Transcranial Stimulation of the Orbitofrontal Cortex Affects Decisions about Magnocellular Optimized Stimuli.

Visual categorization plays an important role in fast and efficient information processing; still the neuronal basis of fast categorization has not been established yet. There are two main hypotheses known; both agree that primary, global impressions are based on the information acquired through the magnocellular pathway (MC). It is unclear whether this information is available through the MC that provides information (also) for the ventral pathway or through top-down mechanisms by connections between the dorsal pathway and the ventral pathway via the frontal cortex. To clarify this, a categorization task was performed by 48 subjects; they had to make decisions about objects' sizes. We created stimuli specific to the magno- and parvocellular pathway (PC) on the basis of their spatial frequency content. Transcranial direct-current stimulation was used to assess the role of frontal areas, a target of the MC. Stimulation did not bias the accuracy of decisions when stimuli optimized for the PC were used. In the case of stimuli optimized for the MC, anodal stimulation improved the subjects' accuracy in the behavioral test, while cathodal stimulation impaired accuracy. Our results support the hypothesis that fast visual categorization processes rely on top-down mechanisms that promote fast predictions through coarse information carried by MC via the orbitofrontal cortex.

Can we still learn from single center experience after PARTNER?

With the publication of the Placement of Aortic Transcatheter Valves (PARTNER) trial, transcatheter aortic valve replacement (TAVR) has undoubtedly become the gold standard for severe aortic stenosis in patients that are not suitable candidate for surgical aortic valve replacement (AVR). The PARTNER trial also showed that TAVR is non-inferior to AVR in high-risk patients. A recent publication by Ben-Dor et al evaluated the outcome of high-risk patients with severe aortic stenosis who were referred to their institution for participation to the PARTNER trial. Only a minority of patients made it in the trial and the majority of patient ended being treated medically. Some patients were also treated with AVR outside the trial. The outcomes of all these patients were stratified by the treatment they received (AVR, TAVR or medical therapy with or without balloon aortic valvuloplasty). The 3 groups were different in their baseline characteristics. Ben-Dor et al found that patients treated medically had greater mortality than patients treated with TAVR or AVR. The survival of patients treated with TAVR was similar to those treated with AVR. Independent predictors of mortality were also found from their analysis. In this commentary, we discuss the finding of this study and compare it with the current literature.

Immunological fingerprinting of group B streptococci: from circulating human antibodies to protective antigens.

Group B streptococcus is one of the most important pathogens in neonates, and causes invasive infections in non-pregnant adults with underlying diseases. Applying a genomic approach that relies on human antibodies we identified antigenic GBS proteins, among them most of the previously published protective antigens. In vitro analyses allowed the selection of conserved candidate antigens that were further evaluated in murine lethal sepsis models using several GBS strains. In active and passive immunization models, we identified four protective GBS antigens, FbsA and BibA, as well as two hypothetical proteins, all shown to contribute to virulence based on gene deletion mutants. These protective antigens have the potential to be components of novel vaccines or targets for passive immune prophylaxis against GBS disease.

Association of the GABRD gene and childhood-onset mood disorders.

The chromosome 1p36 region was previously indicated as a locus for susceptibility to recurrent major depressive disorder based on a linkage study in a sample of 497 sib pairs. We investigated the gamma-aminobutyric acid A (GABA(A)) delta receptor subunit gene, GABRD, as a susceptibility gene to childhood-onset mood disorders (COMD) because of substantial evidence implicating GABAergic dysfunction in mood disorders and the position of this gene near the 1p36 linkage region. Using a sample consisting of 645 Hungarian families with a child/adolescent proband diagnosed with a mood disorder with the onset of the first episode before age 15, we found some evidence for the association of two polymorphisms located within the gene, rs2376805 and rs2376803, as well as significant evidence for biased transmission of the haplotypes of these two markers (global chi(2) test for haplotypes = 12.746, 3 df, P = 0.0052). Furthermore, significant evidence of association was only observed in male subjects (n = 438) when the results were analyzed by sex (chi(2) = 9.000 1 df, P = 0.003 for rs2376805). This was in contrast with the previous linkage findings, as LOD scores exceeding 3 were only in female-female pairs in that study. These findings point to the GABRD gene as a susceptibility gene for COMD; however, this gene may not explain the previous linkage finding.

