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Unraveling Mechanisms of Patient-Specific NRXN1 Mutations in Neuropsychiatric Diseases Using Human Induced Pluripotent Stem Cells.
Rare heterozygous deletions in the neurexin 1 (NRXN1) gene robustly increase an individual's risk of developing neurological and psychiatric disorders. However, the molecular bases by which different mutations result in different clinical presentations, with variable penetrance, are unknown. To better understand the molecular and cellular consequences of heterozygous NRXN1 mutations, Flaherty and colleagues studied how patient mutations influence the NRXN1 isoform repertoire and neuronal phenotypes using induced pluripotent stem (iPS) cells. Advancing from disease association to mechanistic insights, the authors provide insight into how patient mutations might impinge on neuronal function. This research highlights the value of iPS cells for elucidating otherwise elusive links between molecular and neuronal function. In addition, they provide further evidence of the importance of alternative splicing in the pathophysiology of neuropsychiatric diseases.
Sweet anticipation and positive emotions in music, groove, and dance
Across human cultures, music is an important source of emotion, including positive emotions and pleasurable experiences. Our brains and bodies are moved by music as part of an active process in which our brains are constantly generating predictions of what is likely to happen next. The constituent elements of music (melody, harmony, and rhythm) are processed in an active, sustained musical pleasure cycle that gives rise to action, emotion, and learning, led by activity in specific brain networks. The ‘sweet anticipation’ stage of this pleasure cycle is both highly motivating and pleasurable. Here, we highlight research on how music, groove and dance can generate positive emotion. Especially in the case of dance, an important element of this collective positive emotion arises from engagement with other people. Yet, most neuroscientific research on music to date has focused on an individual processing music passively, rather than interacting, and until now very little neuroscientific research has been undertaken on dance. We therefore argue that future research would do well to focus on the dynamics and underlying brain mechanisms of the collective experience of music making and dance.
Effectiveness as an outcome measure for treatment trials in psychiatry
There is at present some confusion about the relative value of clinical trials performed to investigate efficacy vs. those designed to investigate effectiveness. This is particularly challenging when studies performed as experiments for regulators by companies are used to shape and inform clinical practice, especially if studies conducted under more real life conditions fail to support predicted benefits. We review the field in relation to the new antipsychotics, in particular. Other indications, including mood disorders, which are also briefly touched upon, have so far received less definitive attention, but are likely to encounter the same difficulties. We conclude that, where the results of efficacy trials are positive and an effectiveness trial is negative, one should not necessarily prefer the effectiveness trial. it may simply have failed. Where efficacy trials and effectiveness trials point to similar conclusions, then the findings are mutually supportive. © 2009 wydanie polskie, Instytut Psychiatrii i Neurologii.
Psilocin acutely disrupts sleep and affects local but not global sleep homeostasis in laboratory mice
<jats:title>Abstract</jats:title><jats:p>Serotonergic psychedelic drugs, such as psilocin (4-hydroxy-N,N-dimethyltryptamine), profoundly alter the quality of consciousness through mechanisms which are incompletely understood. Growing evidence suggests that a single psychedelic experience can positively impact long-term psychological well-being, with relevance for the treatment of psychiatric disorders, including depression. A prominent factor associated with psychiatric disorders is disturbed sleep, and the sleep-wake cycle is implicated in the regulation of neuronal firing and activity homeostasis. It remains unknown to what extent psychedelic agents directly affect sleep, in terms of both acute arousal and homeostatic sleep regulation. Here, chronic <jats:italic>in vivo</jats:italic> electrophysiological recordings were obtained in mice to track sleep-wake architecture and cortical activity after psilocin injection. Administration of psilocin led to delayed REM sleep onset and reduced NREM sleep maintenance for up to approximately 3 hours after dosing, and the acute EEG response was associated primarily with an enhanced oscillation around 4 Hz. No long-term changes in sleep-wake quantity were found. When combined with sleep deprivation, psilocin did not alter the dynamics of homeostatic sleep rebound during the subsequent recovery period, as reflected in both sleep amount and EEG slow wave activity. However, psilocin decreased the recovery rate of sleep slow wave activity following sleep deprivation in the local field potentials of electrodes targeting medial prefrontal and surrounding cortex. It is concluded that psilocin affects both global vigilance state control and local sleep homeostasis, an effect which may be relevant for its antidepressant efficacy.</jats:p>
Linking the timing of a mother's and child's death: Comparative evidence from two rural South African population-based surveillance studies, 2000-2015.
