The right anterior temporal lobe critically contributes to magnitude knowledge.

Cognitive estimation is a mental ability applied to solve numerical problems when precise facts are unknown, unavailable or impractical to calculate. It has been associated with several underlying cognitive components, most often with executive functions and semantic memory. Little is known about the neural correlates of cognitive estimation. To address this issue, the present cross-sectional study applied lesion-symptom mapping in a group of 55 patients with left hemineglect due to right-hemisphere stroke. Previous evidence suggests a high prevalence of cognitive estimation impairment in these patients, as they might show a general bias towards large magnitudes. Compared to 55 age- and gender-matched healthy controls, the patient group demonstrated impaired cognitive estimation. However, the expected large magnitude bias was not found. Lesion-symptom mapping related their general estimation impairment predominantly to brain damage in the right anterior temporal lobe. Also critically involved were the right uncinate fasciculus, the anterior commissure and the right inferior frontal gyrus. The main findings of this study emphasize the role of semantic memory in cognitive estimation, with reference to a growing body of neuroscientific literature postulating a transmodal hub for semantic cognition situated in the bilateral anterior temporal lobe. That such semantic hub function may also apply to numerical knowledge is not undisputed. We here propose a critical contribution of the right anterior temporal lobe to at least one aspect of number processing, i.e. the knowledge about real-world numerical magnitudes.

Theta burst stimulation in neglect after stroke: functional outcome and response variability origins.

Spatial neglect is a strong and negative predictor of general functional outcome after stroke, and its therapy remains a challenge. Whereas inhibitory non-invasive brain stimulation over the contralesional, intact hemisphere has generally been shown to ameliorate neglect on a group level, a conspicuous variability of the effects at the individual level is typically observed. We aimed to assess the characteristics and determinants of the effects of inhibitory non-invasive brain stimulation in neglect, identifying which patients would respond to this therapeutic approach and which not. To this end, we prospectively included 60 patients with a subacute right-hemispheric stroke. In 30 patients with spatial neglect, continuous theta burst stimulation (cTBS) was applied over the left posterior parietal cortex in a randomized clinical trial, either in eight or 16 trains, or as sham stimulation. Thirty patients without neglect served as a control group. Neglect severity was measured with a neuropsychological test battery and the Catherine Bergego Scale, at admission to and at discharge from inpatient neurorehabilitation, as well as at 3 months follow-up. General functional outcome was assessed by means of the Functional Independence Measure and the Lucerne ICF-based Multidisciplinary Observation Scale. The impact of clinical and demographic factors was evaluated, and the influence of lesion location and extension was assessed by means of voxel-based lesion-symptom mapping. On a group level, both cTBS protocols (i.e. eight and 16 trains) significantly reduced neglect severity in both the Catherine Bergego Scale and the neuropsychological tests, at discharge and 3 months later. Furthermore, cTBS significantly improved general functional outcome. On an individual level, hierarchical cluster and voxel-based lesion-symptom mapping analyses revealed that the variability in the responses to cTBS is determined by the integrity of interhemispheric connections within the corpus callosum, in particular parieto-parietal connections. In cTBS responders, in whom neglect and general functional outcome were significantly improved, the corpus callosum was intact, whereas this was not the case in cTBS non-responders. Moreover, analyses based on the proportional recovery rule and the Maugeri predictive stroke recovery model showed that the recovery of neglect and of the activities of daily living was accelerated only in cTBS responders. Furthermore, the level of activities of daily living recovery of these neglect patients was brought close to the one of right-hemispheric control patients without neglect. Hence, in neglect patients with intact interhemispheric connectivity, cTBS over the contralesional posterior parietal cortex significantly improves and accelerates neglect recovery and, associated with it, general functional outcome.

Crenolanib is a type I tyrosine kinase inhibitor that inhibits mutant KIT D816 isoforms prevalent in systemic mastocytosis and core binding factor leukemia.

