Age Effects in L2 Grammar Processing as Revealed by ERPs and How (Not) to Study Them

In this study we investigate the effect of age of acquisition (AoA) on grammatical processing in second language learners as measured by event-related brain potentials (ERPs). We compare a traditional analysis involving the calculation of averages across a certain time window of the ERP waveform, analyzed with categorical groups (early vs. late), with a generalized additive modeling analysis, which allows us to take into account the full range of variability in both AoA and time. Sixty-six Slavic advanced learners of German listened to German sentences with correct and incorrect use of non-finite verbs and grammatical gender agreement. We show that the ERP signal depends on the AoA of the learner, as well as on the regularity of the structure under investigation. For gender agreement, a gradual change in processing strategies can be shown that varies by AoA, with younger learners showing a P600 and older learners showing a posterior negativity. For verb agreement, all learners show a P600 effect, irrespective of AoA. Based on their behavioral responses in an offline grammaticality judgment task, we argue that the late learners resort to computationally less efficient processing strategies when confronted with (lexically determined) syntactic constructions different from the L1. In addition, this study highlights the insights the explicit focus on the time course of the ERP signal in our analysis framework can offer compared to the traditional analysis.     

Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene

Autism is a genetically complex neurodevelopmental syndrome in which language deficits are a core feature. We describe results from two complimentary approaches used to identify risk variants on chromosome 7 that likely contribute to the etiology of autism. A two-stage association study tested 2758 SNPs across a 10 Mb 7q35 language-related autism QTL in AGRE (Autism Genetic Resource Exchange) trios and found significant association with Contactin Associated Protein-Like 2 (CNTNAP2), a strong a priori candidate. Male-only containing families were identified as primarily responsible for this association signal, consistent with the strong male affection bias in ASD and other language-based disorders. Gene-expression analyses in developing human brain further identified CNTNAP2 as enriched in circuits important for language development. Together, these results provide convergent evidence for involvement of CNTNAP2, a Neurexin family member, in autism, and demonstrate a connection between genetic risk for autism and specific brain structures.     

Shiga Toxin 2-Encoding Bacteriophages in Human Fecal Samples from Healthy Individuals

Shiga toxin-converting bacteriophages (Stx phages) carry the stx gene and convert nonpathogenic bacterial strains into Shiga toxin-producing bacteria. Previous studies have shown that high densities of free and infectious Stx phages are found in environments polluted with feces and also in food samples. Taken together, these two findings suggest that Stx phages could be excreted through feces, but this has not been tested to date. In this study, we purified Stx phages from 100 fecal samples from 100 healthy individuals showing no enteric symptoms. The phages retrieved from each sample were then quantified by quantitative PCR (qPCR). In total, 62% of the samples carried Stx phages, with an average value of 2.6 × 10⁴ Stx phages/g. This result confirms the excretion of free Stx phages by healthy humans. Moreover, the Stx phages from feces were able to propagate in enrichment cultures of stx-negative Escherichia coli (strains C600 and O157:H7) and in Shigella sonnei, indicating that at least a fraction of the Stx phages present were infective. Plaque blot hybridization revealed lysis by Stx phages from feces. Our results confirm the presence of infectious free Stx phages in feces from healthy persons, possibly explaining the environmental prevalence observed in previous studies. It cannot be ruled out, therefore, that some positive stx results obtained during the molecular diagnosis of Shiga toxin-producing Escherichia coli (STEC)-related diseases using stool samples are due to the presence of Stx phages.     

Memory and Language in Middle Childhood in Individuals with a History of Specific Language Impairment

This study reports on the sensitivity of sentence repetition as a marker of specific language impairment (SLI) in different subgroups of children in middle childhood and examines the role of memory and grammatical knowledge in the performance of children with and without language difficulties on this task. Eleven year old children, 197 with a history of SLI and 75 typically developing (TD) peers were administered sentence repetition, phonological short term memory (PSTM) and grammatical morphology tasks. Children with a history of SLI were divided into four subgroups: specific language impairment, non-specific language impairment, low cognition with resolved language and resolved. Performance on the sentence repetition task was significantly impaired in all four subgroups of children with a history of SLI when compared to their age peers. Regression analyses revealed grammatical knowledge was predictive of performance for TD children and children with a history of SLI. However, memory abilities were significantly predictive of sentence repetition task performance for children with a history of SLI only. Processes involved in sentence repetition are more taxing of PSTM for individuals with a history of SLI in middle childhood in a way that does not appear to be the case for TD children.     

