Effects of transcranial magnetic stimulation on reactive response inhibition.

Reactive response inhibition cancels impending actions to enable adaptive behavior in ever-changing environments and has wide neuropsychiatric implications. A canonical paradigm to measure the covert inhibition latency is the stop-signal task (SST). To probe the cortico-subcortical network underlying motor inhibition, transcranial magnetic stimulation (TMS) has been applied over central nodes to modulate SST performance, especially to the right inferior frontal cortex and the presupplementary motor area. Since the vast parameter spaces of SST and TMS enabled diverse implementations, the insights delivered by emerging TMS-SST studies remain inconclusive. Therefore, a systematic review was conducted to account for variability and synthesize converging evidence. Results indicate certain protocol specificity through the consistent perturbations induced by online TMS, whereas offline protocols show paradoxical effects on different target regions besides numerous null effects. Ancillary neuroimaging findings have verified and dissociated the underpinning network dynamics. Sources of heterogeneity in designs and risk of bias are highlighted. Finally, we outline best-practice recommendations to bridge methodological gaps and subserve the validity as well as replicability of future work.

Turning the Light Switch on Binding: Prefrontal Activity for Binding and Retrieval in Action Control.

According to action control theories, responding to a stimulus leads to the binding of response and stimulus features into a common representation, that is, an event file. Repeating any component of an event file retrieves all previously bound information, leading to performance costs for partial repetitions measured in so-called binding effects. Although otherwise robust and stable, binding effects are typically completely absent in "localization tasks," in which participants localize targets with spatially compatible responses. Yet, it is possible to observe binding effects in such when location features have to be translated into response features. We hypothesized that this modulation of binding effects is reflected in task involvement of the dorsolateral pFC (DLPFC). Participants localized targets with either direct (i.e., spatially compatible key) or translated (i.e., diagonally opposite to the spatially compatible key) responses. We measured DLPFC activity with functional near-infrared spectroscopy. On the behavioral level, we observed binding effects in the translated response condition, but not in the direct response condition. Importantly, prefrontal activity was also higher in the translated mapping condition. In addition, we found some evidence for the strength of the difference in binding effects in behavioral data being correlated with the corresponding effects in prefrontal activity. This suggests that activity in the DLPFC reflects the amount of executive control needed for translating location features into responses. More generally, binding effects seem to emerge only when the task at hand involves DLPFC recruitment.

A functional near-infrared spectroscopy study on the prefrontal correlates of cognitive offloading via a personal knowledge assistant.

The saving of previously encoded information boosts both memory for subsequent information (saving-enhanced memory; SEM) as well as cognitive performance in general (saving-enhanced performance; SEP). These findings have been replicated in a setting that involves the assistance by an intelligent software that automatically structures and saves work content in an interactive sidebar. It is assumed that beneficial effects on cognitive performance due to (automatic) saving are caused by a reduction in current workload by means of cognitive offloading. We tested this assumption by measuring neural activity in the dorsolateral prefrontal cortex (DLPFC) via functional near infrared spectroscopy (fNIRS)-once after saving and once after deleting of previously collected information that had to be recalled later-on. On a behavioral level, there was a brief benefit of saving. However, cognitive offloading became most apparent on a neural level: after saving, participants showed significantly lower activation in the right DLPFC. Also, the more participants benefited from cognitive offloading, the more they were able to re-access previously collected, saved information. Thus, fNIRS results indicated reduced mental load after saving, confirming the assumption that saving triggers cognitive offloading.

Time-dependent effects of acute stress on working memory performance: A systematic review and hypothesis.

Laboratory procedures such as the Trier Social Stress Test or the (Socially Evaluated) Cold Pressor Test have been used to investigate working memory performance under stress. Researchers so far have reported a diverse spectrum of stress effects (including the lack thereof) on working memory tasks. We conducted a systematic review of the effect acute stress on working memory performance in standardized laboratory procedures. An overview of the existing literature suggests that acute stress affects working memory in a time-dependent manner, presumably due to the differing time scales of the main stress-reactive hormones involved. Based on the empirical evidence, we hypothesize that the immediate stress-induced release of noradrenaline decreases working memory performance within the first 10 min post stress. In addition, rapid cortisol effects impair working memory at a later time-interval beginning about 25 min post stress. We outline future research directions which could further explore the implications of our insights, as for example combined pharmacological and naturalistic stressor interventions.

The influence of tDCS on perceived bouncing/streaming.