Activating D816 mutations of the class III receptor tyrosine kinase KIT are associated with the majority of patients with systemic mastocytosis (SM), but also core binding factor (CBF) AML, making KIT mutations attractive therapeutic targets for the treatment of these cancers. Crenolanib is a potent and selective inhibitor of wild-type as well as mutant isoforms of the class III receptor tyrosine kinases FLT3 and PDGFRα/ß. Notably, crenolanib inhibits constitutively active mutant-FLT3 isoforms resulting from amino acid substitutions of aspartic acid at codon 835, which is homologous to codon 816 in the KIT gene - suggesting sensitivity against mutant-KIT D816 isoforms as well. Here we demonstrate that crenolanib targets KIT D816 in SM and CBF AML models: crenolanib inhibits cellular proliferation and initiates apoptosis of mastocytosis cell lines expressing these mutations. Target-specificity was confirmed using an isogenic cell model. In addition, we demonstrate that KIT D816 mutations are targetable with clinically achievable doses of crenolanib. Further, a rationale to combine cladribine (2-CDA), the therapeutic standard in SM, with crenolanib is provided. In conclusion, we demonstrate that crenolanib is an inhibitor of mutant-KIT D816 isoforms at clinically achievable concentrations, and thus may be a potential treatment for SM and CBF AML as a monotherapy or in combination approaches.

Transperineal prostate biopsies for diagnosis of prostate cancer are well tolerated: a prospective study using patient-reported outcome measures.

We aimed to determine short-term patient-reported outcomes in men having general anesthetic transperineal (TP) prostate biopsies. A prospective cohort study was performed in men having a diagnostic TP biopsy. This was done using a validated and adapted questionnaire immediately post-biopsy and at follow-up of between 7 and 14 days across three tertiary referral hospitals with a response rate of 51.6%. Immediately after biopsy 43/201 (21.4%) of men felt light-headed, syncopal, or suffered syncope. Fifty-three percent of men felt discomfort after biopsy (with 95% scoring <5 in a 0-10 scale). Twelve out of 196 men (6.1%) felt pain immediately after the procedure. Despite a high incidence of symptoms (e.g., up to 75% had some hematuria, 47% suffered some pain), it was not a moderate or serious problem for most, apart from hemoejaculate which 31 men suffered. Eleven men needed catheterization (5.5%). There were no inpatient admissions due to complications (hematuria, sepsis). On repeat questioning at a later time point, only 25/199 (12.6%) of men said repeat biopsy would be a significant problem despite a significant and marked reduction in erectile function after the procedure. From this study, we conclude that TP biopsy is well tolerated with similar side effect profiles and attitudes of men to repeat biopsy to men having TRUS biopsies. These data allow informed counseling of men prior to TP biopsy and a benchmark for tolerability with local anesthetic TP biopsies being developed for clinical use.

The Tactile Window to Consciousness is Characterized by Frequency-Specific Integration and Segregation of the Primary Somatosensory Cortex.

We recently proposed that besides levels of local cortical excitability, also distinct pre-stimulus network states (windows to consciousness) determine whether a near-threshold stimulus will be consciously perceived. In the present magnetoencephalography study, we scrutinised these pre-stimulus network states with a focus on the primary somatosensory cortex. For this purpose participants performed a simple near-threshold tactile detection task. Confirming previous studies, we found reduced alpha and beta power in the somatosensory region contralateral to stimulation prior to correct stimulus detection as compared to undetected stimuli, and stronger event-related responses following successful stimulus detection. As expected, using graph theoretical measures, we also observed modulated pre-stimulus network level integration. Specifically, the right primary somatosensory cortex contralateral to stimulation showed an increased integration in the theta band, and additionally, a decreased integration in the beta band. Overall, these results underline the importance of network states for enabling conscious perception. Moreover, they indicate that also a reduction of irrelevant functional connections contributes to the window to consciousness by tuning pre-stimulus pathways of information flow.

Defining the learning curve for multiparametric magnetic resonance imaging (MRI) of the prostate using MRI-transrectal ultrasonography (TRUS) fusion-guided transperineal prostate biopsies as a validation tool.