Re-Examination of Chinese Semantic Processing and Syntactic Processing: Evidence from Conventional ERPs and Reconstructed ERPs by Residue Iteration Decomposition (RIDE)

A number of studies have explored the time course of Chinese semantic and syntactic processing. However, whether syntactic processing occurs earlier than semantics during Chinese sentence reading is still under debate. To further explore this issue, an event-related potentials (ERPs) experiment was conducted on 21 native Chinese speakers who read individually-presented Chinese simple sentences (NP1+VP+NP2) word-by-word for comprehension and made semantic plausibility judgments. The transitivity of the verbs was manipulated to form three types of stimuli: congruent sentences (CON), sentences with a semantically violated NP2 following a transitive verb (semantic violation, SEM), and sentences with a semantically violated NP2 following an intransitive verb (combined semantic and syntactic violation, SEM+SYN). The ERPs evoked from the target NP2 were analyzed by using the Residue Iteration Decomposition (RIDE) method to reconstruct the ERP waveform blurred by trial-to-trial variability, as well as by using the conventional ERP method based on stimulus-locked averaging. The conventional ERP analysis showed that, compared with the critical words in CON, those in SEM and SEM+SYN elicited an N400–P600 biphasic pattern. The N400 effects in both violation conditions were of similar size and distribution, but the P600 in SEM+SYN was bigger than that in SEM. Compared with the conventional ERP analysis, RIDE analysis revealed a larger N400 effect and an earlier P600 effect (in the time window of 500–800 ms instead of 570–810ms). Overall, the combination of conventional ERP analysis and the RIDE method for compensating for trial-to-trial variability confirmed the non-significant difference between SEM and SEM+SYN in the earlier N400 time window. Converging with previous findings on other Chinese structures, the current study provides further precise evidence that syntactic processing in Chinese does not occur earlier than semantic processing.     

Fear Conditioning Induced by Interpersonal Conflicts in Healthy Individuals

Psychophysiological markers have been focused to investigate the psychopathology of psychiatric disorders and personality subtypes. In order to understand neurobiological mechanisms underlying these conditions, fear-conditioning model has been widely used. However, simple aversive stimuli are too simplistic to understand mechanisms because most patients with psychiatric disorders are affected by social stressors. The objective of this study was to test the feasibility of a newly-designed conditioning experiment using a stimulus to cause interpersonal conflicts and examine associations between personality traits and response to that stimulus. Twenty-nine healthy individuals underwent the fear conditioning and extinction experiments in response to three types of stimuli: a simple aversive sound, disgusting pictures, and pictures of an actors’ face with unpleasant verbal messages that were designed to cause interpersonal conflicts. Conditioned response was quantified by the skin conductance response (SCR). Correlations between the SCR changes, and personality traits measured by the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) and Revised NEO Personality Inventory were explored. The interpersonal conflict stimulus resulted in successful conditioning, which was subsequently extinguished, in a similar manner as the other two stimuli. Moreover, a greater degree of conditioned response to the interpersonal conflict stimulus correlated with a higher ZAN-BPD total score. Fear conditioning and extinction can be successfully achieved, using interpersonal conflicts as a stimulus. Given that conditioned fear caused by the interpersonal conflicts is likely associated with borderline personality traits, this paradigm could contribute to further understanding of underlying mechanisms of interpersonal fear implicated in borderline personality disorder.     

Internal Jugular Vein Cross-Sectional Area Enlargement Is Associated with Aging in Healthy Individuals

Background

Internal jugular vein (IJV) narrowing has been implicated in central nervous system pathologies, however normal physiological age- and gender-related IJV variance in healthy individuals (HIs) has not been adequately assessed.

Objectives

We assessed the relationship between IJV cross-sectional area (CSA) and aging.

Materials and Methods

This study involved 193 HIs (63 males and 130 females) who received 2-dimensional magnetic resonance venography at 3T. The minimum CSA of the IJVs at cervical levels C2/C3, C4, C5/C6, and C7/T1 was obtained using a semi-automated contouring-thresholding technique. Subjects were grouped by decade. Pearson and partial correlation (controlled for cardiovascular risk factors, including hypertension, heart disease, smoking and body mass index) and analysis of variance analyses were used, with paired t-tests comparing side differences.

