-lox site-specific recombination system.

Incorporation of a selectable marker gene during transformation is essential to obtain transformed plastids. However, once transformation is accomplished, having the marker gene becomes undesirable. Here we report on adapting the P1 bacteriophage CRE-lox site-specific recombination system for the elimination of marker genes from the plastid genome. The system was tested by the elimination of a negative selectable marker, codA, which is flanked by two directly oriented lox sites (>codA>). Highly efficient elimination of >codA> was triggered by introduction of a nuclear-encoded plastid-targeted CRE by Agrobacterium transformation or via pollen. Excision of >codA> in tissue culture cells was frequently accompanied by a large deletion of a plastid genome segment which includes the tRNA-ValUAC gene. However, the large deletions were absent when cre was introduced by pollination. Thus pollination is our preferred protocol for the introduction of cre. Removal of the >codA> coding region occurred at a dramatic speed, in striking contrast to the slow and gradual build-up of transgenic copies during plastid transformation. The nuclear cre gene could subsequently be removed by segregation in the seed progeny. The modified CRE-lox system described here will be a highly efficient tool to obtain marker-free transplastomic plants.

Expression of bar in the plastid genome confers herbicide resistance.

Phosphinothricin (PPT) is the active component of a family of environmentally safe, nonselective herbicides. Resistance to PPT in transgenic crops has been reported by nuclear expression of a bar transgene encoding phosphinothricin acetyltransferase, a detoxifying enzyme. We report here expression of a bacterial bar gene (b-bar1) in tobacco (Nicotiana tabacum cv Petit Havana) plastids that confers field-level tolerance to Liberty, an herbicide containing PPT. We also describe a second bacterial bar gene (b-bar2) and a codon-optimized synthetic bar (s-bar) gene with significantly elevated levels of expression in plastids (>7% of total soluble cellular protein). Although these genes are expressed at a high level, direct selection thus far did not yield transplastomic clones, indicating that subcellular localization rather than the absolute amount of the enzyme is critical for direct selection of transgenic clones. The codon-modified s-bar gene is poorly expressed in Escherichia coli, a common enteric bacterium, due to differences in codon use. We propose to use codon usage differences as a precautionary measure to prevent expression of marker genes in the unlikely event of horizontal gene transfer from plastids to bacteria. Localization of the bar gene in the plastid genome is an attractive alternative to incorporation in the nuclear genome since there is no transmission of plastid-encoded genes via pollen.

The transfer of a timing pattern to the untrained human hand investigated with functional magnetic resonance imaging.

The study investigates cortical hemodynamic responses during continuation tapping using auditory pacing stimuli in five healthy right-handed subjects using functional magnetic resonance imaging. The tasks required the use of either the same finger for synchronization of the tapping movement and for continuation, or to use the contralateral finger for continuation. Results show, that using the contralateral finger increases regional cerebral blood flow in motor areas such as the anterior cerebellar hemispheres and vermis, in the cingulate motor area, but also in the posterior cingulum, when compared to using the same finger. The complementary comparison shows increased regional blood flow in the left hippocampus. The results suggest that in addition to pure executive functions, higher cognitive functions localized in these areas are involved in the transfer of interval timing.

Cortical activations during the mental rotation of different visual objects.

Whole-head functional magnetic resonance imaging was applied to nine healthy right-handed subjects while they were performing three different mental rotation tasks and two visual control tasks. The mental rotation tasks comprised stimuli pairs derived from the "classical" 3D cube figures first used by R. N. Shepard and J. Metzler (1971, Science 171, 701-703), pairs of letters, and pairs of abstract figures developed by J. Hochberg and L. Gellmann (1977, Memory Cognit. 5, 23-26). In some cases, the paired objects were identical except that they were rotated in a certain plane. In other cases, the two objects were incongruent. Subjects were shown one pair of objects at a time and asked to judge whether the two were the same. In line with previous studies we found that decision times increased linearly with the degree of separation between the two objects. Cortical activation converged to demonstrate bilateral core regions in the superior and inferior parietal lobe (centered on the intraparietal sulcus), which were similarly activated during all three mental rotation tasks. Thus, our results suggest that different kinds of stimuli used for mental rotation tasks did not inevitably evoke activations outside the parietal core regions. For example we did not find any activation in brain areas known to be involved in lexical or verbal processing nor activations in cortical regions known to be involved in object identification or classification.

Conservation of RNA editing between rice and maize plastids: are most editing events dispensable?

The extent of conservation of RNA editing sites in the plastid genome of rice was determined by comparing the genomic sequence with that of the cDNA. The presence of a T in the cDNA predicted to be a C by the DNA sequence of the plastid genome, indicated C to U editing. In the 11 plastid transcripts of rice a total of 21 editing sites were found. In maize, a closely related grass species, 26 editing sites have been reported in 13 plastid transcripts. Most editing sites are conserved between the two species, although differences in RNA editing were found at eight sites. In seven cases the T was already encoded at the DNA level, eliminating the requirement for RNA editing. In one case (rpoB, codon 206) the RNA sequence was conserved between the two species, but the mRNA is still not edited in rice. It appears that, although evolutionarily conserved, RNA editing is essential only for a few plastid editing sites. Information about RNA editing in rice plastids will facilitate the design of plastid vectors with broad applicability in grass species.