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Problem: Human papillomavirus infection is integral to developing invasive cervical cancer in the majority of patients. In a recent genome-wide association study, rs9357152 and rs4243652 have been associated with seropositivity for HPV16 or HPV18, respectively. It is unknown whether these variants also associate with cervical cancer triggered by either HPV16 or HPV18. Methods: We investigate whether the two HPV susceptibility variants show association with type-specific cervical cancer in a genetic case-control study with cases stratified by HPV16 or HPV18, respectively. We further tested whether rs9357152 modulates gene expression of any of 36 genes at the human leukocyte antigen locus in 256 cervical tissues. Results: rs9357152 was associated with invasive HPV16-positive cervical cancer (OR 1.33, 95%CI 1.03–1.70, p = 0.03), and rs4243652 was associated with HPV18-positive adenocarcinomas (OR 2.96, 95%CI 1.18–7.41, p = 0.02). These associations remained borderline significant after testing against different sets of controls. rs9357152 was found to be an eQTL for HLA-DRB1 in HPV-positive cervical tissues (pANOVA = 0.0009), with the risk allele lowering mRNA levels. Conclusions: We find evidence that HPV seropositivity variants at chromosome 6 and 14 may modulate type-specific cervical cancer risk. rs9357152 may exert its effect through regulating HLA-DRB1 induction in the presence of HPV. In regard of multiple testing, these results need to be confirmed in larger studies.

Abstract Research on the impact of auditory information on visual anticipation in tennis suggests that the intensity of racket-ball-contact sounds systematically biases estimates of the ball’s speed, thereby influencing anticipatory judgments. Here we examined whether the effect of auditory information on visual anticipation is dependent on the sport-specific context in two separate experiments. In Exp. 1, participants watched short videos of tennis rallies that were occluded at racket-ball-contact. Racket-ball-contact sounds of the final shot were either present or absent. Participants faced different tasks in two counterbalanced blocks: In one block they estimated the ball’s speed; in the other block they indicated the ball’s landing location. Results showed that participants estimated longer ball flight trajectories and higher ball speeds in the sound present condition than in the sound absent condition. To probe whether this effect is dependent on the sport-specific context, Exp. 2 introduced an abstract (i.e., context-free) version of the previous stimuli. Based on the ball locations in the original videos used in Exp. 1, we rendered new videos that displayed only a moving circle against a blank background. Sine tones replaced the original racket-ball contact sounds. Results showed no impact of sound presence on location anticipation judgments. However, similar to Exp. 1, object speeds were judged to be faster when the final sound was present. Together, these findings suggest that the impact of auditory information on anticipation does not seem to be driven by sound alone, but to be moderated by contextual information.

Abstract Neuronal activity in the brain reflects an excitation–inhibition balance that is regulated predominantly by glutamatergic and GABAergic neurotransmission, and often disturbed in neuropsychiatric disorders. Here, we tested the effects of a single oral dose of two anti-glutamatergic drugs (dextromethorphan, an NMDA receptor antagonist; perampanel, an AMPA receptor antagonist) and an L-type voltage-gated calcium channel blocker (nimodipine) on transcranial magnetic stimulation (TMS)-evoked electroencephalographic (EEG) potentials (TEPs) and TMS-induced oscillations (TIOs) in 16 healthy adults in a pseudorandomized, double-blinded, placebo-controlled crossover design. Single-pulse TMS was delivered to the hand area of left primary motor cortex. Dextromethorphan increased the amplitude of the N45 TEP, while it had no effect on TIOs. Perampanel reduced the amplitude of the P60 TEP in the non-stimulated hemisphere, and increased TIOs in the beta-frequency band in the stimulated sensorimotor cortex, and in the alpha-frequency band in midline parietal channels. Nimodipine and placebo had no effect on TEPs and TIOs. The TEP results extend previous pharmaco-TMS-EEG studies by demonstrating that the N45 is regulated by a balance of GABAAergic inhibition and NMDA receptor-mediated glutamatergic excitation. In contrast, AMPA receptor-mediated glutamatergic neurotransmission contributes to propagated activity reflected in the P60 potential and midline parietal induced oscillations. This pharmacological characterization of TMS-EEG responses will be informative for interpreting TMS-EEG abnormalities in neuropsychiatric disorders with pathological excitation–inhibition balance.

