New microscopy technique sees thousands of cells and their activity deep in the brain

Weisenberger et al. manage the amazing feat of imaging and recording activity of ~12,000 neurons in the mouse cortex. Here is their abstract and a clip from their Figure 7.

Highlights

•In vivo Ca 2+ imaging of ∼12,000 neurons in mouse cortex at single-cell resolution

•Simultaneous 2p and 3p Ca 2+ imaging within 1,000 × 1,000 × 1,220 μm at up to 17 Hz

•Volumetric 3p Ca 2+ imaging of hippocampus through intact cortex 

•A new integrated, systems-wide optimized microscopy design paradigm

Summary

Calcium imaging using two-photon scanning microscopy has become an essential tool in neuroscience. However, in its typical implementation, the tradeoffs between fields of view, acquisition speeds, and depth restrictions in scattering brain tissue pose severe limitations. Here, using an integrated systems-wide optimization approach combined with multiple technical innovations, we introduce a new design paradigm for optical microscopy based on maximizing biological information while maintaining the fidelity of obtained neuron signals. Our modular design utilizes hybrid multi-photon acquisition and allows volumetric recording of neuroactivity at single-cell resolution within up to 1 × 1 × 1.22 mm volumes at up to 17 Hz in awake behaving mice. We establish the capabilities and potential of the different configurations of our imaging system at depth and across brain regions by applying it to in vivo recording of up to 12,000 neurons in mouse auditory cortex, posterior parietal cortex, and hippocampus.

McMindfulness - how capitalism captured the mindfulness industry

A great piece in The Guardian by David Forbes, an extract from his forthcoming book "Mindfulness and its Discontents" from which I further extract a few chunks:

On the internet is an image of Ronald McDonald, the McDonald’s hamburger icon, seated in a lotus position. Some Thai Buddhists see this in literal terms as disrespectful to the Buddha...The technical, neutral definition of mindfulness and its relativist lack of a moral foundation has opened up secular mindfulness to a host of dubious uses, now called out by its critics as McMindfulness...Instead of letting go of the ego, McMindfulness promotes self-aggrandizement; its therapeutic function is to comfort, numb, adjust and accommodate the self within a neoliberal, corporatized, militarized, individualistic society based on private gain...McMindfulness aims to reduce the stress of the private individual and does not admit to any interest in the social causes of stress...it does not grasp that an individualistic therapized and commodified society is itself a major generator of social suffering and distress. Instead, the best it can then do, ironically, is to offer to sell us back an individualistic, commodified “cure” – mindfulness – to reduce that distress...Meditation apps monetize mindfulness; Headspace’s revenue is estimated at $50m a year and the company is valued at $250m.

The New York Times Privacy Project

Many MindBlog readers are probably aware of the NYTimes series of articles on privacy, but I point to it for those who may not be. A recent piece by Ross Douthat describes how our emerging post-privacy isn't quite totalitarian, but it's getting there. I was particularly chilled by Valentino-DeVries' description of Google's Sensorvault database - a trove of detailed location records involving at least hundreds of millions of devices worldwide. Law enforcement officers are using it to identify possible suspects near crimes, and can obtain names and email addresses of device owners who appear relevant to the crime. The article has links to Google web pages that let you download all of your location history and any other data Google has on you. Other pages give instructions on deleting location, web, and App activity, as well as turning off such data collection.

Changes in well-being measured by massive online choice experiments.

Brynjolfsson et al. (open source) suggest moving beyond using gross domestic product (GDP) and productivity as a proxy for well-being to include the welfare gains from digital goods having zero price that are currently not captured in GDP.:

Significance

Gross domestic product (GDP) measures production and is not meant to measure well-being. While many people nonetheless use GDP as a proxy for well-being, consumer surplus is a better measure of consumer well-being. This is increasingly true in the digital economy where many digital goods have zero price and as a result the welfare gains from these goods are not reflected in GDP or productivity statistics. We propose a way of directly measuring consumer well-being using massive online choice experiments. We find that digital goods generate a large amount of consumer welfare that is currently not captured in GDP. For example, the median Facebook user needed a compensation of around $48 to give it up for a month.

Abstract

Gross domestic product (GDP) and derived metrics such as productivity have been central to our understanding of economic progress and well-being. In principle, changes in consumer surplus provide a superior, and more direct, measure of changes in well-being, especially for digital goods. In practice, these alternatives have been difficult to quantify. We explore the potential of massive online choice experiments to measure consumer surplus. We illustrate this technique via several empirical examples which quantify the valuations of popular digital goods and categories. Our examples include incentive-compatible discrete-choice experiments where online and laboratory participants receive monetary compensation if and only if they forgo goods for predefined periods. For example, the median user needed a compensation of about $48 to forgo Facebook for 1 mo. Our overall analyses reveal that digital goods have created large gains in well-being that are not reflected in conventional measures of GDP and productivity. By periodically querying a large, representative sample of goods and services, including those which are not priced in existing markets, changes in consumer surplus and other new measures of well-being derived from these online choice experiments have the potential for providing cost-effective supplements to the existing national income and product accounts.

