Cerebral hierarchies: predictive processing, precision and the pulvinar

This paper considers neuronal architectures from a computational perspective and asks what aspects of neuroanatomy and neurophysiology can be disclosed by the nature of neuronal computations? In particular, we extend current formulations of the brain as an organ of inference—based upon hierarchical predictive coding—and consider how these inferences are orchestrated. In other words, what would the brain require to dynamically coordinate and contextualize its message passing to optimize its computational goals? The answer that emerges rests on the delicate (modulatory) gain control of neuronal populations that select and coordinate (prediction error) signals that ascend cortical hierarchies. This is important because it speaks to a hierarchical anatomy of extrinsic (between region) connections that form two distinct classes, namely a class of driving (first-order) connections that are concerned with encoding the content of neuronal representations and a class of modulatory (second-order) connections that establish context—in the form of the salience or precision ascribed to content. We explore the implications of this distinction from a formal perspective (using simulations of feature–ground segregation) and consider the neurobiological substrates of the ensuing precision-engineered dynamics, with a special focus on the pulvinar and attention

Active interoceptive inference and the emotional brain

We review a recent shift in conceptions of interoception and its relationship to hierarchical inference in the brain. The notion of interoceptive inference means that bodily states are regulated by autonomic reflexes that are enslaved by descending predictions from deep generative models of our internal and external milieu. This re-conceptualization illuminates several issues in cognitive and clinical neuroscience with implications for experiences of selfhood and emotion. We first contextualize interoception in terms of active (Bayesian) inference in the brain, highlighting its enactivist (embodied) aspects. We then consider the key role of uncertainty or precision and how this might translate into neuromodulation. We next examine the implications for understanding the functional anatomy of the emotional brain, surveying recent observations on agranular cortex. Finally, we turn to theoretical issues, namely, the role of interoception in shaping a sense of embodied self and feelings. We will draw links between physiological homoeostasis and allostasis, early cybernetic ideas of predictive control and hierarchical generative models in predictive processing. The explanatory scope of interoceptive inference ranges from explanations for autism and depression, through to consciousness. We offer a brief survey of these exciting developments

Cloning, expression, and functional analysis of human dopamine D1 receptors

Aim : To construct an HEK293 cell line stably expressing human dopamine D 1 receptor (D 1 R). Methods : cDNA was amplified by RT-PCR using total RNA from human embryo brain tissue as the template. The PCR products were subcloned into the plasmid pcDNA3 and cloned into the plasmid pcDNA3.1. The cloned D 1 R cDNA was sequenced and stably expressed in HEK293 cells. Expression of D 1 R in HEK293 cells was monitored by the [ 3 H]SCH23390 binding assay. The function of D 1 R was studied by the cAMP accumulation assay, CRE-SEAP reporter gene activity assay, and intracellular calcium assay. Results : An HEK293 cell line stably expressing human D 1 R was obtained. A saturation radioligand binding experiment with [ 3 H]SCH23390 demonstrated that the K d and B max values were 1.5±0.2 nmol/L and 2.94±0.15 nmol/g of protein, respectively. In the [ 3 H]SCH23390 competition assay, D 1 R agonist SKF38393 displaced [ 3 H]SCH23390 with an IC 50 value of 2.0 (1.5–2.8) Μmol/L. SKF38393 increased the intracellular cAMP level and CRE-SEAP activity through D 1 R expressed in HEK293 cells in a concentration-dependent manner with an EC 50 value of 0.25 (0.12–0.53) Μmol/L and 0.39 (0.27–0.57) Μmol/L at 6 h/0.59 (0.22–1.58) Μmol/L at 12 h, respectively. SKF38393 also increased the intracellular calcium level in a concentration-dependent manner with EC 50 value of 27 (8.6–70) nmol/L. Conclusion : An HEK293 cell line stably expressing human D 1 R was obtained successfuly. The study also demonstrated that the CRE-SEAP activity assay could be substituted for the cAMP accumulation assay for measuring increase in cAMP levels. Thus, both intracellular calcium measurements and the CRE-SEAP activity assay are suitable for high-throughput screening in drug research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75187/1/j.1745-7254.2005.00017.x.pd