Processing ambiguous situations is a constant challenge in everyday life and sensory input from different modalities needs to be integrated to form a coherent mental representation on the environment. The bouncing/streaming illusion can be studied to provide insights into the ambiguous perception and processing of multi-modal environments. In short, the likelihood of reporting bouncing rather than streaming impressions increases when a sound coincides with the moment of overlap between two moving disks. Neuroimaging studies revealed that the right posterior parietal cortex is crucial in cross-modal integration and is active during the bouncing/streaming illusion. Consequently, in the present study, we used transcranial direct current stimulation to stimulate this brain area. In the active stimulation conditions, a 9 cm2 electrode was positioned over the P4-EEG position and the 35 cm2 reference positioned over the left upper arm. The stimulation lasted 15 min. Each participant did the bouncing/streaming task three times: before, during and after anodal or sham stimulation. In a sample of N = 60 healthy, young adults, we found no influence of anodal tDCS. Bayesian analysis showed strong evidence against tDCS effects. There are two possible explanations for the finding that anodal tDCS over perceptual areas did not modulate multimodal integration. First, upregulation of multimodal integration is not possible using tDCS over the PPC as the integration process already functions at maximum capacity. Second, prefrontal decision-making areas may have overruled any modulated input from the PPC as it may not have matched their decision-making criterion and compensated for the modulation.

Illuminating the prefrontal neural correlates of action sequence disassembling in response-response binding.

Execution of two independent actions in quick succession results in transient binding of these two actions. Subsequent repetition of any of these actions automatically retrieves the other. This process is probably fundamental for developing complex action sequences. However, rigid bindings between two actions are not always adaptive. Sometimes, it is necessary to repeat only one of the two previously executed actions. In such situations, stored action sequences must be disassembled, for the sake of flexibility. Exact mechanisms that allow for such an active unbinding of actions remain largely unknown, but it stands to reason, that some form of prefrontal executive control is necessary. Building on prior neuronal research that explored other forms of binding (e.g. between distractors and responses and abstract representations and responses), we explored middle and superior frontal correlates of -response binding in a sequential classification task with functional near-infrared spectroscopy. We found that anterior dorsolateral prefrontal cortex activity varied as a function of response-repetition condition. Activity in the right anterior dorsolateral prefrontal cortex correlated with changes in reaction times due to response-response binding. Our results indicate that the right anterior dorsolateral prefrontal cortex dismantles bindings between consecutive actions, whenever such bindings interfere with current action goals.

Impact of age on the cumulative risk of transformation in patients with chronic myelomonocytic leukaemia.

In older patients with chronic myelomonocytic leukaemia (CMML) and limited life expectancy due to age and or comorbidities, it is particularly important to consider the risk of transformation for individualised treatment decisions. There is limited information on potential differences between younger and older CMML patients regarding the cumulative risk of transformation as well as haematological, molecular and biologic characteristics. We analysed data from the Austrian Biodatabase for CMML (ABCMML) to compare these parameters in 518 CMML patients. Categorisation of patients into 3 age-related groups: <60 years, 60-79 years and ≥80 years, showed a significantly lower risk of transformation at higher age by competing risk analysis, with a 4-year risk of 39%, 23% and 13%, respectively (P < .0001). The lower probability of transformation was associated with a lower percentage of blast cells in the peripheral blood (PB) of older patients. Furthermore, we provide a simple score based on age, PB blasts and platelet counts that allowed us to define subgroups of CMML patients with a different cumulative transformation risk, including a low-risk group with a transformation risk of only 5%. Our findings may facilitate reasonable treatment decisions in elderly patients with CMML.

Shedding light on the prefrontal correlates of mental workload in simulated driving: a functional near-infrared spectroscopy study.

Optimal mental workload plays a key role in driving performance. Thus, driver-assisting systems that automatically adapt to a drivers current mental workload via brain-computer interfacing might greatly contribute to traffic safety. To design economic brain computer interfaces that do not compromise driver comfort, it is necessary to identify brain areas that are most sensitive to mental workload changes. In this study, we used functional near-infrared spectroscopy and subjective ratings to measure mental workload in two virtual driving environments with distinct demands. We found that demanding city environments induced both higher subjective workload ratings as well as higher bilateral middle frontal gyrus activation than less demanding country environments. A further analysis with higher spatial resolution revealed a center of activation in the right anterior dorsolateral prefrontal cortex. The area is highly involved in spatial working memory processing. Thus, a main component of drivers' mental workload in complex surroundings might stem from the fact that large amounts of spatial information about the course of the road as well as other road users has to constantly be upheld, processed and updated. We propose that the right middle frontal gyrus might be a suitable region for the application of powerful small-area brain computer interfaces.

Shedding light on the frontal hemodynamics of spatial working memory using functional near-infrared spectroscopy.

The dorsolateral prefrontal cortex has been shown to be a key functional network within the middle frontal gyrus in regards to working memory processing. A commonly used paradigm in this line of research is the n-back task. The standard variant of the task requires participants to state whether the current item has been presented n trials prior (or not). Two possible strategies could be used to complete the task. Participants may either actively uphold the last n items in working memory or they may use item familiarity as basis for a decision. Previous functional near infrared spectroscopy studies using this paradigm have reported differing load dependent patterns of middle frontal gyrus activation which might at least in part be attributed to these different strategies. We used a spatial variant of the n-back task in which participants had to reproduce a pattern of locations n trials after presentation. We could thus eliminate the possibility of relying on familiarity for successful task completion. In line with previous functional magnetic resonance imaging studies we found a rise in middle frontal gyrus activity with rising working memory load. This was mainly reflected by a decrease in concentration of deoxygenated blood in this area. In line with previous research utilizing spatial paradigms, we found a lateralization of activity to the right hemisphere. We propose that the forced recall version of the n-back task is a valid alternative to the standard paradigm and can eliminate unwanted variance due to differing strategies, especially in high load conditions.