BACKGROUND: The effect of the period before a mother's death on child survival has been assessed in only a few studies. We conducted a comparative investigation of the effect of the timing of a mother's death on child survival up to age five years in rural South Africa. METHODS: We used discrete time survival analysis on data from two HIV-endemic population surveillance sites (2000-2015) to estimate a child's risk of dying before and after their mother's death. We tested if this relationship varied between sites and by availability of antiretroviral therapy (ART). We assessed if related adults in the household altered the effect of a mother's death on child survival. FINDINGS: 3,618 children died from 2000-2015. The probability of a child dying began to increase in the 7-11 months prior to the mother's death and increased markedly in the 3 months before (2000-2003 relative risk = 22.2, 95% CI = 14.2-34.6) and 3 months following her death (2000-2003 RR = 20.1; CI = 10.3-39.4). This increased risk pattern was evident at both sites. The pattern attenuated with ART availability but remained even with availability at both sites. The father and maternal grandmother in the household lowered children's mortality risk independent of the association between timing of mother and child mortality. CONCLUSIONS: The persistence of elevated mortality risk both before and after the mother's death for children of different ages suggests that absence of maternal care and abrupt breastfeeding cessation might be crucial risk factors. Formative research is needed to understand the circumstances for children when a mother is very ill or dies, and behavioral and other risk factors that increase both the mother and child's risk of dying. Identifying families when a mother is very ill and implementing training and support strategies for other members of the household are urgently needed to reduce preventable child mortality.
Alcohol affordability: implications for alcohol price policies. A cross-sectional analysis in middle and older adults from UK Biobank
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Increasing the price of alcohol reduces alcohol consumption and harm. The role of food complementarity, transaction costs and inflation on alcohol demand are determined and discussed in relation to alcohol price policies.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>UK Biobank (N = 502,628) was linked by region to retail price quotes for the years 2007 to 2010. The log residual food and alcohol prices, and alcohol availability were regressed onto log daily alcohol consumption. Model standard errors were adjusted for clustering by region.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Associations with alcohol consumption were found for alcohol price (β = −0.56, 95% CI, −0.92 to −0.20) and availability (β = 0.06, 95% CI, 0.04 to 0.07). Introducing, food price reduced the alcohol price consumption association (β = −0.26, 95% CI, −0.50 to −0.03). Alcohol (B = 0.001, 95% CI, 0.0004 to 0.001) and food (B = 0.001, 95% CI, 0.0005 to 0.0006) price increased with time and were associated (ρ = 0.57, P &lt; 0.001).</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Alcohol and food are complements, and the price elasticity of alcohol reduces when the effect of food price is accounted for. Transaction costs did not affect the alcohol price consumption relationship. Fixed alcohol price policies are susceptible to inflation.</jats:p> </jats:sec>
Large-scale societal dynamics are reflected in human mood and brain
<jats:title>Abstract</jats:title><jats:p>The stock market is a bellwether of socio-economic changes that may directly affect individual well-being. Using large-scale UK-biobank data generated over 14 years, we applied specification curve analysis to rigorously identify significant associations between the local stock market index (FTSE100) and 479,791 UK residents’ mood, as well as their alcohol intake and blood pressure adjusting the results for a large number of potential confounders, including age, sex, linear and non-linear effects of time, research site, other stock market indexes. Furthermore, we found similar associations between FTSE100 and volumetric measures of affective brain regions in a subsample (n=39,755; measurements performed over 5.5 years), which were particularly strong around phase transitions characterized by maximum volatility in the market. The main findings did not depend on applied effect-size estimation criteria (linear methods or mutual information criterion) and were replicated in two independent US-based studies (Parkinson’s Progression Markers Initiative; n=424; performed over 2,5 years and MyConnectome; n=1; 81 measurements over 1,5 years). Our results suggest that phase transitions in the society, indexed by stock market, exhibit close relationships with human mood, health and the affective brain from an individual to population level.</jats:p>