Global minimum estimates of children affected by COVID-19-associated orphanhood and deaths of caregivers: a modelling study

BACKGROUND: The COVID-19 pandemic priorities have focused on prevention, detection, and response. Beyond morbidity and mortality, pandemics carry secondary impacts, such as children orphaned or bereft of their caregivers. Such children often face adverse consequences, including poverty, abuse, and institutionalisation. We provide estimates for the magnitude of this problem resulting from COVID-19 and describe the need for resource allocation. METHODS: We used mortality and fertility data to model minimum estimates and rates of COVID-19-associated deaths of primary or secondary caregivers for children younger than 18 years in 21 countries. We considered parents and custodial grandparents as primary caregivers, and co-residing grandparents or older kin (aged 60–84 years) as secondary caregivers. To avoid overcounting, we adjusted for possible clustering of deaths using an estimated secondary attack rate and age-specific infection–fatality ratios for SARS-CoV-2. We used these estimates to model global extrapolations for the number of children who have experienced COVID-19-associated deaths of primary and secondary caregivers. FINDINGS: Globally, from March 1, 2020, to April 30, 2021, we estimate 1 134 000 children (95% credible interval 884 000–1 185 000) experienced the death of primary caregivers, including at least one parent or custodial grandparent. 1 562 000 children (1 299 000–1 683 000) experienced the death of at least one primary or secondary caregiver. Countries in our study set with primary caregiver death rates of at least one per 1000 children included Peru (10·2 per 1000 children), South Africa (5·1), Mexico (3·5), Brazil (2·4), Colombia (2·3), Iran (1·7), the USA (1·5), Argentina (1·1), and Russia (1·0). Numbers of children orphaned exceeded numbers of deaths among those aged 15–50 years. Between two and five times more children had deceased fathers than deceased mothers. INTERPRETATION: Orphanhood and caregiver deaths are a hidden pandemic resulting from COVID-19-associated deaths. Accelerating equitable vaccine delivery is key to prevention. Psychosocial and economic support can help families to nurture children bereft of caregivers and help to ensure that institutionalisation is avoided. These data show the need for an additional pillar of our response: prevent, detect, respond, and care for children. FUNDING: UK Research and Innovation (Global Challenges Research Fund, Engineering and Physical Sciences Research Council, Medical Research Council), UK National Institute for Health Research, US National Institutes of Health, and Imperial College London

Global, regional, and national minimum estimates of children affected by COVID-19-associated orphanhood and caregiver death, by age and family circumstance up to Oct 31, 2021: an updated modelling study

