Decoding expectation and surprise in dementia: the paradigm of music

Making predictions about the world and responding appropriately to unexpected events are essential functions of the healthy brain. In neurodegenerative disorders, such as frontotemporal dementia and Alzheimer's disease, impaired processing of 'surprise' may underpin a diverse array of symptoms, particularly abnormalities of social and emotional behaviour, but is challenging to characterize. Here, we addressed this issue using a novel paradigm: music. We studied 62 patients (24 female; aged 53-88) representing major syndromes of frontotemporal dementia (behavioural variant, semantic variant primary progressive aphasia, non-fluent-agrammatic variant primary progressive aphasia) and typical amnestic Alzheimer's disease, in relation to 33 healthy controls (18 female; aged 54-78). Participants heard famous melodies containing no deviants or one of three types of deviant note-acoustic (white-noise burst), syntactic (key-violating pitch change) or semantic (key-preserving pitch change). Using a regression model that took elementary perceptual, executive and musical competence into account, we assessed accuracy detecting melodic deviants and simultaneously recorded pupillary responses and related these to deviant surprise value (information-content) and carrier melody predictability (entropy), calculated using an unsupervised machine learning model of music. Neuroanatomical associations of deviant detection accuracy and coupling of detection to deviant surprise value were assessed using voxel-based morphometry of patients' brain MRI. Whereas Alzheimer's disease was associated with normal deviant detection accuracy, behavioural and semantic variant frontotemporal dementia syndromes were associated with strikingly similar profiles of impaired syntactic and semantic deviant detection accuracy and impaired behavioural and autonomic sensitivity to deviant information-content (all P < 0.05). On the other hand, non-fluent-agrammatic primary progressive aphasia was associated with generalized impairment of deviant discriminability (P < 0.05) due to excessive false-alarms, despite retained behavioural and autonomic sensitivity to deviant information-content and melody predictability. Across the patient cohort, grey matter correlates of acoustic deviant detection accuracy were identified in precuneus, mid and mesial temporal regions; correlates of syntactic deviant detection accuracy and information-content processing, in inferior frontal and anterior temporal cortices, putamen and nucleus accumbens; and a common correlate of musical salience coding in supplementary motor area (all P < 0.05, corrected for multiple comparisons in pre-specified regions of interest). Our findings suggest that major dementias have distinct profiles of sensory 'surprise' processing, as instantiated in music. Music may be a useful and informative paradigm for probing the predictive decoding of complex sensory environments in neurodegenerative proteinopathies, with implications for understanding and measuring the core pathophysiology of these diseases

Branch Mode Selection during Early Lung Development

Many organs of higher organisms, such as the vascular system, lung, kidney, pancreas, liver and glands, are heavily branched structures. The branching process during lung development has been studied in great detail and is remarkably stereotyped. The branched tree is generated by the sequential, non-random use of three geometrically simple modes of branching (domain branching, planar and orthogonal bifurcation). While many regulatory components and local interactions have been defined an integrated understanding of the regulatory network that controls the branching process is lacking. We have developed a deterministic, spatio-temporal differential-equation based model of the core signaling network that governs lung branching morphogenesis. The model focuses on the two key signaling factors that have been identified in experiments, fibroblast growth factor (FGF10) and sonic hedgehog (SHH) as well as the SHH receptor patched (Ptc). We show that the reported biochemical interactions give rise to a Schnakenberg-type Turing patterning mechanisms that allows us to reproduce experimental observations in wildtype and mutant mice. The kinetic parameters as well as the domain shape are based on experimental data where available. The developed model is robust to small absolute and large relative changes in the parameter values. At the same time there is a strong regulatory potential in that the switching between branching modes can be achieved by targeted changes in the parameter values. We note that the sequence of different branching events may also be the result of different growth speeds: fast growth triggers lateral branching while slow growth favours bifurcations in our model. We conclude that the FGF10-SHH-Ptc1 module is sufficient to generate pattern that correspond to the observed branching modesComment: Initially published at PLoS Comput Bio

Tuberculosis Contact Screening and Isoniazid Preventive Therapy in a South Indian District: Operational Issues for Programmatic Consideration

