The Role of Finger Representations and Saccades for Number Processing: An fMRI Study in Children

A possible functional role of finger representations for the development of early numerical cognition has been the subject of recent debate; however, until now, only behavioral studies have directly supported this view. Working from recent models of number processing, we focused on the neural networks involved in numerical tasks and their relationship to the areas underlying finger representations and saccades in children aged 6–12 years. We were able to differentiate three parietal circuits that were related to distinct aspects of number processing. Abstract magnitude processing was subserved by an association area also activated by saccades and visually guided finger movements. Addition processes led to activation in an area only engaged during saccade encoding, whereas counting processes resulted in the activation of an area only activated during visually guided finger movements, namely in the anterior intraparietal sulcus. Apart from this area, a large network of specifically finger-related brain areas including the ventral precentral sulcus, supplementary motor area, dorso-lateral prefrontal cortex, insula, thalamus, midbrain, and cerebellum was activated during (particularly non-symbolic) exact addition but not during magnitude comparison. Moreover, a finger-related activation cluster in the right ventral precentral sulcus was only present during non-symbolic addition and magnitude comparison, but not during symbolic number processing tasks. We conclude that finger counting may critically mediate the step from non-symbolic to symbolic and exact number processing via somatosensory integration processes and therefore represents an important example of embodied cognition

Role of marker lesion when applying intravesical instillations of IL-2 for non-muscle-invasive bladder cancer comparison of the therapeutic effects in two pilot studies

Comparison of the therapeutic effect of treatment of non-muscle invasive bladder carcinoma (NMIBC) after intravesical Interleukin-2 (IL-2) instillations in the presence and absence of a marker tumour. Two pilot studies were performed in patients with NMIBC. The first study (10 patients) was performed in Krakow (Poland), the second (26 patients) in Vilnius (Lithuania). In Krakow the tumours were treated with incomplete transurethral resection (TUR) leaving a marker tumour of 0.5-1.0-cm followed by IL-2 instillations (3 × 10(6) IU IL-2) on five consecutive days. In Vilnius the tumours were treated with complete TUR, followed by IL-2 instillations (9 × 10(6) IU IL-2) on five consecutive days. During 30 months follow-up, the recurrence-free survival was 5/10 (50%) and 6/26 (23%) after incomplete and complete TUR, respectively. So, the ratio of the recurrence-free survival after incomplete/complete TUR of 50/23=2.2. The median of the recurrence-free survival is >20.5 months and 7 months after incomplete and complete TUR, respectively. So, this ratio was >20.5/7= >2.9. The hazard ratio which combines both the chance of the disease recurrence and its timing for both censored and uncensored cases was 0.53, again confirming the better outcome after incomplete TUR. A possible explanation for the better therapeutic effects after incomplete TUR compared with complete TUR is that the marker tumour has tumour-associated antigens (TAA) that could lead to an immune reaction that is stimulated by local application of IL-2. After complete TUR, no TAA are available to initiate and to stimulate an immune reaction; consequently, local IL-2 therapy is less effective after complete TUR. The results of these two pilot studies have led to the recent start of a randomised prospective clinical trial in which therapeutic effects of local IL-2 therapy after complete and incomplete TUR are compare

Auditory mismatch impairments are characterized by core neural dysfunctions in schizophrenia

Reduced mismatch negativity is a well-established phenomenon in schizophrenia, but its underlying mechanisms are unclear. Using fMRI, Gaebler et al. reveal that auditory mismatch stimuli trigger multiple neural dysfunctions associated with schizophrenia. The fMRI response enables diagnostic separation of patients and controls with high accuracy, suggesting biomarker potentia

Local therapy of cancer with free IL-2

This is a position paper about the therapeutic effects of locally applied free IL-2 in the treatment of cancer. Local therapy: IL-2 therapy of cancer was originally introduced as a systemic therapy. This therapy led to about 20% objective responses. Systemic therapy however was very toxic due to the vascular leakage syndrome. Nevertheless, this treatment was a break-through in cancer immunotherapy and stimulated some interesting questions: Supposing that the mechanism of IL-2 treatment is both proliferation and tumoricidal activity of the tumor infiltrating cells, then locally applied IL-2 should result in a much higher local IL-2 concentration than systemic IL-2 application. Consequently a greater beneficial effect could be expected after local IL-2 application (peritumoral = juxtatumoral, intratumoral, intra-arterial, intracavitary, or intratracheal = inhalation). Free IL-2: Many groups have tried to prepare a more effective IL-2 formulation than free IL-2. Examples are slow release systems, insertion of the IL-2 gene into a tumor cell causing prolonged IL-2 release. However, logistically free IL-2 is much easier to apply; hence we concentrated in this review and in most of our experiments on the use of free IL-2. Local therapy with free IL-2 may be effective against transplanted tumors in experimental animals, and against various spontaneous carcinomas, sarcomas, and melanoma in veterinary and human cancer patients. It may induce rejection of very large, metastasized tumor loads, for instance advanced clinical tumors. The effects of even a single IL-2 application may be impressive. Not each tumor or tumor type is sensitive to local IL-2 application. For instance transplanted EL4 lymphoma or TLX9 lymphoma were not sensitive in our hands. Also the extent of sensitivity differs: In Bovine Ocular Squamous Cell Carcinoma (BOSCC) often a complete regression is obtained, whereas with the Bovine Vulval Papilloma and Carcinoma Complex (BVPCC) mainly stable disease is attained. Analysis of the results of local IL-2 therapy in 288 cases of cancer in human patients shows that there were 27% Complete Regressions (CR), 23% Partial Regressions (PR), 18% Stable Disease (SD), and 32% Progressive Disease (PD). In all tumors analyzed, local IL-2 therapy was more effective than systemic IL-2 treatment. Intratumoral IL-2 applications are more effective than peritumoral application or application at a distant site. Tumor regression induced by intratumoral IL-2 application may be a fast process (requiring about a week) in the case of a highly vascular tumor since IL-2 induces vascular leakage/edema and consequently massive tumor necrosis. The latter then stimulates an immune response. In less vascular tumors or less vascular tumor sites, regression may require 9–20 months; this regression is mainly caused by a cytotoxic leukocyte reaction. Hence the disadvantageous vascular leakage syndrome complicating systemic treatment is however advantageous in local treatment, since local edema may initiate tumor necrosis. Thus the therapeutic effect of local IL-2 treatment is not primarily based on tumor immunity, but tumor immunity seems to be useful as a secondary component of the IL-2 induced local processes. If local IL-2 is combined with surgery, radiotherapy or local chemotherapy the therapeutic effect is usually greater than with either therapy alone. Hence local free IL-2 application can be recommended as an addition to standard treatment protocols. Local treatment with free IL-2 is straightforward and can readily be applied even during surgical interventions. Local IL-2 treatment is usually without serious side effects and besides minor complaints it is generally well supported. Only small quantities of IL-2 are required. Hence the therapy is relatively cheap. A single IL-2 application of 4.5 million U IL-2 costs about 70 Euros. Thus combined local treatment may offer an alternative in those circumstances when more expensive forms of treatment are not available, for instance in resource poor countries