BACKGROUND: In the 6 months following our estimates from March 1, 2020, to April 30, 2021, the proliferation of new coronavirus variants, updated mortality data, and disparities in vaccine access increased the amount of children experiencing COVID-19-associated orphanhood. To inform responses, we aimed to model the increases in numbers of children affected by COVID-19-associated orphanhood and caregiver death, as well as the cumulative orphanhood age-group distribution and circumstance (maternal or paternal orphanhood). METHODS: We used updated excess mortality and fertility data to model increases in minimum estimates of COVID-19-associated orphanhood and caregiver deaths from our original study period of March 1, 2020-April 30, 2021, to include the new period of May 1-Oct 31, 2021, for 21 countries. Orphanhood was defined as the death of one or both parents; primary caregiver loss included parental death or the death of one or both custodial grandparents; and secondary caregiver loss included co-residing grandparents or kin. We used logistic regression and further incorporated a fixed effect for western European countries into our previous model to avoid over-predicting caregiver loss in that region. For the entire 20-month period, we grouped children by age (0-4 years, 5-9 years, and 10-17 years) and maternal or paternal orphanhood, using fertility contributions, and we modelled global and regional extrapolations of numbers of orphans. 95% credible intervals (CrIs) are given for all estimates. FINDINGS: The number of children affected by COVID-19-associated orphanhood and caregiver death is estimated to have increased by 90·0% (95% CrI 89·7-90·4) from April 30 to Oct 31, 2021, from 2 737 300 (95% CrI 1 976 100-2 987 000) to 5 200 300 (3 619 400-5 731 400). Between March 1, 2020, and Oct 31, 2021, 491 300 (95% CrI 485 100-497 900) children aged 0-4 years, 736 800 (726 900-746 500) children aged 5-9 years, and 2 146 700 (2 120 900-2 174 200) children aged 10-17 years are estimated to have experienced COVID-19-associated orphanhood. Globally, 76·5% (95% CrI 76·3-76·7) of children were paternal orphans, whereas 23·5% (23·3-23·7) were maternal orphans. In each age group and region, the prevalence of paternal orphanhood exceeded that of maternal orphanhood. INTERPRETATION: Our findings show that numbers of children affected by COVID-19-associated orphanhood and caregiver death almost doubled in 6 months compared with the amount after the first 14 months of the pandemic. Over the entire 20-month period, 5·0 million COVID-19 deaths meant that 5·2 million children lost a parent or caregiver. Our data on children's ages and circumstances should support pandemic response planning for children globally. FUNDING: UK Research and Innovation (Global Challenges Research Fund, Engineering and Physical Sciences Research Council, and Medical Research Council), Oak Foundation, UK National Institute for Health Research, US National Institutes of Health, and Imperial College London

Developmental changes in human dopamine neurotransmission: cortical receptors and terminators

<p>Abstract</p> <p>Background</p> <p>Dopamine is integral to cognition, learning and memory, and dysfunctions of the frontal cortical dopamine system have been implicated in several developmental neuropsychiatric disorders. The dorsolateral prefrontal cortex (DLPFC) is critical for working memory which does not fully mature until the third decade of life. Few studies have reported on the normal development of the dopamine system in human DLPFC during postnatal life. We assessed pre- and postsynaptic components of the dopamine system including tyrosine hydroxylase, the dopamine receptors (D1, D2 short and D2 long isoforms, D4, D5), catechol-<it>O</it>-methyltransferase, and monoamine oxidase (A and B) in the developing human DLPFC (6 weeks -50 years).</p> <p>Results</p> <p>Gene expression was first analysed by microarray and then by quantitative real-time PCR. Protein expression was analysed by western blot. Protein levels for tyrosine hydroxylase peaked during the first year of life (p < 0.001) then gradually declined to adulthood. Similarly, mRNA levels of dopamine receptors D2S (p < 0.001) and D2L (p = 0.003) isoforms, monoamine oxidase A (p < 0.001) and catechol-<it>O</it>-methyltransferase (p = 0.024) were significantly higher in neonates and infants as was catechol-<it>O</it>-methyltransferase protein (32 kDa, p = 0.027). In contrast, dopamine D1 receptor mRNA correlated positively with age (p = 0.002) and dopamine D1 receptor protein expression increased throughout development (p < 0.001) with adults having the highest D1 protein levels (p ≤ 0.01). Monoamine oxidase B mRNA and protein (p < 0.001) levels also increased significantly throughout development. Interestingly, dopamine D5 receptor mRNA levels negatively correlated with age (r = -0.31, p = 0.018) in an expression profile opposite to that of the dopamine D1 receptor.</p> <p>Conclusions</p> <p>We find distinct developmental changes in key components of the dopamine system in DLPFC over postnatal life. Those genes that are highly expressed during the first year of postnatal life may influence and orchestrate the early development of cortical neural circuitry while genes portraying a pattern of increasing expression with age may indicate a role in DLPFC maturation and attainment of adult levels of cognitive function.</p