Results

Mean right IJV CSA ranges were: in males, 41.6 mm² (C2/C3) to 82.0 mm² (C7/T1); in females, 38.0 mm² (C2/C3) to 62.3 mm² (C7/T1), while the equivalent left side ranges were: in males, 28.0 mm² (C2/C3) to 52.2 mm² (C7/T1); in females, 27.2 mm² (C2/C3) to 47.8 mm² (C7/T1). The CSA of the right IJVs was significantly larger (p<0.001) than the left at all cervical levels. Controlling for cardiovascular risk factors, the correlation between age and IJV CSA was more robust in males than in the females for all cervical levels.

Conclusions

In HIs age, gender, hand side and cervical location all affect IJV CSA. These findings suggest that any definition of IJV stenosis needs to account for these factors.     

Relationships between Platelets and Blood Cells in Postprandial Glycemia in Healthy Individuals

The relationships between platelet aggregation and blood cell amount were studied in healthy subjects after fasting and after a standard carbohydrate breakfast. Positive relationships were revealed between certain parameters of platelet aggregation and the amounts of monocytes and eosinophils. Negative relationships were revealed between most parameters of platelet aggregation and the amount of platelets. Along with the well-known food leukocytosis and increased fibrinogen, postprandial conditions were characterized by an increase in certain parameters of platelet aggregation, destruction of the relationship between the fibrinogen concentration and platelet aggregation, impairment of the inverse relationship between the amount and aggregation of platelets, and moderate direct or inverse relationships between certain parameters of the first and the second stages of platelet aggregation and the erythrocyte parameters. As a disturbing factor, postprandial conditions activated platelet hemostasis by modulating the initial stages of aggregation and substantially changed the interrelations between blood cells.     

Family History as a Predictor for Disease Risk in Healthy Individuals: A Cross-Sectional Study in Slovenia

Background

Family history can be used as a genetic risk predictor for common non-communicable diseases. The aim of this study was to determine the prevalence of healthy individuals at risk of developing these diseases, based on their self-reported family history.

Methods and Findings

This was a cross-sectional observational study. Data were collected in the three largest occupational practices in primary health care centres in Slovenia, a Central European country. The study population consisted of consecutive individuals who came to occupational practices for their regular preventive check-up from November 2010 to June 2012. We included 1,696 individuals. Data were collected by a self-developed questionnaire. The main outcome was the number of participants at a moderate or high risk for the development of cardiovascular diseases, diabetes, and cancer.The final sample consisted of 1,340 respondents. Moderate or high risk for the development of cardiovascular diseases was present in 280 (20.9%) participants, for the development of diabetes in 154 (11.5%) participants and for cancer in 163 (12.1%) participants.

Conclusions

In this study, we found a significant proportion of healthy individuals with an increased genetic risk for common non-communicable diseases; consequently further genetic and clinical evaluation and preventive measures should be offered.     

The juxtaparanodal proteins CNTNAP2 and TAG1 regulate diet-induced obesity

Despite considerable effort, the identification of genes that regulate complex multigenic traits such as obesity has proven difficult with conventional methodologies. The use of a chromosome substitution strain-based mapping strategy based on deep congenic analysis overcame many of the difficulties associated with gene discovery and led to the finding that the juxtaparanodal proteins CNTNAP2 and TAG1 regulate diet-induced obesity. The effects of a mild Cntnap2 mutation on body weight were highly dependent on genetic background, as both obesity-promoting and obesity-resistant effects of Cntnap2 were observed on different genetic backgrounds. The more severe effect of complete TAG1 deficiency, by decreasing food intake, completely prevented the weight gain normally associated with high-fat-diet feeding. Together, these studies implicate two novel proteins in the regulation of diet-induced obesity. Moreover, as juxtaparanodal proteins have previously been implicated in various neurological disorders, our results suggest a potential genetic and molecular link between obesity and diseases such as autism and epilepsy.     