OBJECTIVES: To determine the accuracy of multiparametric magnetic resonance imaging (mpMRI) during the learning curve of radiologists using MRI targeted, transrectal ultrasonography (TRUS) guided transperineal fusion biopsy (MTTP) for validation. PATIENTS AND METHODS: Prospective data on 340 men who underwent mpMRI (T2-weighted and diffusion-weighted MRI) followed by MTTP prostate biopsy, was collected according to Ginsburg Study Group and Standards for Reporting of Diagnostic Accuracy standards. MRI data were reported by two experienced radiologists and scored on a Likert scale. Biopsies were performed by consultant urologists not 'blinded' to the MRI result and men had both targeted and systematic sector biopsies, which were reviewed by a dedicated uropathologist. The cohorts were divided into groups representing five consecutive time intervals in the study. Sensitivity and specificity of positive MRI reports, prostate cancer detection by positive MRI, distribution of significant Gleason score and negative MRI with false negative for prostate cancer were calculated. Data were sequentially analysed and the learning curve was determined by comparing the first and last group. RESULTS: We detected a positive mpMRI in 64 patients from Group A (91%) and 52 patients from Group E (74%). The prostate cancer detection rate on mpMRI increased from 42% (27/64) in Group A to 81% (42/52) in Group E (P < 0.001). The prostate cancer detection rate by targeted biopsy increased from 27% (17/64) in Group A to 63% (33/52) in Group E (P < 0.001). The negative predictive value of MRI for significant cancer (>Gleason 3+3) was 88.9% in Group E compared with 66.6% in Group A. CONCLUSION: We demonstrate an improvement in detection of prostate cancer for MRI reporting over time, suggesting a learning curve for the technique. With an improved negative predictive value for significant cancer, decision for biopsy should be based on patient/surgeon factors and risk attributes alongside the MRI findings.

Prestimulus Network Integration of Auditory Cortex Predisposes Near-Threshold Perception Independently of Local Excitability.

An ever-increasing number of studies are pointing to the importance of network properties of the brain for understanding behavior such as conscious perception. However, with regards to the influence of prestimulus brain states on perception, this network perspective has rarely been taken. Our recent framework predicts that brain regions crucial for a conscious percept are coupled prior to stimulus arrival, forming pre-established pathways of information flow and influencing perceptual awareness. Using magnetoencephalography (MEG) and graph theoretical measures, we investigated auditory conscious perception in a near-threshold (NT) task and found strong support for this framework. Relevant auditory regions showed an increased prestimulus interhemispheric connectivity. The left auditory cortex was characterized by a hub-like behavior and an enhanced integration into the brain functional network prior to perceptual awareness. Right auditory regions were decoupled from non-auditory regions, presumably forming an integrated information processing unit with the left auditory cortex. In addition, we show for the first time for the auditory modality that local excitability, measured by decreased alpha power in the auditory cortex, increases prior to conscious percepts. Importantly, we were able to show that connectivity states seem to be largely independent from local excitability states in the context of a NT paradigm.

Prevalence of "complicated" stress urinary incontinence in female patients: can urodynamics provide more information in such patients?

INTRODUCTION AND HYPOTHESIS: The role of urodynamic investigation has been recently questioned on the basis of data from a selected population of patients with stress urinary incontinence defined as uncomplicated. The aim of this study was to determine the proportion of patients who underwent urodynamic investigation in our centre in whom the stress urinary incontinence could be defined as uncomplicated. The secondary aim was to assess the number of women in whom the urodynamic investigation added information to the preurodynamic assessment. METHODS: This was a retrospective single-centre study. The data from female patients who underwent urodynamic evaluation prior to surgery for stress urinary incontinence between 2008 and 2012 were considered. Patients were categorized as presenting with uncomplicated or complicated stress urinary incontinence according to the definitions used in the ValUE trial. Urodynamic observations were then compared with preurodynamic data. RESULTS: Data from 244 female patients were considered. Due to incomplete data, 33 of these patients were excluded from the evaluation. Only 47 patients (22.3 %) were considered to have uncomplicated stress urinary incontinence according to the definition used in the ValUE trial. The remaining 164 patients (77.7 %) were considered to have complicated stress urinary incontinence. Urodynamic observations differed from the preurodynamic data in 134 of 211 patients (63.5 %). A diagnosis of voiding dysfunction was obtained in 25.6 % of patients. CONCLUSIONS: The majority of our patients had complicated stress urinary incontinence. In a relevant percentage of these patients, a urodynamic test added some new information, including a diagnosis of voiding dysfunction. The role of urodynamic investigation needs to be explored in this patient group.

Not so different after all: The same oscillatory processes support different types of attention.