Background: Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is an effective treatment for major depressive disorder (MDD), but response rates are low and effect sizes small. Synchronizing TMS pulses with instantaneous brain oscillations can reduce variability and increase efficacy of TMS-induced plasticity. Objective: To study whether brain oscillation-synchronized rTMS is feasible, safe and has neuromodulatory effects when targeting the DLPFC of patients with MDD. Methods: Using real-time EEG-triggered TMS we conducted a pseudo-randomized controlled single-session crossover trial of brain oscillation-synchronized rTMS of left DLPFC in 17 adult patients with antidepressant-resistant MDD. Stimulation conditions in separate sessions were: (1) rTMS triggered at the negative EEG peak of instantaneous alpha oscillations (alpha-synchronized rTMS), (2) a variation of intermittent theta-burst stimulation (modified iTBS), and (3) a random alpha phase control condition. Results: Triggering TMS at the negative peak of instantaneous alpha oscillations by real-time analysis of the electrode F5 EEG signal was successful in 15 subjects. Two subjects reported mild transient discomfort at the site of stimulation during stimulation; no serious adverse events were reported. Alpha-synchronized rTMS, but not modified iTBS or the random alpha phase control condition, reduced resting-state alpha activity in left DLPFC and increased TMS-induced beta oscillations over frontocentral channels. Conclusions: Alpha-synchronized rTMS of left DLPFC is feasible, safe and has specific single-session neuromodulatory effects in patients with antidepressant-resistant MDD. Future studies need to further elucidate the mechanisms, optimize the parameters and investigate the therapeutic potential and efficacy of brain oscillation-synchronized rTMS in MDD.

Established research has documented the pervasive influence of incentives (i.e., food, sex, money) on animal and human behavior. Additionally, motivational theories postulating intra-individually stable preferences for specific types of incentives (i.e., motives) highlight that effects of a given incentive are highly dependent on the motive disposition of the individual. Indeed, also research on motor performance has documented the interactive effects of motives and motive-specific incentives on motor outcomes. However, the majority of this research has relied on correlational designs focusing on the effects of the achievement motive, with few studies addressing the role of the affiliation and power motive. In order to extend findings in this domain, we tested whether a fit between individuals' power (affiliation) motive and incentives of competition (cooperation) would improve motor performance. Following baseline measures, participants performed a dart-throwing task as part of a dyadic performance (i.e., cooperative) or a one-on-one competition scenario. In the dyadic performance scenario, a stronger affiliation motive did not translate to better performance. However, in the one-on-one competition scenario a stronger power motive was associated with better performance. Results highlight the role of the power motive in predicting motor performance, particularly in competitive situations.

Neurologic music therapy in rehabilitation of stroke patients has been shown to be a promising supplement to the often strenuous conventional rehabilitation strategies. The aim of this study was threefold: (i) replicate results from a previous study with a sample from one clinic (henceforth called Site 1; N = 12) using an already established recording system, and (ii) conceptually replicate previous findings with a less costly hand-tracking system in Site 2 (N = 30), and (iii) compare both sub-studies’ outcomes to estimate the efficiency of neurologic music therapy. Stroke patients in both sites were randomly assigned to treatment or control groups and received daily training of guided sequential upper limb movements additional to their standard stroke rehabilitation protocol. Treatment groups received sonification (i.e., changes in musical pitch) of their movements when they moved their affected hand up and down to reproduce a sequence of the first six notes of a C major scale. Controls received the same movement protocol, however, without auditory feedback. Sensors at the upper arm and the forearm (Xsens) or an optic sensor device (Leapmotion) allowed to measure kinematics of movements and movement smoothness. Behavioral measures pre and post intervention included the Fugl-Meyer assessment (FMA) and the Stroke Impact Scale (SIS) and movement data. Bayesian regression did not show evidence supporting an additional effect of sonification on clinical mobility assessments. However, combined movement data from both sites showed slight improvements in movement smoothness for the treatment group, and an advantage for one of the two motion capturing systems. Exploratory analyses of EEG-EMG phase coherence during movement of the paretic arm in a subset of patients suggested increases in cortico-muscular phase coherence specifically in the ipsilesional hemisphere after sonification therapy, but not after standard rehabilitation therapy. Our findings show that musical sonification is a viable treatment supplement to current neurorehabilitation methods, with limited clinical benefits. However, given patients’ enthusiasm during training and the low hardware price of one of the systems it may be considered as an add-on home-based neurorehabilitation therapy.