Mutation screen and association analysis of the glucocorticoid receptor gene (NR3C1) in childhood-onset mood disorders (COMD).

Depressive disorders are highly heterogeneous psychiatric disorders involving deficits to cognitive, psychomotor, and emotional processing. Considerable evidence links disruption to the hypothalamic-pituitary-adrenal (HPA) axis to the etiology of depression, with specific deficits reported in glucocorticoid receptor (GR)-mediated negative feedback. Given the role of GR-mediated negative feedback in mediating response to stress, and the clear link between stress and depression, it is plausible that polymorphisms in the GR gene (NR3C1) act to increase susceptibility. Maternal behavior in rats epigenetically alters a NGF1-A transcription factor binding-site in the promoter region of the GR gene, providing a mechanism by which environmental cues can regulate GR expression and thus response to stress. The analogous region of the human GR gene (NR3C1) has not been studied, but it is possible that polymorphisms in this region may alter the binding of transcription factors known to regulate GR expression. In this study, we have performed bioinformatic analyses on the promoter region of NR3C1 to identify conserved promoter sequences and predicted transcription factor binding sites. These regions were screened with denaturing high-performance liquid chromatography (DHPLC) and direct re-sequencing, and several novel polymorphic variants were identified. We genotyped nine polymorphisms across NR3C1 in a large sample of Hungarian nuclear families ascertained through affected probands with a diagnosis of childhood-onset mood disorders (COMD). Single-marker analysis provided little evidence for an association of this gene with COMD, but multi-marker analysis across a region of high linkage disequilibrium revealed modest evidence for the biased transmission of several haplotypes.

Cytokine Genes TNF, IL1A, IL1B, IL6, IL1RN and IL10, and childhood-onset mood disorders.

BACKGROUND/AIMS: Inflammatory cytokines induce a behavioral syndrome, known as sickness behavior, that strongly resembles symptoms typically seen in depression. This resemblance has led to the theory that an imbalance of inflammatory cytokine activity may be a contributing factor in depressive disorders. Support for this is found in multiple lines of evidence, such as the effects of cytokines on the activities of the hypothalamic-pituitary-adrenal axis, serotonin and brain-derived neurotrophic factor, and hippocampal function, all of which are implicated in the etiology of depression. In addition, associations between inflammatory activity and depressive symptomology have been documented in a number of studies, and the depressogenic effects of cytokine therapy are well known. Accordingly, given that depression has a substantial genetic basis, genes involved in the regulation of inflammatory cytokine activity are strong candidates for involvement in genetic susceptibility to depressive disorders. Here, we have tested 6 key genes of this type, TNF, IL1A, IL1B, IL6, IL1RN and IL10, as candidates for involvement in childhood-onset mood disorders. METHODS: In this study of 384 families, each ascertained through a child with depression diagnosed before the age of 15 years, 11 polymorphisms of known or likely functional significance (coding and regulatory variants) were analyzed. RESULTS: Testing for biased transmission of alleles from parents to their affected offspring, we found no evidence for an association between childhood-onset mood disorders and any of the polymorphisms, either individually or as haplotypes. CONCLUSION: The present study does not support the involvement of the TNF, IL1A, IL1B, IL6, IL1RN and IL10 variants as major genetic risk factors contributing to early-onset mood disorders.

Oscillatory brain activity and transcranial direct current stimulation in humans.

