Frequency-specific transcranial neuromodulation of alpha power alters visuospatial attention performance.

Transcranial alternating current stimulation (tACS) at 10 Hz has been shown to modulate spatial attention. However, the frequency-specificity and the oscillatory changes underlying this tACS effect are still largely unclear. Here, we applied high-definition tACS at individual alpha frequency (IAF), two control frequencies (IAF+/-2Hz) and sham to the left posterior parietal cortex and measured its effects on visuospatial attention performance and offline alpha power (using electroencephalography, EEG). We revealed a behavioural and electrophysiological stimulation effect relative to sham for IAF but not control frequency stimulation conditions: there was a leftward lateralization of alpha power for IAF tACS, which differed from sham for the first out of three minutes following tACS. At a high value of this EEG effect (moderation effect), we observed a leftward attention bias relative to sham. This effect was task-specific, i.e., it could be found in an endogenous attention but not in a detection task. Only in the IAF tACS condition, we also found a correlation between the magnitude of the alpha lateralization and the attentional bias effect. Our results support a functional role of alpha oscillations in visuospatial attention and the potential of tACS to modulate it. The frequency-specificity of the effects suggests that an individualization of the stimulation frequency is necessary in heterogeneous target groups with a large variation in IAF.

[Brain stimulation: the most direct form of neurostimulation]. / Hersenstimulatie: de meest directe vorm van neuromodulatie.

BACKGROUND: Brain stimulation is the most direct form of neuromodulation. Direct brain stimulation is an older procedure that has taken various forms, but 'non-invasive brain stimulation' is a more recent development. AIM: To provide an overview of the current arsenal of non-invasive brain stimulation techniques. METHOD: We discuss the underlying principles, the pros and cons, and the applicability of non-invasive brain stimulation in experimental research and treatment of neuropsychiatric disorders. RESULTS: Non-invasive brain stimulation is a direct form of neuromodulation, which is not invasive, harmful or painful. Its effects are in principle temporary, which makes the technique suitable for experimental research. At the same time, temporary effects can have lasting clinical consequences, if they target neuroplasticity to aid rehabilitation or alleviate symptoms. CONCLUSION: Whereas the value of non-invasive brain stimulation for research purposes is undisputed, its efficacy and value as a treatment for neuropsychiatric disorders are still being debated. Nevertheless, the accumulated evidence about the clinical efficacy of the treatment for certain disorders is sufficiently compelling to start thinking about European regulations and standard medical insurance coverage.

Seeing in the dark: Phosphene thresholds with eyes open versus closed in the absence of visual inputs.

BACKGROUND: Voluntarily opening or closing our eyes results in fundamentally different input patterns and expectancies. Yet it remains unclear how our brains and visual systems adapt to these ocular states. OBJECTIVE/HYPOTHESIS: We here used transcranial magnetic stimulation (TMS) to probe the excitability of the human visual system with eyes open or closed, in the complete absence of visual inputs. METHODS: Combining Bayesian staircase procedures with computer control of TMS pulse intensity allowed interleaved determination of phosphene thresholds (PT) in both conditions. We measured parieto-occipital EEG baseline activity in several stages to track oscillatory power in the alpha (8-12 Hz) frequency-band, which has previously been shown to be inversely related to phosphene perception. RESULTS: Since closing the eyes generally increases alpha power, one might have expected a decrease in excitability (higher PT). While we confirmed a rise in alpha power with eyes closed, visual excitability was actually increased (PT was lower) with eyes closed. CONCLUSIONS: This suggests that, aside from oscillatory alpha power, additional neuronal mechanisms influence the excitability of early visual cortex. One of these may involve a more internally oriented mode of brain operation, engaged by closing the eyes. In this state, visual cortex may be more susceptible to top-down inputs, to facilitate for example multisensory integration or imagery/working memory, although alternative explanations remain possible.

Endoplasmic reticulum stress activates autophagy but not the proteasome in neuronal cells: implications for Alzheimer's disease.

Protein folding stress in the endoplasmic reticulum (ER) may lead to activation of the unfolded protein response (UPR), aimed to restore cellular homeostasis via transcriptional and post-transcriptional mechanisms. ER stress is also reported to activate the ER overload response (EOR), which activates transcription via NF-κB. We previously demonstrated that UPR activation is an early event in pre-tangle neurons in Alzheimer's disease (AD) brain. Misfolded and unfolded proteins are degraded via the ubiquitin proteasome system (UPS) or autophagy. UPR activation is found in AD neurons displaying both early UPS pathology and autophagic pathology. Here we investigate whether activation of the UPR and/or EOR is employed to enhance the proteolytic capacity of neuronal cells. Expression of the immunoproteasome subunits ß2i and ß5i is increased in AD brain. However, expression of the proteasome subunits is not increased by the UPR or EOR. UPR activation does not relocalize the proteasome or increase overall proteasome activity. Therefore proteasomal degradation is not increased by ER stress. In contrast, UPR activation enhances autophagy and LC3 levels are increased in neurons displaying UPR activation in AD brain. Our data suggest that autophagy is the major degradational pathway following UPR activation in neuronal cells and indicate a connection between UPR activation and autophagic pathology in AD brain.