Scientific research from the last two decades has provided a vast amount of evidence that brain oscillations reflect physiological activity enabling diverse cognitive processes. The goal of this review is to give a broad empirical and conceptual overview of how ongoing oscillatory activity may support attention processes. Keeping in mind that definitions of cognitive constructs like attention are prone to being blurry and ambiguous, the present review focuses mainly on the neural correlates of 'top-down' attention deployment. In particular, we will discuss modulations of (ongoing) oscillatory activity during spatial, temporal, selective, and internal attention. Across these seemingly distinct attentional domains, we will summarize studies showing the involvement of two oscillatory processes observed during attention deployment: power modulations mainly in the alpha band, and phase modulations in lower frequency bands. This article is part of a Special Issue entitled SI: Prediction and Attention.

Sex-dependent dissociation between emotional appraisal and memory: a large-scale behavioral and fMRI study.

Extensive evidence indicates that women outperform men in episodic memory tasks. Furthermore, women are known to evaluate emotional stimuli as more arousing than men. Because emotional arousal typically increases episodic memory formation, the females' memory advantage might be more pronounced for emotionally arousing information than for neutral information. Here, we report behavioral data from 3398 subjects, who performed picture rating and memory tasks, and corresponding fMRI data from up to 696 subjects. We were interested in the interaction between sex and valence category on emotional appraisal, memory performances, and fMRI activity. The behavioral results showed that females evaluate in particular negative (p < 10(-16)) and positive (p = 2 × 10(-4)), but not neutral pictures, as emotionally more arousing (pinteraction < 10(-16)) than males. However, in the free recall females outperformed males not only in positive (p < 10(-16)) and negative (p < 5 × 10(-5)), but also in neutral picture recall (p < 3.4 × 10(-8)), with a particular advantage for positive pictures (pinteraction < 4.4 × 10(-10)). Importantly, females' memory advantage during free recall was absent in a recognition setting. We identified activation differences in fMRI, which corresponded to the females' stronger appraisal of especially negative pictures, but no activation differences that reflected the interaction effect in the free recall memory task. In conclusion, females' valence-category-specific memory advantage is only observed in a free recall, but not a recognition setting and does not depend on females' higher emotional appraisal.

Investigating the ability of multiparametric MRI to exclude significant prostate cancer prior to transperineal biopsy.

INTRODUCTION: We characterized false negative prostate magnetic resonance imaging (MRI) reporting by using histology derived from MRI-transrectal ultrasound (TRUS)-guided transperineal (MTTP) fusion biopsies. METHODS: In total, 148 consecutive patients were retrospectively reviewed. Men underwent multiparametric MRI (mpMRI), reported by a consultant/attending radiologist in line with European Society of Urogenital Radiology (ESUR) standards. MTTP biopsy of the lesions was performed according to the Ginsburg recommendations. Cases with an MRI-histology mismatch were identified and underwent a second read by an experienced radiologist. A third review was performed with direct histology comparison to determine a true miss from an MRI-occult cancer. Statistical analysis was performed with McNemar's test. RESULTS: False negative lesions were identified in 29 MRI examinations (19.6%), with a total of 46 lesions. Most false negative lesions (21/46) were located in the anterior sectors of the prostate. The second read led to a significant decrease of false-negative lesions with 7/29 further studies identified as positive on a patient-by-patient basis (24.1% of studies, p = 0.016) and 11/46 lesions (23.9%; p = 0.001). Of these, 30 lesions following the first read and 23 lesions after the second read were considered significant cancer according to the University College London criteria. However, on direct comparison with histology, most lesions were MRI occult. CONCLUSION: We demonstrate that MRI can fail to detect clinically relevant lesions. Improved results were achieved with a second read but despite this, a number of lesions remain MRI-occult. Further advances in imaging are required to reduce false negative results.

Evolution of repeat prostate biopsy strategies incorporating transperineal and MRI-TRUS fusion techniques.