The aim of this study was to induce changes of the oscillatory activity in the visual cortex of healthy human subjects by modulation of neuronal excitability using weak transcranial direct current stimulation (tDCS). tDCS is a non-invasive stimulation method which induces prolonged, polarity-dependent increases or reductions in cortical excitability. An increase in high frequency oscillatory activity in the beta and gamma frequency ranges is closely related in time to the N70 peak of the primary visual evoked potential (VEP), which is an early sensory component of visual activation. Therefore this potential can be used to observe tDCS-induced changes related to oscillatory activity. VEPs were recorded using sinusoidal luminance gratings in an on/off mode before, immediately after and 10, 20, 30 min after the end of 10 min anodal or cathodal stimulation. Cathodal stimulation significantly decreased while anodal stimulation slightly increased the normalized beta and gamma frequency powers. We have shown here that tDCS transiently and reversibly changed the organized cortical activity elicited by visual stimulation. Since gamma activity is also related to a higher level of information processing, tDCS might be a suitable method to affect higher order cognitive processes.

Direct current stimulation over V5 enhances visuomotor coordination by improving motion perception in humans.

The primary aim of this study was to determine the extent to which human MT+/V5, an extrastriate visual area known to mediate motion processing, is involved in visuomotor coordination. To pursue this we increased or decreased the excitability of MT+/V5, primary motor, and primary visual cortex by the application of 7 min of anodal and cathodal transcranial direct current stimulation (tDCS) in healthy human subjects while they were performing a visuomotor tracking task involving hand movements. The percentage of correct tracking movements increased specifically during and immediately after cathodal stimulation, which decreases cortical excitability, only when V5 was stimulated. None of the other stimulation conditions affected visuomotor performance. We propose that the improvement in performance caused by cathodal tDCS of V5 is due to a focusing effect on to the complex motion perception conditions involved in this task. This hypothesis was proven by additional experiments: Testing simple and complex motion perception in dot kinetograms, we found that a diminution in excitability induced by cathodal stimulation improved the subject's perception of the direction of the coherent motion only if this was presented among random dots (complex motion perception), and worsened it if only one motion direction was presented (simple movement perception). Our data suggest that area V5 is critically involved in complex motion perception and identification processes important for visuomotor coordination. The results also raise the possibility of the usefulness of tDCS in rehabilitation strategies for neurological patients with visuomotor disorders.

Facilitation of visuo-motor learning by transcranial direct current stimulation of the motor and extrastriate visual areas in humans.

Performance of visuo-motor tasks requires the transfer of visual data to motor performance and depends highly on visual perception and cognitive processing, mainly during the learning phase. The primary aim of this study was to determine if the human middle temporal (MT)+/V5, an extrastriate visual area that is known to mediate motion processing, and the primary motor cortex are involved in learning of visuo-motor coordination tasks. To pursue this, we increased or decreased MT+/V5, primary contralateral motor (M1) and primary visual cortex excitability by 10 min of anodal or cathodal transcranial direct current stimulation in healthy human subjects during the learning phase of a visually guided tracking task. The percentage of correct tracking movements increased significantly in the early learning phase during anodal stimulation, but only when the left V5 or M1 was stimulated. Cathodal stimulation had no significant effect. Also, stimulation of the primary visual cortex was not effective for this kind of task. Our data suggest that the areas V5 and M1 are involved in the early phase of learning of visuo-motor coordination.

No correlation between moving phosphene and motor thresholds: a transcranial magnetic stimulation study.

The aim of this study was to investigate the temporal stability of moving phosphenes and to assess whether moving phosphene thresholds (PTs) correlate with motor thresholds (MTs). Small moving sensations, so-called moving phosphenes, are perceived when V5, an area important for visual motion analysis, is stimulated by transcranial magnetic stimulation (TMS). However, it is still a matter of debate if V5 phosphenes are stable sensations across measurements and if they are a reasonable index of the cortical excitability of V5. Currently, MT is more commonly used as an index of global cortical excitability. However, previous studies have indicated that stationary PTs are suitable alternatives when the primary visual cortex is stimulated by TMS. Using paired-pulse TMS, stationary and moving PTs and applying single pulse TMS, MTs were measured in 11 subjects. PTs were retested in nine subjects 5-7 days later. Stationary and moving PTs were stable within subjects across the two sessions and showed a high inter-correlation. Conversely, PTs and MTs did not correlate. Our results are in agreement with previous studies showing that excitatory measurements of one specific cortex cannot be generalized to the excitability of the whole cortex. Thus, we propose specific measures for cortices of interest: PT for visual experiments and MT for motor experiments.

