Visual mismatch negativity to masked stimuli presented at very brief presentation rates

Mismatch Negativity (MMN) has been characterised as a ‘pre-attentive’ component of an event-related potential (ERP) that is related to discrimination and error prediction processes. The aim of the current experiment was to establish whether visual MMN could be recorded to briefly presented, backward and forward masked visual stimuli, given both below and above levels of subjective experience. Evidence of visual MMN elicitation in the absence of the ability to consciously report stimuli would provide strong evidence for the automaticity of the visual MMN mechanism. Using an oddball paradigm, two stimuli that differed in orientation from each other, an + and an x were presented on a computer screen. Electroencephalogram (EEG) was recorded from nine participants (six females), mean age 21.4 years. Results showed that for stimuli that were effectively masked at 7ms presentation, there was little variation in the ERPs evoked to standard and deviant stimuli or in the subtraction waveform employed to delineate the visual MMN. At 14 ms stimulus presentation, when participants were able to report stimulus presence, an enhanced negativity at around 175 ms and 305 ms was observed to the deviant and was evident in the subtraction waveform. Although some of the difference observed in the ERPs can be attributed to stimulus characteristics, the use of a ‘lonely’ deviant protocol revealed attenuated visual MMN components at 14 ms stimulus presentation. Overall, results suggest that some degree of conscious attention is required before visual MMN components emerge, suggesting visual MMN is not an entirely pre-attentive process

Neurophysiologic Markers of Abnormal Brain Activity in Schizophrenia

Cortical electrophysiologic event-related potentials are multidimensional measures of information processing that are well-suited for efficiently parsing automatic and controlled components of cognition that span the range of deficits evidenced in schizophrenia patients. These information processes are key cognitive measures that are recognized as informative and valid targets for understanding the neurobiology of schizophrenia. These measures may be used in concert with the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) neurocognitive measures in the development of novel treatments for schizophrenia and related neuropsychiatric disorders. The employment of novel event-related potential paradigms designed to carefully characterize the early spectrum of perceptual and cognitive information processing allows investigators to identify the neurophysiologic basis of cognitive dysfunction in schizophrenia and to examine the associated clinical and functional impairments

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Sleep, fatigue, depression, and circadian activity rhythms in women with breast cancer before and after treatment: A 1-year longitudinal study

Purpose: Sleep disturbance, fatigue and depression are common complaints in patients with cancer, and often contribute to worse quality of life (QoL). Circadian activity rhythms (CARs) are often disrupted in cancer patients. These symptoms worsen during treatment, but less is known about their long-term trajectory. Methods: Sixty-eight women with stage I-III breast cancer (BC) scheduled to receive ≥4 cycles of chemotherapy, and age-, ethnicity-, and education-matched normal, cancer-free controls (NC) participated. Sleep was measured with actigraphy (nocturnal total sleep time [nocturnal TST] and daytime total nap time [NAPTIME]) and with the Pittsburgh Sleep Quality Index (PSQI); fatigue with the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF); depression with the Center of Epidemiological Studies-Depression (CES-D). CARs were derived from actigraphy. Several measures of QoL were administered. Data were collected at three time points: before (baseline), end of cycle 4 (cycle 4), and 1 year post-chemotherapy (1 year). Results: Compared to NC, BC had longer NAPTIME, worse sleep quality, more fatigue, more depressive symptoms, more disrupted CARs, and worse QoL at baseline (all p values <0.05). At cycle 4, BC showed worse sleep, increased fatigue, more depressive symptoms, and more disrupted CARs compared to their own baseline levels and to NC (all p values <0.05). By 1 year, BC's fatigue, depressive symptoms, and QoL returned to baseline levels but were still worse than those of NC, while NAPTIME and CARs did not differ from NC's. Conclusion: Additional research is needed to determine if beginning treatment of these symptoms before the start of chemotherapy will minimize symptom severity over time. © Springer-Verlag 2014

Daytime sleepiness and the COMT val158met polymorphism in patients with Parkinson disease.

STUDY OBJECTIVE: A preliminary study by our group suggested an association between daytime sleepiness and the catechol-O-methyltransferase (COMT) val158met polymorphism (rs4680) in patients with Parkinson disease (PD). We sought to confirm this association in a large group of patients with PD. DESIGN: Genetic association study in patients with PD. SETTING: Movement disorder sections at 2 university hospitals. PARTICIPANTS: PD patients with and without episodes of suddenly falling asleep matched for antiparkinsonian medication, disease duration, sex, and age, who participated in a previous genetic study on dopamine-receptor polymorphisms. INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS: In this study, 240 patients with PD (154 men; age 65.1 +/- 6.1 years; disease duration 9.4 +/- 6.0 years) were included. Seventy had the met-met (LL), 116 the met-val (LH), and 54 the val-val (HH) genotype. In the combined LL+LH group (featuring reduced COMT activity), the mean Epworth Sleepiness Scale (ESS) score was 9.0 +/- 5.9 versus 11.0 +/- 6.1 in the HH (high COMT activity) group (P = .047). Forty-seven percent of the LL and LH patients had sudden sleep onset compared with 61% of the HH patients (P = .07). Logistic regression, however, showed that both pathologic ESS scores (i.e., > 10) and sudden sleep onset were predicted by subjective disease severity (P < .001 each) but not by the COMT genotype. CONCLUSIONS: Our previous finding that the L-allele may be associated with daytime sleepiness could not be confirmed in the present study. Altogether, our data do not support a clinically relevant effect of the COMT genotype on daytime sleepiness in PD