Quality of life, characteristics and survival of patients with HIV and lymphoma

We sought to compare the quality of life (QOL), characteristics, and survival of patients with non-Hodgkin lymphoma (NHL) with and without human immunodeficiency virus (HIV) infection. Using the population-based cancer registry for Orange and San Diego Counties, We recruited 50 patients with HIV and systemic NHL (cases) and 50 age, sex and race-matched NHL patients without HIV (controls) diagnosed with NHL during 2002–2006. Patients completed a medical history survey and QOL instrument, the Functional Assessment of Human Immunodeficiency Virus Infection (FAHI) for cases and Functional Assessment of Cancer Therapy-General (FACT G) for controls. HIV-infected patients had worse overall QOL and survival than uninfected patients. QOL differences were more marked in the areas of functional, physical and social well-being than in the area of emotional well-being. HIV-infected patients had lower income and were less likely to have private insurance and more likely to have diffuse large B cell histology than uninfected patients. HIV-infected NHL patients had worse QOL and survival than uninfected patients, due to a combination of co-morbidity, aggressive histology and lack of social support. However, their emotional well-being was comparable to that of uninfected NHL patients and better than historical norms for the HIV-infected

SPECULOOS exoplanet search and its prototype on TRAPPIST

One of the most significant goals of modern science is establishing whether life exists around other suns. The most direct path towards its achievement is the detection and atmospheric characterization of terrestrial exoplanets with potentially habitable surface conditions. The nearest ultracool dwarfs (UCDs), i.e. very-low-mass stars and brown dwarfs with effective temperatures lower than 2700 K, represent a unique opportunity to reach this goal within the next decade. The potential of the transit method for detecting potentially habitable Earth-sized planets around these objects is drastically increased compared to Earth-Sun analogs. Furthermore, only a terrestrial planet transiting a nearby UCD would be amenable for a thorough atmospheric characterization, including the search for possible biosignatures, with near-future facilities such as the James Webb Space Telescope. In this chapter, we first describe the physical properties of UCDs as well as the unique potential they offer for the detection of potentially habitable Earth-sized planets suitable for atmospheric characterization. Then, we present the SPECULOOS ground-based transit survey, that will search for Earth-sized planets transiting the nearest UCDs, as well as its prototype survey on the TRAPPIST telescopes. We conclude by discussing the prospects offered by the recent detection by this prototype survey of a system of seven temperate Earth-sized planets transiting a nearby UCD, TRAPPIST-1.Comment: Submitted as a chapter in the "Handbook of Exoplanets" (editors: H. Deeg & J.A. Belmonte; Section Editor: N. Narita). 16 pages, 4 figure

Dopaminergic modulation of appetitive trace conditioning: the role of D1 receptors in medial prefrontal cortex

Rationale: Trace conditioning may provide a behavioural model suitable to examine the maintenance of ‘on line’ information and its underlying neural substrates. Objectives: Experiment la was run to establish trace conditioning in a shortened procedure which would be suitable to test the effects of dopamine (DA) D1 receptor agents administered by microinjection directly into the brain. Experiment lb examined the effects of the DA D1 agonist SKF81297 and the DA D1 antagonist SCH23390 following systemic administration in pre-trained animals. Experiment 2 went on to test the effects of systemically administered SKF81297 on the acquisition of trace conditioning. In experiment 3, SKF81297 was administered directly in prelimbic (PL) and infralimbic (IL) sub-regions of medial prefrontal cortex (mPFC) to compare the role of different mPFC sub-regions. Results: Whilst treatment with SCH23390 impaired motor responding and/or motivation, SKF81297 had relatively little effect in the pre-trained animals tested in experiment 1b. However, systemic SKF81297 depressed the acquisition function at the 2-s trace interval in experiment 2. Similarly, in experiment 3, SKF81297 (0.1 μg in 1.0 μl) microinjected into either PL or IL mPFC impaired appetitive conditioning at the 2-s trace interval. Conclusions: Impaired trace conditioning under SKF81297 is likely to be mediated in part (but not exclusively) within the IL and PL mPFC sub-regions. The finding that trace conditioning was impaired rather than enhanced under SKF81297 provides further evidence for the inverse U-function which has been suggested to be characteristic of mPFC DA function