Excitability changes induced in the human primary visual cortex by transcranial direct current stimulation: direct electrophysiological evidence.

PURPOSE: Transcranial direct current stimulation (tDCS) has been shown to modify the perception threshold of phosphenes elicited by transcranial magnetic stimulation (TMS). The current study was undertaken to examine whether tDCS, when applied over the occipital cortex, is also able to affect visual-evoked potentials (VEPs), which characterize occipital activation in response to visual stimulation, in a polarity-specific way. METHOD: For this purpose, VEPs evoked by sinusoidal luminance grating in an on/off mode were recorded before, immediately after, and 10, 20, and 30 minutes after the end of 5, 10, or 15 minutes of anodal or cathodal tDCS of the primary visual cortex. RESULTS: Significant effects were observed only when low-contrast visual stimuli were applied. Cathodal stimulation decreased, whereas anodal stimulation increased the amplitude of the N70 component. The effect of cathodal stimulation was significant immediately after and 10 minutes after the end of stimulation, if the stimulation duration was sufficiently long (i.e., 10-15 minutes). An increase of N70 amplitude by anodal stimulation was significant only 10 minutes after the end of the 15 minutes tDCS. Cathodal stimulation tended also to affect the amplitude of the P100 component; however, the effect of stimulation was inverse. The amplitude increased immediately after the end of cathodal stimulation. In contrast, anodal stimulation did not affect the P100. The latencies of the N70 and the P100 were not affected by tDCS. CONCLUSIONS: tDCS appears to be a suitable method of inducing reversible excitability changes in a polarity-specific way, not only in the motor but also in the primary visual cortex. The duration of the induced aftereffects depends not only on stimulation duration but also on stimulation polarity. Cathodal stimulation seems to be more effective, in line with previous reports on the motor cortex.

Facilitation of probabilistic classification learning by transcranial direct current stimulation of the prefrontal cortex in the human.

The aim of our study was to test if the electrical stimulation of the prefrontal cortex (PFC) could modify probabilistic classification learning (PCL). Transcranial direct current stimulation (tDCS) was administered to the left prefrontal and to the primary visual cortex of 22 healthy subjects while they performed a PCL task. In this task subjects learned which of two outcomes would occur on each trial after presentation of a particular combination of cues. Ten minutes of anodal, but not cathodal, stimulation improved implicit learning only when the left PFC was stimulated. Our results show that implicit PLC can be modified by weak anodal tDCS, which probably increases neural excitability, as has been shown in the motor and visual cortices previously. Our results suggest that further studies on the facilitation of learning and memory processes by tDCS are warranted.

Modulation of moving phosphene thresholds by transcranial direct current stimulation of V1 in human.

Small moving sensations, so-called moving phosphenes are perceived, when V5, a visual area important for visual motion analysis, is stimulated by transcranial magnetic stimulation (TMS). However, it is still a matter of debate if only V5 takes part in movement perception or other visual areas are also involved in this process. In this study we tested the involvement of V1 in the perception of moving phosphenes by applying transcranial direct current stimulation (tDCS) to this area. tDCS is a non-invasive stimulation technique known to modulate cortical excitability in a polarity-specific manner. Moving and stationary phosphene thresholds (PT) were measured by TMS before, immediately after and 10, 20 and 30 min after the end of 10 min cathodal and anodal tDCS in nine healthy subjects. Reduced PTs were detected immediately and 10 min after the end of anodal tDCS while cathodal stimulation resulted in an opposite effect. Our results show that the excitability shifts induced by V1 stimulation can modulate moving phosphene perception. tDCS elicits transient, but yet reversible effects, thus presenting a promising tool for neuroplasticity research.