Identification of propositions as the core of attitudes and beliefs (De Houwer, 2014) has resulted in the development of implicit measures targeting personal evaluations of complex sentences (e.g., the IRAP or the RRT). Whereas their utility is uncontested, these paradigms are subject to limitations inherent in their block-based design, such as allowing assessment of only a single belief at a time. We introduce the Propositional Evaluation Paradigm (PEP) for assessment of multiple propositional beliefs within a single experimental block. Two experiments provide first evidence for the PEP’s validity. In Experiment 1, endorsement of racist beliefs measured with the PEP was related to criterion variables such as explicit racism assessed via questionnaire and indicators of behavioral tendencies. Experiment 2 indicates that the PEP’s implicit racism scores may predict actual behavior over and above explicit, self-report measures. Finally, Experiment 3 tested the PEP’s applicability in the domain of hiring discrimination. Whereas general PEP-based gender stereotypes were not related to hiring bias, results suggest a possible role of female stereotypes in hiring discrimination. In the context of these findings, we discuss both the potential and possible challenges in adopting the PEP to different beliefs. In sum, these initial findings suggest that the PEP may offer researchers a reliable and easily administrable option for the indirect assessment of propositional evaluations.

Two decades ago, the introduction of the Implicit Association Test (IAT) sparked enthusiastic reactions. With implicit measures like the IAT, researchers hoped to finally be able to bridge the gap between self-reported attitudes on one hand and behavior on the other. Twenty years of research and several meta-analyses later, however, we have to conclude that neither the IAT nor its derivatives have fulfilled these expectations. Their predictive value for behavioral criteria is weak and their incremental validity over and above self-report measures is negligible. In our review, we present an overview of explanations for these unsatisfactory findings and delineate promising ways forward. Over the years, several reasons for the IAT’s weak predictive validity have been proposed. They point to four potentially problematic features: First, the IAT is by no means a pure measure of individual differences in associations but suffers from extraneous influences like recoding. Hence, the predictive validity of IAT-scores should not be confused with the predictive validity of associations. Second, with the IAT, we usually aim to measure evaluation (“liking”) instead of motivation (“wanting”). Yet, behavior might be determined much more often by the latter than the former. Third, the IAT focuses on measuring associations instead of propositional beliefs and thus taps into a construct that might be too unspecific to account for behavior. Finally, studies on predictive validity are often characterized by a mismatch between predictor and criterion (e.g., while behavior is highly context-specific, the IAT usually takes into account neither the situation nor the domain). Recent research, however, also revealed advances addressing each of these problems, namely (1) procedural and analytical advances to control for recoding in the IAT, (2) measurement procedures to assess implicit wanting, (3) measurement procedures to assess implicit beliefs, and (4) approaches to increase the fit between implicit measures and behavioral criteria (e.g., by incorporating contextual information). Implicit measures like the IAT hold an enormous potential. In order to allow them to fulfill this potential, however, we have to refine our understanding of these measures, and we should incorporate recent conceptual and methodological advancements. This review provides specific recommendations on how to do so.

