Auditory event-related potentials at preschool age in children born very preterm

ObjectiveTo assess auditory event-related potentials at preschool age in children born very preterm (VP, 27.4 ± 1.9 gestational weeks, n = 70) with a high risk of cognitive dysfunction.MethodsWe used an oddball paradigm consisting of a standard tone randomly replaced by one of three infrequent deviants (differing in frequency, sound direction or duration).ResultsThe P1 and N2 latencies were inversely correlated to age (50–63 months) both in VP (r = −0.451, p < 0.001, and r = −0.305, p = 0.01, respectively) and term born controls (TC; n = 15). VP children had smaller P1 than near-term (n = 12) or TC (1.70 ± 0.17 μV vs 2.68 ± 0.41 and 2.92 ± 0.43, respectively; p < 0.05). Mismatch negativity response did not differ between groups.ConclusionsOur data suggest a fast maturation of P1 and N2 responses with fast decrease in P1 and N2 latencies around the age of 5 years. Mismatch negativity response does not seem to be a robust measure for defining abnormalities in VP children.SignificanceIn ERP studies in preschool children, even small, non-significant group differences in age at recording should be corrected for. Very preterm born children at preschool age have aERP patterns as earlier described in full-term born children with cognitive deficits.     

A mechanistic model of mismatch negativity in the ageing brain

ObjectiveWe investigated the neurophysiological mechanisms underpinning the generation of the mismatch negativity (MMN) in the ageing brain.MethodsWe used dynamic causal modelling (DCM) to study connectivity models for healthy young and old subjects. MMN was elicited with an auditory odd-ball paradigm in two groups of healthy subjects with mean age 74 (n = 30) and 26 (n = 26). DCM was implemented using up to five cortical nodes. We tested models with different hierarchical complexities.ResultsWe showed that the network generating MMN consisted of 5 nodes that could modulate all intra- and inter-nodal connections. The inversion of this model showed that old subjects had increased input from rSTG to the rIFG (p < 0.01) together with increased inhibition of pyramidal cells (p < 0.05). Furthermore, there was reduced modulation of activity within rIFG (p < 0.02) on stimulus change.ConclusionThe age related change in MMN is due to a decline in frontal-based control mechanisms, with alterations in connectivity between temporal and frontal regions together with a dysregulation of the excitatory–inhibitory balance in the rIFG.SignificanceThis study provides for the first time a neurobiological explanation for the age related changes of the MMN in the ageing brain.     

Optimizing assessments of post-error slowing: A neurobehavioral investigation of a flanker task

Appropriately adjusting to errors is essential for adaptive behavior. Post-error slowing (PES) refers to the increased reaction times on trials following incorrect relative to correct responses. PES has been used as a metric of cognitive control in basic cognitive neuroscience research as well as clinical contexts. However, calculation of PES varies widely among studies and has not yet been standardized, despite recent calls to optimize its measurement. Here, using behavioral and electrophysiological data from a modified flanker task, we considered different methods of calculating PES, assessed their internal consistency, examined their convergent correlations with behavioral performance and error-related event-related brain potentials (ERPs), and evaluated their sensitivity to task demands (e.g., presence of trial-to-trial feedback). Results indicated that the so-called robust measure of PES, calculated using only error-surrounding trials, provided an estimate of PES that was three times larger in magnitude than the traditional calculation. This robust PES correlated with the amplitude of the error positivity (Pe), an index of attention allocation to errors, just as well as the traditional method. However, all PES estimates had very weak internal consistency. Implications for measurement are discussed.     

Valence-dependent brain potentials of processing augmented feedback in learning a complex arm movement sequence

ERPs in the EEG were scrutinized in learning a complex arm movement sequence with the aim to examine valence effects on processing augmented feedback during practice. Twenty-four healthy subjects practiced one session with 192 feedback trials according to an adaptive bandwidth feedback approach with a high informational level of feedback information (i.e., amplitude and direction of errors). The bandwidth for successful performance (increase of a score for a monetary competition) was manipulated to yield a success rate (positive feedback frequency) of approximately 50% adaptive to the current performance level. This allowed a variation of feedback valence unconfounded by success rate. In line with our hypotheses, the EEG data showed a valence-dependent feedback-related negativity (FRN) and a later fronto-central component at the FCz electrode as well as a P300 component at the Pz electrode. Moreover, the P300 and amplitudes in the FRN time window reduced in the second half of practice but were still dependent on feedback valence. Behavioral adjustments were larger after feedback with negative valence and were predicted by the late fronto-central component. The data support the assumption of feedback valence-dependent modulation of attentional cognitive involvement in motor control and learning.     