Correlation of RAS-Pathway Mutations and Spontaneous Myeloid Colony Growth with Progression and Transformation in Chronic Myelomonocytic Leukemia-A Retrospective Analysis in 337 Patients.

Although the RAS-pathway has been implicated as an important driver in the pathogenesis of chronic myelomonocytic leukemia (CMML) a comprehensive study including molecular and functional analyses in patients with progression and transformation has not been performed. A close correlation between RASopathy gene mutations and spontaneous in vitro myeloid colony (CFU-GM) growth in CMML has been described. Molecular and/or functional analyses were performed in three cohorts of 337 CMML patients: in patients without (A, n = 236) and with (B, n = 61) progression/transformation during follow-up, and in patients already transformed at the time of sampling (C, n = 40 + 26 who were before in B). The frequencies of RAS-pathway mutations (variant allele frequency ≥ 20%) in cohorts A, B, and C were 30%, 47%, and 71% (p < 0.0001), and of high colony growth (≥20/105 peripheral blood mononuclear cells) 31%, 44%, and 80% (p < 0.0001), respectively. Increases in allele burden of RAS-pathway mutations and in numbers of spontaneously formed CFU-GM before and after transformation could be shown in individual patients. Finally, the presence of mutations in RASopathy genes as well as the presence of high colony growth prior to transformation was significantly associated with an increased risk of acute myeloid leukemia (AML) development. Together, RAS-pathway mutations in CMML correlate with an augmented autonomous expansion of neoplastic precursor cells and indicate an increased risk of AML development which may be relevant for targeted treatment strategies.

It is more than Interference: Examining the neurohemodynamic correlates of the flanker task with functional near-infrared spectroscopy.

Previous functional near-infrared spectroscopy studies using the Eriksen flanker task, in contrast to functional magnetic resonance imaging studies, revealed the quite puzzling finding of an inverted conflict effect, that is, greater middle and superior frontal activation in response compatible than in response incompatible trials. However, since neither prior functional near-infrared spectroscopy studies nor most previous functional magnetic resonance imaging studies separated between an identical and a compatible condition, it is hard to pinpoint whether this discrepancy occurs on the level of stimulus processing or response generation. By assigning two letters to both left (D, F) and right (J, K) hand reactions, we were able to separate identical (e.g., JJJ) and compatible (e.g., JKJ) conditions that solely differ in their stimulus congruency. Replicating prior functional magnetic resonance imaging findings, we found the standard conflict effect at the transition of superior and middle frontal gyrus, when comparing the activation in compatible trials to that in incompatible trials. Both changes in oxygenated and deoxygenated hemoglobin thus pointed to more effortful processing in incompatible trials. Interestingly, however, identical trials showed the highest activation in this region, according to both changes in oxygenated and deoxygenated blood. A finding that mirrors and extends prior functional near-infrared spectroscopy findings, which only regarded oxygenated blood. We argue that this pattern of results does not reflect the standard conflict effect. We rather assume that other processes like perceptual familiarity or strategic readjustment might be at play.

The Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) : A representative and useful real-life data source for further biomedical research.

In the Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) clinicolaboratory real-life data have been captured from 606 CMML patients from 14 different hospitals over the last 30 years. It is the only large biodatabase worldwide in which functional methods such as semisolid in vitro cultures complement modern molecular methods such as next generation sequencing. This provides the possibility to comprehensively study the biology of CMML. The aim of this study was to compare patient characteristics with published CMML cohorts and to validate established prognostic parameters in order to examine if this real-life database can serve as a representative and useful data source for further research. After exclusion of patients in transformation characteristics of 531 patients were compared with published CMML cohorts. Median values for age, leukocytes, hemoglobin, platelets, lactate dehydrogenase (LDH) and circulating blasts were within the ranges of reported CMML series. Established prognostic parameters including leukocytes, hemoglobin, blasts and adverse cytogenetics were able to discriminate patients with different outcome. Myeloproliferative (MP) as compared to myelodysplastic (MD)-CMML patients had higher values for circulating blasts, LDH, RAS-pathway mutations and for spontaneous myelomonocytic colony growth in vitro as well as more often splenomegaly. This study demonstrates that the patient cohort of the ABCMML shares clinicolaboratory characteristics with reported CMML cohorts from other countries and confirms phenotypic and genotypic differences between MP-CMML and MD-CMML. Therefore, results obtained from molecular and biological analyses using material from the national cohort will also be applicable to other CMML series and thus may have a more general significance.