Null results in TMS: from absence of evidence to evidence of absence.

It is always difficult to interpret null results. But as a research method, transcranial magnetic stimulation (TMS) has so many degrees of freedom that null results are often dismissed as meaningless. We feel that this may be unnecessary, if not counterproductive. Null results seem to inherently fulfill an important role in brain mapping. In fact, without null results, neuroimaging as an enterprise would not make sense. We argue that null results are similarly important in TMS research. By itself, neuroimaging research leaves room for doubt concerning whether or not an activated region is actually necessary for intact task performance. Interference methods such as TMS can therefore complement brain research by testing the functional relevance of that region. However, if then only positive TMS results are taken seriously, the brain interference paradigm seems less informative than promised. But how can null results inform us if they only constitute absence of evidence? We suggest that three main arguments contravene interpretation of null results in TMS. These we call the localization argument, the neural efficacy argument, and the power argument. We proceed to discuss in turn how, and under which conditions, each of these arguments may be nuanced. These considerations lead us to value null results along a gradient of meaningfulness, rather than a dichotomy. This perspective may open up a new range of TMS applications, where research questions about the lack of functional relevance of a particular brain region become valid. In this context we make specific recommendations on experimentation and interpretation. We propose that it is often not only meaningful to interpret null results, but also useful to make such findings available to the community, especially now that improved methods and an expanded knowledge base make null results more interpretable than they have been in the past.

Hepatitis B vaccination strategies tailored to different endemicity levels: some considerations.

Hepatitis B is a serious public health problem. Worldwide three different levels of hepatitis B endemicity (high, intermediate and low) can be distinguished. Areas with different levels of endemicity require tailored vaccination strategies to fit the needs for individuals at risk and/or countries, depending on the infection risk per age group, vaccination rate, duration of protection after vaccination, cost effectiveness of vaccination strategies and ease of implementation in the national immunization schedules.This opinion paper evaluates these factors and proposes a combination of infant risk group and universal adolescent vaccination for low endemic countries thus targeting the different groups at risk. A universal infant vaccination schedule starting with a newborn vaccination within 24h after birth is more appropriate in intermediate- and high-endemic regions.

Measurement of hemodialysis vascular access flow using extracorporeal temperature gradients.

A reduction in vascular access flow poses a risk for thrombosis. We present a new technique to measure vascular access flow during dialysis based on extracorporeal temperature gradients, and their changes, on reversing the extracorporeal bloodlines without having to inject an indicator. Fistula temperatures were measured by the blood temperature monitor with normal line position and after manual switching of the bloodlines using the same extracorporeal blood flow. The access flow by our temperature gradient method (TGM) was compared to access flow derived by saline dilution with measurements in the same patients repeated in subsequent weeks. In 70 pairs of TGM and saline dilution measurements in 35 patients, the repeatability of the TGM measurements was not significantly different from that of saline dilution. There was a highly significant correlation between the two techniques with an acceptable confidence level for limits of agreement for the difference between them. It took about 9 min to complete the TGM method and about 5 min for saline dilution. Our studies show that the novel TGM method showed excellent agreement and reproducibility with the saline dilution method without the need for indicator dilution.

Selection of oral microbial adhesion antagonists using biotinylated Streptococcus sanguis and a human mixed oral microflora.

A microtitre assay has been developed using hydroxyapatite-coated wells and Streptococcus sanguis NCTC 10904 at 10(7) cells per ml. A number of models representing toothpaste and mouthwash usage were adopted to detect the anti-adherent efficacy of a polyvinylmethylether maleic acid copolymer (PVM/MA), polyoxypropylene/polyoxyethylene block copolymer (PO/EO), two casein-derived peptides and selected silicones. The results not only confirmed the anti-adherence property of the selected components but also indicated possible molecular interactions leading to the observed performance. To account for the diversity of oral microbial cells in vivo, a further testing system was developed. This involved submerging a hydroxyapatite disc in a mixed culture of human salivary microbial cells, and exposing it to different treatments using the active component either in an aqueous dispersion or in a toothpaste. The effect of toothpastes containing PO/EO, dimethicone copoyol or PVM/MA was investigated over a 4-h incubation with microflora. These tests showed that in a toothpaste formulation the anti-adherent efficacy may be reduced when compared with an aqueous dispersion containing the same or nearly the same concentration of the active component.

A family therapeutic approach to transgenerational traumatization.