Incorporation of molecular characteristics into endometrial cancer management

Histopathological evaluation including subtyping and grading is the current cornerstone for endometrial cancer (EC) classification. This provides clinicians with prognostic information and input for further treatment recommendations. Nonetheless, patients with histologically similar ECs may have very different outcomes, notably in patients with high-grade endometrial carcinomas. For endometrial cancer, four molecular subgroups have undergone extensive studies in recent years: POLE ultramutated (POLEmut), mismatch repair-deficient (MMRd), p53 mutant (p53abn) and those EC lacking any of these alterations, referred to as NSMP (non-specific molecular profile). Several large studies confirm the prognostic relevance of these molecular subgroups. However, this ‘histomolecular’ approach has so far not been implemented in clinical routine. The ongoing PORTEC4a trial is the first clinical setting in which the added value of integrating molecular parameters in adjuvant treatment decisions will be determined. For diagnostics, the incorporation of the molecular parameters in EC classification will add a level of objectivity which will yield biologically more homogeneous subclasses. Here we illustrate how the management of individual EC patients may be impacted when applying the molecular EC classification. We describe our current approach to the integrated diagnoses of EC with a focus on scenarios with conflicting morphological and molecular findings. We also address several pitfalls accompanying the diagnostic implementation of molecular EC classification and give practical suggestions for diagnostic scenarios.     

Sequencing‐based microsatellite instability testing using as few as six markers for high‐throughput clinical diagnostics

Microsatellite instability (MSI) testing of colorectal cancers (CRCs) is used to screen for Lynch syndrome (LS), a hereditary cancer‐predisposition, and can be used to predict response to immunotherapy. Here, we present a single‐molecule molecular inversion probe and sequencing‐based MSI assay and demonstrate its clinical validity according to existing guidelines. We amplified 24 microsatellites in multiplex and trained a classifier using 98 CRCs, which accommodates marker specific sensitivities to MSI. Sample classification achieved 100% concordance with the MSI Analysis System v1.2 (Promega) in three independent cohorts, totaling 220 CRCs. Backward–forward stepwise selection was used to identify a 6‐marker subset of equal accuracy to the 24‐marker panel. Assessment of assay detection limits showed that the 24‐marker panel is marginally more robust to sample variables than the 6‐marker subset, detecting as little as 3% high levels of MSI DNA in sample mixtures, and requiring a minimum of 10 template molecules to be sequenced per marker for >95% accuracy. BRAF c.1799 mutation analysis was also included to streamline LS testing, with all c.1799T>A variants being correctly identified. The assay, therefore, provides a cheap, robust, automatable, and scalable MSI test with internal quality controls, suitable for clinical cancer diagnostics.     

The spectrum of Lynch syndrome-associated germ-line mutations in Russia

Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome (LS), is a common cancer-predisposing syndrome. This study aimed to investigate the spectrum of germ-line mutations in Russian LS patients. LS-related mismatch repair (MMR) genes were analyzed in 16 patients, who were forwarded to genetic testing due to strong clinical features of LS and had high-level microsatellite instability (MSI-H) in the tumor (n = 14) or unknown MSI status (n = 2). In addition, 672 consecutive colorectal cancer (CRC) cases were screened for family history; 15 patients were younger than 50 years and reported 2 or more instances of LS-related cancers in 1st- or 2nd-degree relatives. Seven of these cases demonstrated MSI-H and therefore were subjected to DNA germ-line testing. Overall, 17/23 (74%) subjects carried LS-associated gene variants (MLH1: 10; MSH2: 4; MSH6: 2; PMS2: 1), with 2 alleles (MLH1 c.677G > T and MSH2 с.1906G > C) detected twice. Testing for recurrent mutations of 30 consecutive MSI-H CRCs led to the identification of 2 additional subjects with LS. The analysis of all relevant publications identified 28 unrelated LS patients presented in Russian medical literature and 3 unrelated Russian LS subjects described in international journals. Overall, 15/49 (31%) genetic defects revealed in Russian LS patients were represented by six recurrent alleles (MLH1: c.350C > T, c.677G > T, c.1852_1854del; MSH2: c.942+3A > T, c.1861C > T, с.1906G > C). We conclude that the founder effect for LS in Russia is seemingly less pronounced than the one for hereditary breast-ovarian cancer syndrome, however testing for recurrent LS mutations may be considered feasible in some circumstances.     