Identifying Metabolically Healthy but Obese Individuals in Sedentary Postmenopausal Women

The purpose of this study was to compare different methods to identify metabolically healthy but obese (MHO) individuals in a cohort of obese postmenopausal women. We examined the anthropometric and metabolic characteristics of 113 obese (age: 57.3 ± 4.8 years; BMI: 34.2 ± 2.7 kg/m²), sedentary postmenopausal women. The following methods were used to identify MHO subjects: the hyperinsulinemic–euglycemic clamp (MHO: upper quartile of glucose disposal rates); the Matsuda index (MHO: upper quartile of the Matsuda index); the homeostasis model assessment (HOMA) index (MHO: lower quartile of the HOMA index); having 0–1 cardiometabolic abnormalities (systolic/diastolic blood pressure ≥130/85 mm Hg, triglycerides (TG) ≥1.7 mmol/l, glucose ≥5.6 mmol/l, HOMA >5.13, high‐sensitive C‐reactive protein (hsCRP) >0.1 mg/l, high‐density lipoprotein‐cholesterol (HDL‐C) <1.3 mmol/l); and meeting four out of five metabolic factors (HOMA ≤2.7, TG ≤1.7 mmol/l, HDL‐C ≥1.3 mmol/l, low‐density lipoprotein‐cholesterol ≤2.6 mmol/l, hsCRP ≤3.0 mg/l). Thereafter, we measured insulin sensitivity, body composition (dual‐energy X‐ray absorptiometry), body fat distribution (computed tomography scan), energy expenditure, plasma lipids, inflammation markers, resting blood pressure, and cardiorespiratory fitness. We found significant differences in body composition (i.e., peripheral fat mass, central lean body mass (LBM)) and metabolic risk factors (i.e., HDL‐C, hsCRP) between MHO and at risk individuals using the different methods to identify both groups. In addition, significant differences between MHO subjects using the different methods to identify MHO individuals were observed such as age, TG/HDL, hsCRP, and fasting insulin. However, independently of the methods used, we noted some recurrent characteristics that identify MHO subjects such as TG, apolipoprotein B, and ferritin. In conclusion, the present study shows variations in body composition and metabolic profile based on the methods studied to define the MHO phenotype. Therefore, an expert consensus may be needed to standardize the identification of MHO individuals.     

CNTNAP2 variants affect early language development in the general population

Early language development is known to be under genetic influence, but the genes affecting normal variation in the general population remain largely elusive. Recent studies of disorder reported that variants of the CNTNAP2 gene are associated both with language deficits in specific language impairment (SLI) and with language delays in autism. We tested the hypothesis that these CNTNAP2 variants affect communicative behavior, measured at 2 years of age in a large epidemiological sample, the Western Australian Pregnancy Cohort (Raine) Study. Singlepoint analyses of 1149 children (606 males and 543 females) revealed patterns of association which were strikingly reminiscent of those observed in previous investigations of impaired language, centered on the same genetic markers and with a consistent direction of effect (rs2710102, P = 0.0239; rs759178, P = 0.0248). On the basis of these findings, we performed analyses of four-marker haplotypes of rs2710102-rs759178-rs17236239-rs2538976 and identified significant association (haplotype TTAA, P = 0.049; haplotype CGAG, [corrected] P = .0014). Our study suggests that common variants in the exon 13-15 region of CNTNAP2 influence early language acquisition, as assessed at age 2, in the general population. We propose that these CNTNAP2 variants increase susceptibility to SLI or autism when they occur together with other risk factors.     

Analysis of Micro-RNA-144 Expression Profile in Patients with Multiple Sclerosis in Comparison with Healthy Individuals.

Background:Etiology of multiple sclerosis is non-clarified. It seems that environmental factors impact epigenetic in this disease. Micro-RNAs (MIR) as epigenetic factors are one of the most important factors in non-genetically neurodegenerative diseases. It has been found MIR-144 plays a main role in the regulation of many processes in the central nervous system. Here, we aimed to investigation of MIR-144 expression alteration in Multiple sclerosis (MS) patients.Methods:In this study 32 healthy and 32 MS patient''s blood sample were analyzed by quantitative Real-Time PCR method and obtained data analyzed by REST 2009 software.Results:Analysis of Real-Time PCR data revealed that miR-144 Increase significantly in MS patients compared to healthy controls.Conclusion:The increase of MIR-144 expression in MS patients is obvious. MIR-144 can be used as a biomarker of MS and help to early diagnosis and treatment of this disease.Key Words: MicroRNA (miRNA), MiRNA-144, Multiple Sclerosis (MS)     

CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder

Gilles de la Tourette syndrome (GTS) is a sporadic or inherited complex neuropsychiatric disorder characterized by involuntary motor and vocal tics. There is comorbidity with disorders like obsessive compulsive disorder and attention deficit hyperactivity disorder. Until now linkage analysis has pointed to a number of chromosomal locations, but has failed to identify a clear candidate gene(s). We have investigated a GTS family with a complex chromosomal insertion/translocation involving chromosomes 2 and 7. The affected father [46,XY,inv(2) (p23q22),ins(7;2) (q35-q36;p21p23)] and two affected children [46,XX,der(7)ins(7;2)(q35-q36;p21p23) and 46,XY,der(7)ins(7;2)(q35-q36;p213p23)] share a chromosome 2p21-p23 insertion on chromosome 7q35-q36, thereby interrupting the contactin-associated protein 2 gene (CNTNAP2). This gene encodes a membrane protein located in a specific compartment at the nodes of Ranvier of axons. We hypothesize that disruption or decreased expression of CNTNAP2 could lead to a disturbed distribution of the K(+) channels in the nervous system, thereby influencing conduction and/or repolarization of action potentials, causing unwanted actions or movements in GTS.     

Genetic Effects on Postprandial Variations of Inflammatory Markers in Healthy Individuals

Circulating levels of inflammatory markers predict the risk of cardiovascular disease (CVD), mediated perhaps in part by dietary fat intake, through mechanisms only partially understood. To evaluate post‐fat load changes in inflammatory markers and genetic influences on these changes, we administered a standardized high‐fat meal to 838 related Amish subjects as part of the Heredity and Phenotype Intervention (HAPI) Heart Study and measured a panel of inflammatory markers, including C‐reactive protein (CRP), interleukin‐1β (IL‐1β), matrix metalloproteinase‐1 and ‐9 (MMP‐1 and MMP‐9), and white blood cell (WBC) count, before and 4 h after fat challenge (CRP prechallenge only). Heritabilities (h² ± s.d.) of basal inflammatory levels ranged from 16 ± 8% for MMP‐9 (P = 0.02) to 90 ± 7% for MMP‐1 (P < 0.0001). Post‐fat load, circulating levels of WBC, MMP‐1, and MMP‐9 increased by 16, 32, and 43% (all P < 0.0001), with no significant changes in IL‐1β. Postprandial changes over the 4‐h period were modestly heritable for WBC (age‐ and sex‐adjusted h² = 14 ± 9%, P = 0.04), but the larger MMP‐1 and MMP‐9 changes appeared to be independent of additive genetic effects. These results reveal that a high‐fat meal induces a considerable inflammatory response. Genetic factors appear to play a significant role influencing basal inflammatory levels but to have minimal influence on post‐fat intake inflammatory changes.     

Alpha Band Cortico-Muscular Coherence Occurs in Healthy Individuals during Mechanically-Induced Tremor

The present work aimed at investigating the effects of mechanically amplified tremor on cortico-muscular coherence (CMC) in the alpha band. The study of CMC in this specific band is of particular interest because this coherence is usually absent in healthy individuals and it is an aberrant feature in patients affected by pathological tremors; understanding its mechanisms is therefore important. Thirteen healthy volunteers (23±4 years) performed elbow flexor sustained contractions both against a spring load and in isometric conditions at 20% of maximal voluntary isometric contraction (MVC). Spring stiffness was selected to induce instability in the stretch reflex servo loop. 64 EEG channels, surface EMG from the biceps brachii muscle and force were simultaneously recorded. Contractions against the spring resulted in greater fluctuations of the force signal and EMG amplitude compared to isometric conditions (p<.05). During isometric contractions CMC was systematically found in the beta band and sporadically observed in the alpha band. However, during the contractions against the spring load, CMC in the alpha band was observed in 12 out of 13 volunteers. Partial directed coherence (PDC) revealed an increased information flow in the EMG to EEG direction in the alpha band (p<.05). Therefore, coherence in the alpha band between the sensory-motor cortex and the biceps brachii muscle can be systematically induced in healthy individuals by mechanically amplifying tremor. The increased information flow in the EMG to EEG direction may reflect enhanced afferent activity from the muscle spindles. These results may contribute to the understanding of the presence of alpha band CMC in tremor related pathologies by suggesting that the origin of this phenomenon may not only be at cortical level but may also be affected by spinal circuit loops.