Grunting in tennis is a widespread phenomenon and whether it influences opponents' predictions of ball trajectory-and if so, why-is subject of ongoing debate. Two alternative hypotheses have been proposed to explain why grunting may impede opponents' predictions, referred to as the distraction account (i.e., grunts capture attentional resources necessary for anticipation) and the multisensory integration account (i.e., auditory information from the grunt systematically influences ball trajectory prediction typically assumed to rely on visual information). To put these competing hypotheses to test, in the current study we presented tennis players with a series of temporally occluded video clips of tennis rallies featuring experimentally amplified, attenuated, or muted grunting sounds. Participants were asked to predict the ball landing position. Results indicated that higher grunt intensities yielded judgments of longer ball trajectories whereas radial prediction errors were not affected. These results are clearly at odds with the distraction account of grunting, predicting increased prediction errors after higher intensity grunts. In contrast, our findings provide strong support for the multisensory integration account by demonstrating that grunt intensity systematically influences judgments of ball trajectory.

Repetitive transcranial magnetic stimulation (rTMS) is widely used as a therapeutic tool yet its effect on inhibitory networks in the brain has not been studied. Here, the authors demonstrate that 10Hz rTMS specifically reduces dendritic inhibition onto pyramidal neurons accompanied by remodeling of postsynaptic gephyrin clusters.

In migratory songbirds, older individuals are thought to be more efficient migrants than younger individuals. Age‐specific differences in migratory efficiency have been reported mainly in respect of arrival timing, energy stores, rate of energy accumulation, departure behaviour, and departure direction. Yet, these traits were rarely assessed simultaneously in a single species. We further lack information whether age‐specific differences in behavioural traits present in autumn still manifest to the same degree in spring. Here we used the northern wheatear Oenanthe oenanthe, a long‐distance nocturnal songbird migrant, and investigated age‐specific differences in energy stores at capture (autumn: 1059 birds/spring: 803 birds), rate of energy accumulation (168/147), nocturnal departure timing (126/105), and departure direction (94/77) for both seasons. We found that in autumn, young northern wheatears departed significantly later in the night than older birds. This difference was not observed in spring. The resulting advance in nocturnal departure timing by young birds from autumn to spring may be due to learning based on experience gained during autumn, and/or to selective disappearance of those young individuals showing late departure times during autumn. We found no age‐specific difference in any of the other migratory traits investigated. To get a better understanding of age effects in songbird migrants, we need to study the potential adjustments of migratory behaviour within the individual over its life time. By individually tracking songbirds throughout their lifetime, we could start estimating whether a certain migratory decision (fuelling, departure, orientation) translates into higher (or lower) fitness, and whether individuals adjust their migratory behaviour based on learning from ‘wrong decisions’.

Evoked potentials (EPs) are well established in clinical practice for diagnosis and prognosis in multiple sclerosis (MS). However, their value is limited to the assessment of their respective functional systems. Here, we used transcranial magnetic stimulation (TMS) coupled with electroencephalography (TMS-EEG) to investigate cortical excitability and spatiotemporal dynamics of TMS-evoked neural activity in MS patients. Thirteen patients with early relapsing–remitting MS (RRMS) with a median Expanded Disability Status Scale (EDSS) of 1.0 (range 0–2.5) and 16 age- and gender-matched healthy controls received single-pulse TMS of left and right primary motor cortex (L-M1 and R-M1), respectively. Resting motor threshold for L-M1 and R-M1 was increased in MS patients. Latencies and amplitudes of N45, P70, N100, P180, and N280 TMS-evoked EEG potentials (TEPs) were not different between groups, except a significantly increased amplitude of the N280 TEP in the MS group, both for L-M1 and R-M1 stimulation. Interhemispheric signal propagation (ISP), estimated from the area under the curve of TEPs in the non-stimulated vs. stimulated M1, also did not differ between groups. In summary, findings show that ISP and TEPs were preserved in early-stage RRMS, except for an exaggerated N280 amplitude. Our findings indicate that TMS-EEG is feasible in testing excitability and connectivity in cortical neural networks in MS patients, complementary to conventional EPs. However, relevance and pathophysiological correlates of the enhanced N280 will need further study.