BACKGROUND: Under India's Revised National Tuberculosis Control Programme (RNTCP), all household contacts of sputum smear positive Pulmonary Tuberculosis (PTB) patients are screened for TB. In the absence of active TB disease, household contacts aged <6 years are eligible for Isoniazid Preventive Therapy (IPT) (5 milligrams/kilogram body weight/day) for 6 months. OBJECTIVES: To estimate the number of household contacts aged <6 years, of sputum smear positive PTB patients registered for treatment under RNTCP from April to June'2008 in Krishna District, to assess the extent to which they are screened for TB disease and in its absence initiated on IPT. METHODS: A cross sectional study was conducted. Households of all smear positive PTB cases (n = 848) registered for treatment from April to June'2008 were included. Data on the number of household contacts aged <6 years, the extent to which they were screened for TB disease, and the status of initiation of IPT, was collected. RESULTS: Households of 825 (97%) patients were visited, and 172 household contacts aged <6 years were identified. Of them, 116 (67%) were evaluated for TB disease; none were found to be TB diseased and 97 (84%) contacts were initiated on IPT and 19 (16%) contacts were not initiated on IPT due to shortage of INH tablets in peripheral health centers. The reasons for non-evaluation of the remaining eligible children (n = 56, 33%) include no home visit by the health staff in 25 contacts, home visit done but not evaluated in 31 contacts. House-hold contacts in rural areas were less likely to be evaluated and initiated on IPT [risk ratio 6.65 (95% CI; 3.06-14.42)]. CONCLUSION: Contact screening and IPT implementation under routine programmatic conditions is sub-optimal. There is an urgent need to sensitize all concerned programme staff on its importance and establishment of mechanisms for rigorous monitoring

Bovine colostrum supplementation and upper respiratory symptoms during exercise training: a systematic review and meta-analysis of randomised controlled trials

Abstract Background Bovine colostrum is proposed as a nutritional countermeasure to the risk of upper respiratory symptoms (URS) during exercise training. The aim of this systematic review and meta-analysis was to estimate the size of the effect of bovine colostrum supplementation on URS. Methods Databases (CDSR, CENTRAL, Cinahl, ClinicalTrials.gov, Current Controlled Trials, DARE, EMBASE, Medline, PROSPERO and Web of Science) of published, unpublished and ongoing studies were searched for randomised controlled trials of healthy adults (≥18 years), evaluating the effect of oral bovine colostrum supplementation compared to a concurrent control group on URS. Results Five trials (152 participants) met the inclusion criteria, all of which involved individuals involved in regular exercise training. Over an 8–12 week follow-up period, bovine colostrum supplementation when compared to placebo significantly reduced the incidence rate of URS days (rate ratio 0.56, 95 % confidence intervals 0.43 to 0.72, P value < 0.001) and URS episodes (0.62, 0.40 to 0.99, P value = 0.04) by 44 and 38 % respectively. There were limited data and considerable variation in results of included studies for duration of URS episodes hence a meta-analysis of this outcome was deemed inappropriate. The risk of bias assessment in this review was hindered by poor reporting practices of included studies. Due to incomplete reporting of study methods, four of the five studies were judged to have a moderate or high risk of overall bias. Our findings must be interpreted in relation to quantity and quality of the available evidence. Conclusions The present systematic review and meta-analysis provides evidence that bovine colostrum supplementation may be effective in preventing the incidence of URS days and episodes in adults engaged in exercise training. The fact that the majority of included studies did not report significant effects on URS outcomes mitigates concerns about publication bias. The point estimates of the random-effects meta-analyses are greater than the smallest clinically important difference, but the low precision of the individual study estimates means the evidence presented in this review needs to be followed up with an appropriately designed and adequately powered, randomised control trial

A systematic exploration of differences in contextual factors related to implementing the MOVE! weight management program in VA: A mixed methods study