The phenomenon of transgenerational traumatization has currently become widely recognized and described, although the task of disentangling the underlying interactional mechanisms remains a difficult one. These transgenerational mechanisms were first detected in families of the survivors of the Holocaust, but they may be equally prominent in families of parents who have been traumatized in other ways, for example, as victims of child neglect and abuse, as orphaned children, or during military service. In cases in which parents have themselves been subjected to early parental deprivation, one or more children may become projectively identified with a parent's (posttraumatic) "bad child"-self, whereas the parent him/herself has identified with--enacts the role of--the idealized internal "martyr" parent. A case study is presented describing the individual and family therapeutic treatment of a woman who, as a child, had been traumatically separated from her parents.

Expression of proteins correlated with the unique cisplatin-sensitivity of testicular cancer.

Cisplatin (CDDP) has a curative effect in approximately 80%, of patients with testicular cancer, in contrast to the frequent development of resistance in patients with small cell lung cancer and ovarian cancer, and to the natural resistance of colon cancer. At present it is unknown which factors explain the unique curability of testicular cancer. Since it is very likely that the absence or presence of specific proteins plays an important role in cellular sensitivity towards CDDP, we have screened the protein patterns of various human CDDP-sensitive cell lines and cell lines with acquired or intrinsic resistance to CDDP of testicular, lung and colon origin. The expression of several proteins appeared to correlate with in vitro CDDP sensitivity. The most striking difference found was a relative increase in expression lactate dehydrogenase (LDH) H-subunit expression in the germ cell lines. In testis and colon tumour samples some of these proteins, LDH-H included, also appeared to correlate with in vivo CDDP sensitivity. In the analysis of the mechanisms of drug-resistance, screening of the protein patterns of intrinsic sensitive and resistant cell lines could be a valuable approach.

Effects of low dose methotrexate therapy on the concentration and the glycosylation of alpha 1-acid glycoprotein in the serum of patients with rheumatoid arthritis: a longitudinal study.

OBJECTIVE: The concentration, and the degree of fucosylation and sialylation of human serum alpha 1-acid glycoprotein (AGP) were investigated for changes during 24-week low-dose methotrexate (MTX) or azathioprine treatment (AZA) in rheumatoid arthritis (RA) patients. METHODS: Serum samples from a longitudinal study were analyzed by crossed affinoimmunoelectrophoresis with the fucose specific Aleuria aurantia lectin. RESULTS: In general, the degree of fucosylation of AGP in RA sera was higher than in control sera, but decreased markedly under the influence of successful therapy with MTX. Concomitantly, the degree of sialylation of AGP increased and the concentration decreased. For alpha 1-protease inhibitor and haptoglobin similar results were obtained. In AZA responders less pronounced changes than in MTX responders were observed. In MTX nonresponders no significant trends were found. As in control sera, large interindividual differences in the AGP values were found. CONCLUSION: The heavy fucosylation of AGP in RA sera reflects disease activity rather than an intrinsic characteristic of people genetically predisposed to RA, since it was found to decrease upon disease improvement. The differences in effects on AGP of MTX and AZA suggest either a gradual difference in a similar mechanism of action, or a different mechanism of action of the drugs. Fucosylated and sialylated AGP could be important in the etiopathogenesis of RA, because these molecules potentially can bind to adhesion receptors (selectins), which could prevent the extravasation of leukocytes into inflamed joints.

Antimetabolite-induced increases in the invasive capacity of murine leukaemia L1210 cells.

Pretreatment of murine leukaemia L1210 cells with non-lethal concentrations of various antimetabolites increased the in vitro invasive capacity of these cells into monolayers of rat embryo fibroblasts. The increase in invasive capacity was partly correlated with the induced cell cycle arrest. The concomitant increase in cell surface fucosylation and inhibition of invasion with sulphate indicate a role for glycoproteins in this process. Our results suggest that treatment with antimetabolites may lead to a more aggressive phenotype by altering cell surface properties.

Assay and purification of Fv fragments in fermenter cultures: design and evaluation of generic binding reagents.

Fv fragments whose genes have been cloned using common PCR primers carry identical peptide motifs at their termini. We have raised antibodies against the C-terminal motif of the VH chain GQGTTVTVSS and evaluated their utility as reagents for the assay and purification of Fvs in the fermenter culture. Three different Fvs were included in the investigation. We found that the motif was exposed and available for capture when Fv fragments were blotted onto nitrocellulose paper or adsorbed directly onto microtiter plates. In contrast, the motif was either partially or totally obscured when the Fv was complexed with immobilised antigen or when free in solution. This reactivity profile enabled us to develop a general-purpose assay for Fv protein, but not a general-purpose assay for monitoring active Fv. The apparent inaccessibility of the C-terminus of VH conflicts with currently held views on the three-dimensional structure of these molecules.