The pre-supplementary motor area (pre-SMA) is engaged in speech comprehension under difficult circumstances such as poor acoustic signal quality or time-critical conditions. Previous studies found that left pre-SMA is activated when subjects listen to accelerated speech. Here, the functional role of pre-SMA was tested for accelerated speech comprehension by inducing a transient “virtual lesion” using continuous theta-burst stimulation (cTBS). Participants were tested (1) prior to (pre-baseline), (2) 10 min after (test condition for the cTBS effect), and (3) 60 min after stimulation (post-baseline) using a sentence repetition task (formant-synthesized at rates of 8, 10, 12, 14, and 16 syllables/s). Speech comprehension was quantified by the percentage of correctly reproduced speech material. For high speech rates, subjects showed decreased performance after cTBS of pre-SMA. Regarding the error pattern, the number of incorrect words without any semantic or phonological similarity to the target context increased, while related words decreased. Thus, the transient impairment of pre-SMA seems to affect its inhibitory function that normally eliminates erroneous speech material prior to speaking or, in case of perception, prior to encoding into a semantically/pragmatically meaningful message.

Executive dysfunctions frequently occur in patients with Major Depressive Disorder and have been shown to improve during effective antidepressant treatment. However, the time course of improvement and its relationship to treatment outcome is unknown. The aim of the study was to assess the test performance and clinical outcome by repetitive assessments of executive test procedures during antidepressant treatment. Executive test performance was assessed in 209 -patients with Major Depressive Disorder (mean age 39.3 ± 11.4 years) and 84 healthy controls five times in biweekly intervals from baseline to week 8. Patients were treated by a defined treatment algorithm within the early medication change study (EMC trial; ClinicalTrials.gov NCT00974155), controls did not receive any intervention. Cognitive domains were processing speed, cognitive flexibility, phonemic and semantic verbal fluency. Intelligence was assessed at baseline. Depression severity was tested once a week by the Hamilton Depression Rating Scale (HAMD17). 130 patients (62%) showed executive dysfunctions in at least one of four tests at baseline. Linear mixed regression models revealed that the course of depression severity was associated to the course of cognitive flexibility (p = 0.004) and semantic verbal fluency (p = 0.020). Cognitive flexibility and semantic verbal fluency may be candidates easily to apply for therapy response prediction in clinical routine, which should be tested in further prospective studies.ClinicalTrials.gov NCT00974155 EudraCT: 2008-008280-96.

Sexual reproduction is a critical process in the life-cycle of plants and very sensitive to environmental perturbations. To better understand the effect of high temperature on plant reproduction, we cultivated tomato (Solanum lycopersicum) plants in continuous mild heat. Under this condition we observed a simultaneous reduction in pollen viability and appearance of anthers with pistil-like structures, while in a more thermotolerant genotype, both traits were improved. Ectopic expression of two pistil-specific genes, TRANSMITTING TISSUE SPECIFIC and TOMATO AGAMOUS LIKE11, in the anthers confirmed that the anthers had gained partial pistil identity. Concomitantly, expression of the B-class genes TOMATO APETALA3, TOMATO MADS BOX GENE6 (TM6) and LePISTILLATA was reduced in anthers under continuous mild heat. Plants in which TM6 was partially silenced reacted hypersensitively to temperature elevation with regard to the frequency of pistilloid anthers, pollen viability and pollen quantity. Taken together, these results suggest that high-temperature-induced down-regulation of tomato B-class genes contributes to anther deformations and reduced male fertility. Improving our understanding of how temperature perturbs the molecular mechanisms of anther and pollen development will be important in the view of maintaining agricultural output under current climate changes.