Perceptual categorization is impaired in Huntington's disease: an electrophysiological study.

Recent evidence raised the possibility that the neostriatum and the corticostriatal circuits could play an important role in semantic categorization. In this study, we examined the electrophysiological correlates of natural scene categorization in Huntington's disease (HD) patients and their asymptomatic relatives who were Huntington's disease mutation carriers (HDC). Event-related potentials were recorded in HD patients, HDC subjects, and age-matched control subjects using a natural scene categorization task. The subjects had to decide whether a briefly presented image contained animals or no animals. Concerning the N1 component (150-250 ms), the mean amplitudes were more negative for nonanimal scenes as compared with stimuli containing animals at all electrode sites in the control group and at all but the lateral temporal electrode sites (T3, T4) in the HD group. Between-group comparison demonstrated that the N1 amplitudes were significantly smaller for both kinds of stimuli in the HD group in spite of a normal primary occipital component (P100). The HDC subjects were not significantly different from the controls concerning the N1 amplitudes. These results suggest that perceptual (N1) processes related to the categorization of natural scenes are specifically impaired in HD. The findings are in agreement with the hypothesis emphasizing the importance of neostriatal mechanisms in human categorization functions.

Manipulation of phosphene thresholds by transcranial direct current stimulation in man.

Transcranial direct current stimulation (tDCS) can modulate the excitability of the human motor cortex, as revealed by the amplitude of the motor-evoked potentials (MEP). The aim of our study has been to produce localized changes of cerebral excitability of the visual cortex in the intact human by weak anodal and cathodal stimulation. For quantification of current-induced excitability changes, we measured phosphene threshold (PT) using short trains of 5-Hz transcranial magnetic stimulation (TMS) pulses in nine healthy subjects before, immediately after, 10 min, and 20 min after the end of tDCS. PTs are suggested as representative values of visual cortex excitability changes. Reduced PT was detected immediately and 10 min after the end of anodal stimulation, while cathodal stimulation resulted in an opposite effect. Our results show that tDCS elicits a transient, reversible excitability alteration of the visual cortex, thus representing a promising tool for neuroplasticity research.

Pulse configuration-dependent effects of repetitive transcranial magnetic stimulation on visual perception.

Transcranial magnetic stimulation (TMS) is a noninvasive technique for direct stimulation of the neocortex. In the last two decades it is successfully applied in the study of motor and sensory physiology. TMS uses the indirect induction of electrical fields in the brain generated by intense changes of magnetic fields applied to the scalp. It encompasses two widely used waveform configurations: mono-phasic magnetic pulses induce a single current in the brain while biphasic pulses induce at least two currents of inverse direction. As has been shown for the motor cortex, efficacy of repetitive transcranial magnetic stimulation (rTMS) may depend on pulse configuration. In order to clarify this question with regard to visual perception, static contrast sensitivities (sCS) were evaluated before, during, immediately after and 10 minutes after monophasic and biphasic low frequency (1 Hz) rTMS applied to the occipital cortex of 15 healthy subjects. The intensity of stimulation was the phosphene threshold of each individual subject. Using 4 c/d spatial frequency, significant sCS loss was found during and immediately after 10 min of monophasic stimulation, while biphasic stimulation resulted in no significant effect. Ten minutes after the end of stimulation, the sCS values were at baseline level again. However, reversed current flow direction resulted in an increased efficacy of biphasic and decreased efficacy of monophasic stimulation. Our results are in agreement with previous findings showing that primary visual functions, such as contrast detection, can be transiently altered by low frequency transcranial magnetic stimulation. However the effect of modulation significantly depends on the current waveform and direction.