Neural correlates of error processing reflect individual differences in interoceptive sensitivity

Although self-monitoring is an important process for adaptive behaviors in multiple domains, the exact relationship among different internal monitoring systems is unclear. Here, we aimed to determine whether and how physiological monitoring (interoception) and behavioral monitoring (error processing) are related to each other. To this end we examined within-subject correlations among measures representing each function. Score on the heartbeat counting task (HCT) was used as a measure of interoceptive awareness. The amplitude of two event-related potentials (error-related negativity [ERN] and error-positivity [Pe]) elicited in error trials of a choice-reaction task (Simon task) were used as measures of error processing. The Simon task presented three types of stimuli (objects, faces showing disgust, and happy faces) to further examine how emotional context might affect inter-domain associations. Results showed that HCT score was robustly correlated with Pe amplitude (the later portion of error-related neural activity), irrespective of stimulus condition. In contrast, HCT score was correlated with ERN amplitude (the early component) only when participants were presented with disgust-faces as stimuli, which may have automatically elicited a physiological response. Behavioral data showed that HCT score was associated with the degree to which reaction times slowed after committing errors in the object condition. Cardiac activity measures indicated that vigilance level would not explain these correlations. These results suggest a relationship between physiological and behavioral monitoring. Furthermore, the degree to which behavioral monitoring relies on physiological monitoring appears to be flexible and depend on the situation.     

Role of endometrial cancer abnormal MMR protein in screening Lynch-syndrome families

Objective: To identify patients with endometrial cancer with potential Lynch-related DNA mismatch repair (MMR) protein expression defects and to explore the role of these defects in screening for LS. Methods: Endometrial cancers from 173 patients recruited to the Nanchong Central Hospital were tested for MMR (MLH1, MSH2, PMS2, and MSH6) protein expression using immunohistochemistry (IHC). Results: In the 173 tumor tissue samples, the expression loss rates of MSH6, MSH2, PMS2 and MLH1 protein were 16.18% (28/173), 12.14% (21/173), 7.51% (13/173) and 5.78% (10/173), respectively. The total loss rate of MMR protein was 29.89% (27/87). There were 19 patients with a family history of cancer, of which 18 patients demonstrated loss of expression of MMR protein. In the 22 abnormal MMR patients without family history, five families were found to have Lynch-associated cancer (colorectal cancer, endometrial cancer, ovarian cancer, stomach cancer) after follow-up for two years. Conclusion: MMR proteins play an important role in the progress of endometrial cancer. The routine testing of MMR proteins in endometrial cancer can contribute to the screening of LS families, especially small families.     

Hereditary nonpolyposis colorectal cancer: Review of clinical,molecular genetics,and counseling aspects

Lynch syndrome, or hereditary nonpolyposis colon cancer (HNPCC), is an autosomal-dominant disease accounting for approximately 1–5% of all colorectal cancer cases. Due to the lack of pathognomonic morphological or biomolecular markers, HNPCC has traditionally posed unique problems to clinicians and geneticists alike, both in terms of diagnosis and clinical management. Recently, novel insight into the pathogenesis of this syndrome has been provided by the identification of its molecular basis. In HNPCC families, germline mutations in any of four genes encoding proteins of a specialized DNA repair system, the mismatch repair, predispose to cancer development. Mutations in mismatch repair genes lead to an overall increase of the mutation rate and are associated with a phenotype of length instability of microsatellite loci. The present report summarizes the clinicopathological aspects of HNPCC and reviews the most recent molecular and biochemical findings. © 1996 Wiley-Liss, Inc.