Paired associative stimulation (PASLTP) of the human primary motor cortex (M1) can induce LTP-like plasticity by increasing corticospinal excitability beyond the stimulation period. Previous studies showed that two consecutive PASLTP protocols interact by homeostatic metaplasticity, but animal experiments provided evidence that LTP can be augmented by repeated stimulation protocols spaced by ~30 min. Here we tested in twelve healthy selected PASLTP responders the possibility that LTP-like plasticity can be augmented in the human M1 by systematically varying the interval between two consecutive PASLTP protocols. The first PASLTP protocol (PAS1) induced strong LTP-like plasticity lasting for 30-60 min. The effect of a second identical PASLTP protocol (PAS2) critically depended on the time between PAS1 and PAS2. At 10 min, PAS2 prolonged the PAS1-induced LTP-like plasticity. At 30 min, PAS2 augmented the LTP-like plasticity induced by PAS1, by increasing both magnitude and duration. At 60 min and 180 min, PAS2 had no effect on corticospinal excitability. The cumulative LTP-like plasticity after PAS1 and PAS2 at 30 min exceeded significantly the effect of PAS1 alone, and the cumulative PAS1 and PAS2 effects at 60 min and 180 min. In summary, consecutive PASLTP protocols interact in human M1 in a time-dependent manner. If spaced by 30 min, two consecutive PASLTP sessions can augment LTP-like plasticity in human M1. Findings may inspire further research on optimized therapeutic applications of non-invasive brain stimulation in neurological and psychiatric diseases.

In this manuscript we describe for the first time mirror image catalytic nucleic acids (Spiegelzymes), which hydrolyze sequence specifically L-ribonucleic acid molecules. The mirror image nucleic acid ribozymes designed are based upon the known hammerhead ribozyme and DNAzyme structures that contain L-ribose or L-deoxyribose instead of the naturally occurring D-ribose or D-deoxyribose, respectively. Both Spiegelzymes show similar hydrolytic activities with the same L-RNA target molecules and they also exhibit extra ordinary stabilities when tested with three different human sera. In this respect they are very similar to Spiegelmers (mirror image aptamers), which we had previously developed and for which it has been shown that they are non-toxic and non-immunogenic. Since we are also able to demonstrate that the hammerhead and DNAzyme Spiegelzymes can also hydrolyze mirror image oligonucleotide sequences, like they occur in Spiegelmers, in vivo, it seems reasonable to assume that Spiegelzymes may in principle be used as an antidote against Spiegelmers. Since the Spiegelzymes contain the same building blocks as the Spiegelmers, it can be expected that they will have similar favorable biological characteristics concerning toxicity and immunogenety. In trying to understand the mechanism of action of the Spiegelzymes described in this study, we have initiated for the first time a model building system with L-nucleic acids. The models for L-hammerhead ribozyme and L-DNAzyme interaction with the same L-RNA target will be presented.

Spike-timing dependent plasticity (STDP) has been studied extensively in a variety of animal models during the past decade but whether it can be studied at the systems level of the human cortex has been a matter of debate. Only recently newly developed non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) have made it possible to induce and assess timing dependent plasticity in conscious human subjects. This review will present a critical synopsis of these experiments, which suggest that several of the principal characteristics and molecular mechanisms of TMS-induced plasticity correspond to those of STDP as studied at a cellular level. TMS combined with a second phasic stimulation modality can induce bidirectional long-lasting changes in the excitability of the stimulated cortex, whose polarity depends on the order of the associated stimulus-evoked events within a critical time window of tens of milliseconds. Pharmacological evidence suggests an NMDA receptor mediated form of synaptic plasticity. Studies in human motor cortex demonstrated that motor learning significantly modulates TMS-induced timing dependent plasticity, and, conversely, may be modulated bidirectionally by prior TMS-induced plasticity, providing circumstantial evidence that long-term potentiation-like mechanisms may be involved in motor learning. In summary, convergent evidence is being accumulated for the contention that it is now possible to induce STDP-like changes in the intact human central nervous system by means of TMS to study and interfere with synaptic plasticity in neural circuits in the context of behaviour such as learning and memory.