Micro and macro pattern analyses of fMRI data support both early and late interaction of numerical and spatial information

Numbers and space are two semantic primitives that interact with each other. Both recruit brain regions along the dorsal pathway, notably parietal cortex. This makes parietal cortex a candidate for the origin of numerical spatial interaction. The underlying cognitive architecture of the interaction is still under scrutiny. Two classes of explanations can be distinguished. The early interaction approach assumes that numerical and spatial information are integrated into a single representation at a semantic level. A second approach postulates independent semantic representations. Only at the stage of response selection and preparation these two streams interact.In this study we used a numerical landmark task to identify the locus of the interaction between numbers and space. While lying in an MR scanner participants decided on the smaller of two numerical intervals in a visually presented number triplet. The spatial position of the middle number was varied; hence spatial intervals were congruent or incongruent with the numerical intervals. Responses in incongruent trials were slower and less accurate than in congruent trials. By combining across vertex correlations (micro pattern) with a cluster analysis (macro pattern) we identified three networks that were devoted to number processing, eye movements, and sensory motor functions. Using support vector machine classifiers in different regions of interest along the IPS, the frontal eye fields and supplementary motor area to distinguish between congruent and incongruent trials we were able to distinguish between congruent and incongruent trials in each of the three networks. We suggest that the three identified networks participate in the integration of numerical and spatial information and that the exclusive assumption of either an early or a late interaction between numerical and spatial information does not do justice to the complex interaction between both dimensions

Micro and macro pattern analyses of fMRI data support both early and late interaction of numerical and spatial information

Numbers and space are two semantic primitives that interact with each other. Both recruit brain regions along the dorsal pathway, notably parietal cortex. This makes parietal cortex a candidate for the origin of numerical–spatial interaction. The underlying cognitive architecture of the interaction is still under scrutiny. Two classes of explanations can be distinguished. The early interaction approach assumes that numerical and spatial information are integrated into a single representation at a semantic level. A second approach postulates independent semantic representations. Only at the stage of response selection and preparation these two streams interact. In this study we used a numerical landmark task to identify the locus of the interaction between numbers and space. While lying in an MR scanner participants decided on the smaller of two numerical intervals in a visually presented number triplet. The spatial position of the middle number was varied; hence spatial intervals were congruent or incongruent with the numerical intervals. Responses in incongruent trials were slower and less accurate than in congruent trials. By combining across-vertex correlations (micro pattern) with a cluster analysis (macro pattern) we identified large-scale networks that were devoted to number processing, eye movements, and sensory–motor functions. Using support vector classification in different regions of interest along the intraparietal sulcus, the frontal eye fields, and supplementary motor area we were able to distinguish between congruent and incongruent trials in each of the networks. We suggest that the identified networks participate in the integration of numerical and spatial information and that the exclusive assumption of either an early or a late interaction between numerical and spatial information does not do justice to the complex interaction between both dimensions

An attempt to model the causal structure behind white matter aging and cognitive decline

Abstract In this diffusion tension imaging study, voxel wise structural equation modeling was used to unravel the relation between white matter, cognition, and age. Four neurocognitive ageing models describing the interplay between age, white matter integrity, and cognition were investigated but only two models survived an Akaike information criterion-based model selection procedure. The independent factor model predicts that there is no relation between white matter integrity and cognition although both systems are affected by age. The cognitive mediation model predicts that the relation between age and white matter integrity is mediated through cognition. Roughly 60% of the observed voxels were in agreement with the independent factor model while 16% of the observed voxels were in agreement with the cognitive mediation model. Imaging results of the latter model suggest that the deterioration of fibers—that connect the two hemispheres with each other—is partly caused by an age-related decline in cognitive functioning