<p>Abstract</p> <p>Background</p> <p>In January 2006, Veterans Affairs (VA) disseminated the MOVE!^®Weight Management Program to VA medical centers to address the high prevalence of overweight/obesity. In its second year, MOVE! implementation varied widely across facilities. The objective of this study was to understand contextual factors that facilitated or impeded implementation of MOVE! in VA medical centers in the second year after its dissemination.</p> <p>Methods</p> <p>We used an embedded mixed methods cross-sectional study design. Qualitative and quantitative data were collected simultaneously with the primary purpose to explore contextual factors most likely to influence MOVE! implementation effectiveness at five purposively selected facilities. Facilities were selected to maximize variation with respect to participation in MOVE! by candidate Veterans. Semi-structured phone interviews were conducted with 24 staff across the five facilities. Quantitative responses were elicited followed by open-ended questions. The quantitative measures were adapted from a published implementation model. Qualitative analysis was conducted using rigorous content analysis methods.</p> <p>Results</p> <p>Qualitative and quantitative data converged to strengthen findings that point to several recommendations. Management support can help increase visibility of the program, commit needed resources, and communicate the importance of implementation efforts. Establishing a receptive implementation climate can be accomplished by emphasizing the important role that weight management may have in reducing incidence and severity of obesity-related chronic conditions. Coalescing highly functioning multi-disciplinary teams was an essential step for more effective implementation of MOVE!. In some situations, local champions can overcome challenging barriers in facilities that lack sufficient management support.</p> <p>Conclusions</p> <p>Key organizational factors at local VA medical centers were strongly associated with MOVE! implementation. Results pointed to recommendations that can help accelerate large-scale dissemination of complex weight management programs.</p

Carbon storage in soils of Southeastern Nigeria under different management practices

<p>Abstract</p> <p>Background</p> <p>Changes in agricultural practices-notably changes in crop varieties, application of fertilizer and manure, rotation and tillage practices-influence how much and at what rate carbon is stored in, or released from, soils. Quantification of the impacts of land use on carbon stocks in sub-Saharan Africa is challenging because of the spatial heterogeneity of soil, climate, management conditions, and due to the lack of data on soil carbon pools of most common agroecosystems. This paper provides data on soil carbon stocks that were collected at 10 sites in southeastern Nigeria to characterize the impact of soil management practices.</p> <p>Results</p> <p>The highest carbon stocks, 7906-9510 gC m^-2, were found at the sites representing natural forest, artificial forest and artificial grassland ecosystems. Continuously cropped and conventionally tilled soils had about 70% lower carbon stock (1978-2822 gC m^-2). Thus, the soil carbon stock in a 45-year old <it>Gmelina </it>forest was 8987 gC m^-2, whereas the parts of this forest, that were cleared and continuously cultivated for 15 years, had 75% lower carbon stock (1978 gC m^-2). The carbon stock of continuously cropped and conventionally tilled soils was also 25% lower than the carbon stock of the soil cultivated by use of conservation tillage.</p> <p>Conclusion</p> <p>Introducing conservation tillage practices may reduce the loss of soil carbon stocks associated with land conversion. However, the positive effect of conservation tillage is not comparable to the negative effect of land conversion, and may not result in significant accumulation of carbon in southeastern Nigeria soils.</p

The CBI-R detects early behavioural impairment in genetic frontotemporal dementia

Introduction: Behavioural dysfunction is a key feature of genetic frontotemporal dementia (FTD) but validated clinical scales measuring behaviour are lacking at present. Methods: We assessed behaviour using the revised version of the Cambridge Behavioural Inventory (CBI-R) in 733 participants from the Genetic FTD Initiative study: 466 mutation carriers (195 C9orf72, 76 MAPT, 195 GRN) and 267 non-mutation carriers (controls). All mutation carriers were stratified according to their global CDR plus NACC FTLD score into three groups: asymptomatic (CDR = 0), prodromal (CDR = 0.5) and symptomatic (CDR = 1+). Mixed-effects models adjusted for age, education, sex and family clustering were used to compare between the groups. Neuroanatomical correlates of the individual domains were assessed within each genetic group. Results: CBI-R total scores were significantly higher in all CDR 1+ mutation carrier groups compared with controls [C9orf72 mean 70.5 (standard deviation 27.8), GRN 56.2 (33.5), MAPT 62.1 (36.9)] as well as their respective CDR 0.5 groups [C9orf72 13.5 (14.4), GRN 13.3 (13.5), MAPT 9.4 (10.4)] and CDR 0 groups [C9orf72 6.0 (7.9), GRN 3.6 (6.0), MAPT 8.5 (13.3)]. The C9orf72 and GRN 0.5 groups scored significantly higher than the controls. The greatest impairment was seen in the Motivation domain for the C9orf72 and GRN symptomatic groups, whilst in the symptomatic MAPTgroup, the highest-scoring domains were Stereotypic and Motor Behaviours and Memory and Orientation. Neural correlates of each CBI-R domain largely overlapped across the different mutation carrier groups. Conclusions: The CBI-R detects early behavioural change in genetic FTD, suggesting that it could be a useful measure within future clinical trials

Targeted Delivery of Neural Stem Cells to the Brain Using MRI-Guided Focused Ultrasound to Disrupt the Blood-Brain Barrier