Rare long-range cortical connections enhance information processing
<jats:title>Summary</jats:title><jats:p>A fundamental and unanswered question concerns the key topological features of connectivity that are critically relevant for generating the dynamics underlying efficient cortical function. A candidate feature that has recently emerged is that the connectivity of the mammalian cortex follows an exponential distance rule, which uniquely includes a small proportion of long-range high-weight anatomical connections. We investigate how these long-range connections influence whole-brain dynamics with coupled oscillators. To understand the causal function of long-range connections, we first studied these connections in simple ring structures and then in complex empirical brain architectures. A small proportion of long-range connections are sufficient for significantly improving information transmission, i.e. information cascade. Large-scale empirical neuroimaging modelling point to the immense functional benefits for information processing of a brain architecture with long-range coupling that improves the information cascade thanks to the underlying turbulent regime of brain dynamics.</jats:p>
Decoding brain states on the intrinsic manifold of human brain dynamics across wakefulness and sleep
<jats:title>Abstract</jats:title><jats:p>Current state-of-the-art functional magnetic resonance imaging (fMRI) offers remarkable imaging quality and resolution, yet, the <jats:italic>intrinsic</jats:italic> dimensionality of brain dynamics in different states (wakefulness, light and deep sleep) remains unknown. Here we present a novel method to reveal the low dimensional intrinsic manifold underlying human brain dynamics, which is invariant of the high dimensional spatio-temporal representation of the neuroimaging technology. By applying this novel <jats:italic>intrinsic manifold</jats:italic> framework to fMRI data acquired in wakefulness and sleep, we reveal the nonlinear differences between wakefulness and three different sleep stages, and successfully decode these different brain states with an average accuracy of 96%. Remarkably, a further group analysis shows that the intrinsic manifolds of all participants share a common topology. Overall, our results reveal the intrinsic manifold underlying the spatiotemporal dynamics of brain activity and demonstrate how this manifold enables the decoding of different brain states such as wakefulness and various sleep stages.</jats:p>
Young people's moral attitudes and motivations towards direct-to-consumer genetic testing for inherited risk of Alzheimer disease.
PURPOSE: Since the U.S. Food and Drug Administration approved sales of genetic tests for late-onset Alzheimer's disease (LOAD) risk, a heated debate has arisen over whether these tests should indeed be offered online and direct-to-consumer (DTC). As this debate progresses, it is important to understand the ethical perspectives and motivations of young people, who are a key target group for DTC services. METHODS: Thirty-one grandchildren of people with LOAD, aged 16-26, were interviewed about their moral attitudes and motivations with regards to DTC genetic testing for LOAD. RESULTS: Even though most participants claimed that people should have the right to access these services, they also expressed concerns about potential distress in response to learning about risk, particularly for minors. About a third were interested in testing, primarily to gain self-knowledge regarding one's health; however, face-to-face services were vastly preferred over the online option. CONCLUSION: While DTC genetic companies often market their services as a "fun consumer product", DTC testing for LOAD was largely understood as a serious health screening procedure and a vulnerable moment in the lives of young people in Alzheimer's families. This points to the importance of appropriate standards of information and support to young people pre- and post-testing.
Response to Achieving Consensus in the Measurement of Psychological Adjustment to Cleft Lip and/or Palate at Age 8+ Years.
In this letter, we discuss the recently published paper by Stock et al, entitled Achieving Consensus in the Measurement of Psychological Adjustment to Cleft Lip and/or Palate at Age 8+ Years.