PURPOSE: To test the hypothesis that MRI-TRUS fusion technique can increase the detection rate of prostate cancer (PC) in patients with previously negative biopsy. METHODS: Patient records of men with persisting suspicion for PC after previous negative biopsy having undergone either extensive transrectal prostate biopsies (MD Anderson protocol; MDA), transperineal saturation (STP) or magnetic resonance imaging (MRI)/transrectal ultrasound (TRUS) fusion transperineal biopsies (MTTP) in three consecutive time intervals were reviewed retrospectively. The respective approach was the standard for the above indication at these episodes. In Cambridge, 70 patients underwent MDA biopsies, 75 STP underwent biopsies and 74 patients underwent MTTP biopsies. In total, 164 MTTP patients with the same indication from Heidelberg were analysed as reference standard. In total, 383 men were included into analysis. Low-grade PC was defined as Gleason score 7 (3 + 4) or lower. RESULTS: Even though MTTP patients had significantly larger prostates, the overall cancer detection rate for PC was the highest in MTTP (24.2 % MDA, 41.3 % STP, 44.5 % MTTP, p = 0.027, Kruskal-Wallis test). The detection rate for clinically relevant high-grade PC was highest in MTTP; however, this did not reach statistical significance compared with MDA (23.5 % MDA, 12.9 % STP, 27.2 % MTTP, p = 0.25, Fischer's exact test). Comparing MTTP between Cambridge and Heidelberg, detection rates did not differ significantly (44.5 vs. 48 %, p = 0.58). There was a higher detection rate of high-grade cancer in Heidelberg. (36.3 vs. 27.2 %, p = 0.04). CONCLUSION: Patients whom are considered for repeat biopsies may benefit from undergoing MRI-targeted TRUS fusion technique due to higher cancer detection rate of significant PC.

Selective modulation of auditory cortical alpha activity in an audiovisual spatial attention task.

Despite substantial research on attentional modulations of visual alpha activity, doubts remain as to the existence and functional relevance of auditory cortical alpha-band oscillations. It has been argued that auditory cortical alpha does not exist, cannot be measured noninvasively, or that it is dependent on visual alpha generators. This study aimed to address these remaining doubts concerning auditory cortical alpha. A magnetoencephalography study was conducted using a combined audiovisual spatial cueing paradigm. In each trial, a cue indicated the side (left or right) and the modality (auditory or visual) to attend, followed by a short lateralized auditory or visual stimulus. Participants were instructed to respond to the stimuli by a button press. Results show that auditory cortical alpha power is selectively modulated by the audiospatial, but not the visuospatial, attention task. These findings provide further evidence for a distinct auditory cortical alpha generator, which can be measured noninvasively.

Prestimulus oscillatory power and connectivity patterns predispose conscious somatosensory perception.

Which aspects of our sensory environment enter conscious awareness does not only depend on physical features of the stimulus, but also critically on the so-called current brain state. Results from magnetoencephalography/EEG studies using near-threshold stimuli have consistently pointed to reduced levels of α- (8-12 Hz) power in relevant sensory areas to predict whether a stimulus will be consciously perceived or not. These findings have been mainly interpreted in strictly "local" terms of enhanced excitability of neuronal ensembles in respective cortical regions. The present study aims to introduce a framework that complements this rather local perspective, by stating that the functional connectivity architecture before stimulation will predetermine information flow. Thus, information computed at a local level will be distributed throughout a network, thereby becoming consciously accessible. Data from a previously published experiment on conscious somatosensory near-threshold perception was reanalyzed focusing on the prestimulus period. Analysis of spectral power showed reduced α-power mainly in the contralateral S2 and middle frontal gyrus to precede hits, thus overall supporting the current literature. Furthermore, differences between hits and misses were obtained on global network (graph theoretical) features in the same interval. Most importantly, in accordance with our framework, we could show that the somatosensory cortex is "more efficiently" integrated into a distributed network in the prestimulus period. This finding means that when a relevant sensory stimulus impinges upon the system, it will encounter preestablished pathways for information flow. In this sense, prestimulus functional connectivity patterns form "windows" to conscious perception.

Neural responses to facial expressions support the role of the amygdala in processing threat.

The amygdala is known to play an important role in the response to facial expressions that convey fear. However, it remains unclear whether the amygdala's response to fear reflects its role in the interpretation of danger and threat, or whether it is to some extent activated by all facial expressions of emotion. Previous attempts to address this issue using neuroimaging have been confounded by differences in the use of control stimuli across studies. Here, we address this issue using a block design functional magnetic resonance imaging paradigm, in which we compared the response to face images posing expressions of fear, anger, happiness, disgust and sadness with a range of control conditions. The responses in the amygdala to different facial expressions were compared with the responses to a non-face condition (buildings), to mildly happy faces and to neutral faces. Results showed that only fear and anger elicited significantly greater responses compared with the control conditions involving faces. Overall, these findings are consistent with the role of the amygdala in processing threat, rather than in the processing of all facial expressions of emotion, and demonstrate the critical importance of the choice of comparison condition to the pattern of results.