Stem cell therapy is a promising strategy to treat neurodegenerative diseases, traumatic brain injury, and stroke. For stem cells to progress towards clinical use, the risks associated with invasive intracranial surgery used to deliver the cells to the brain, needs to be reduced. Here, we show that MRI-guided focused ultrasound (MRIgFUS) is a novel method for non-invasive delivery of stem cells from the blood to the brain by opening the blood brain barrier (BBB) in specific brain regions. We used MRI guidance to target the ultrasound beam thereby delivering the iron-labeled, green fluorescent protein (GFP)-expressing neural stem cells specifically to the striatum and the hippocampus of the rat brain. Detection of cellular iron using MRI established that the cells crossed the BBB to enter the brain. After sacrifice, 24 hours later, immunohistochemical analysis confirmed the presence of GFP-positive cells in the targeted brain regions. We determined that the neural stem cells expressed common stem cell markers (nestin and polysialic acid) suggesting they survived after transplantation with MRIgFUS. Furthermore, delivered stem cells expressed doublecortin in vivo indicating the stem cells were capable of differentiating into neurons. Together, we demonstrate that transient opening of the BBB with MRIgFUS is sufficient for transplantation of stem cells from the blood to targeted brain structures. These results suggest that MRIgFUS may be an effective alternative to invasive intracranial surgery for stem cell transplantation

In Vitro Reassortment between Endemic H1N2 and 2009 H1N1 Pandemic Swine Influenza Viruses Generates Attenuated Viruses

The pandemic H1N1 (pH1N1) influenza virus was first reported in humans in the spring of 2009 and soon thereafter was identified in numerous species, including swine. Reassortant viruses, presumably arising from the co-infection of pH1N1 and endemic swine influenza virus (SIV), were subsequently identified from diagnostic samples collected from swine. In this study, co-infection of swine testicle (ST) cells with swine-derived endemic H1N2 (MN745) and pH1N1 (MN432) yielded two reassortant H1N2 viruses (R1 and R2), both possessing a matrix gene derived from pH1N1. In ST cells, the reassortant viruses had growth kinetics similar to the parental H1N2 virus and reached titers approximately 2 log10 TCID50/mL higher than the pH1N1 virus, while in A549 cells these viruses had similar growth kinetics. Intranasal challenge of pigs with H1N2, pH1N1, R1 or R2 found that all viruses were capable of infecting and transmitting between direct contact pigs as measured by real time reverse transcription PCR of nasal swabs. Lung samples were also PCR-positive for all challenge groups and influenza-associated microscopic lesions were detected by histology. Interestingly, infectious virus was detected in lung samples for pigs challenged with the parental H1N2 and pH1N1 at levels significantly higher than either reassortant virus despite similar levels of viral RNA. Results of our experiment suggested that the reassortant viruses generated through in vitro cell culture system were attenuated without gaining any selective growth advantage in pigs over the parental lineages. Thus, reassortant influenza viruses described in this study may provide a good system to study genetic basis of the attenuation and its mechanism

A Potential Neural Substrate for Processing Functional Classes of Complex Acoustic Signals

Categorization is essential to all cognitive processes, but identifying the neural substrates underlying categorization processes is a real challenge. Among animals that have been shown to be able of categorization, songbirds are particularly interesting because they provide researchers with clear examples of categories of acoustic signals allowing different levels of recognition, and they possess a system of specialized brain structures found only in birds that learn to sing: the song system. Moreover, an avian brain nucleus that is analogous to the mammalian secondary auditory cortex (the caudo-medial nidopallium, or NCM) has recently emerged as a plausible site for sensory representation of birdsong, and appears as a well positioned brain region for categorization of songs. Hence, we tested responses in this non-primary, associative area to clear and distinct classes of songs with different functions and social values, and for a possible correspondence between these responses and the functional aspects of songs, in a highly social songbird species: the European starling. Our results clearly show differential neuronal responses to the ethologically defined classes of songs, both in the number of neurons responding, and in the response magnitude of these neurons. Most importantly, these differential responses corresponded to the functional classes of songs, with increasing activation from non-specific to species-specific and from species-specific to individual-specific sounds. These data therefore suggest a potential neural substrate for sorting natural communication signals into categories, and for individual vocal recognition of same-species members. Given the many parallels that exist between birdsong and speech, these results may contribute to a better understanding of the neural bases of speech