Tracking emotions of unseen persons by their context.

Martinez does a commentary on work by Chen and Whitney (open source) in the same issue of PNAS.  Here is a clip from that commentary:

Face perception is a fundamental component of our cognitive system and, arguably, a core ability that allowed humans to create the large, advanced societies of today. When we look at someone else’s face, we recognize who they are, whether they are female or male, attractive or unattractive, and happy or sad; that is, their affective state. Correctly interpreting these signals is essential for a functional, cooperative society. For example, when looking at the faces in Fig. 1, most people identify a female expressing sadness on the left and an angry male on the right. But while identity and other attributes are recognized quite accurately, affect is not. To see this, look at the images in Fig. 2A and B. What expressions would you now say these two individuals express? Most of us classify them as expressing excitement or euphoria; that is, positive emotions. What is behind this radical change in our interpretation of these images? Context. Our interpretation of a facial configuration is dependent on the context in which the facial expression is situated. In an ambitious new study in PNAS, Chen and Whitney show that people make reasonably good predictions of people’s affect when only the contextual information is known; that is, when the face is not observable (Fig. 2C). This inference is shown to be accurate, even when the whole body of the person is masked (Fig. 2D), thus preventing an inference based on body pose. Context, therefore, is not only necessary for a correct interpretation of how others feel but, in some instances, it is sufficient. This surprising result will provide renewed interest in the value that context plays in our interpretation of how others feel.

Fig. 1. When asked to identify the emotions shown in these images, most people agree that the left image expresses sadness, while the right image is a clear display of anger. If asked whether these expressions communicate positive or negative valence, most people agree that both correspond to a negative expression. The problem with these assessments is that context is not observable, which may lead to incorrect interpretations. Images courtesy of (Left) Imgflip and (Right) Getty Images/Michael Steele.

Fig. 2. Adding context to the facial expressions previously seen in Fig. 1 radically changes our interpretation of the emotion being experienced by a person. (A and B) In these two images, most observers agree that the people shown are experiencing a joyful event (i.e., positive valence). (C and D) When the face and body are blurred out, inference of valence and arousal is still possible. Images courtesy of (Upper Left, Lower Left, and Lower Right) Imgflip and (Upper Right) Getty Images/Michael Steele.

Here is the Chen and Whitney abstract:

Emotion recognition is an essential human ability critical for social functioning. It is widely assumed that identifying facial expression is the key to this, and models of emotion recognition have mainly focused on facial and bodily features in static, unnatural conditions. We developed a method called affective tracking to reveal and quantify the enormous contribution of visual context to affect (valence and arousal) perception. When characters’ faces and bodies were masked in silent videos, viewers inferred the affect of the invisible characters successfully and in high agreement based solely on visual context. We further show that the context is not only sufficient but also necessary to accurately perceive human affect over time, as it provides a substantial and unique contribution beyond the information available from face and body. Our method (which we have made publicly available) reveals that emotion recognition is, at its heart, an issue of context as much as it is about faces.

Studies on brain renewal and enhancement

I want to point to two recent examples of studies on brain renewal in aging humans and other animals. First, a Stanford group finds that the normal decay in the effectiveness of the microglial brain cells that clean up brain garbage (protein deposits and cellular debris) correlates with the increased appearance of a single gene product, the B cell receptor protein CD22. They find that "Long-term central nervous system delivery of an antibody that blocks CD22 function reprograms microglia towards a homeostatic transcriptional state and improves cognitive function in aged mice."

Second, Zimmer does a nice review of work on the brain protein Klotho. Mice bred to make extra Klotho live 30 percent longer, and protects those with symptoms of Alzheimer's disease from cognitive decline. Klotho not only protects, but enhanced brain function, even in young mice. A recent study suggests that Klotho may also provide some protection from Alzheimer’s disease to people as well.

Synchronizing rhythmic brain circuits improves working memory in older adults.

Our short term memory depends on theta rhythms (~6-10 Hz) and gamma rhythms (~25-100 Hz) in different parts of our brain being coupled and in synchrony with each other. They become increasingly uncoordinated as we age, resulting in observable cognitive decline by the time we reach 60 or 70 years of age. Reinhart and Nguyen compare the working memory of subjects in their 20s with 60-70 year olds, and find that 25 min of noninvasive stimulation, frequency-tuned to individual brain network dynamics, dramatically improves the working memory of the older group, making it similar to the younger group.

Understanding normal brain aging and developing methods to maintain or improve cognition in older adults are major goals of fundamental and translational neuroscience. Here we show a core feature of cognitive decline—working-memory deficits—emerges from disconnected local and long-range circuits instantiated by theta–gamma phase–amplitude coupling in temporal cortex and theta phase synchronization across frontotemporal cortex. We developed a noninvasive stimulation procedure for modulating long-range theta interactions in adults aged 60–76 years. After 25 min of stimulation, frequency-tuned to individual brain network dynamics, we observed a preferential increase in neural synchronization patterns and the return of sender–receiver relationships of information flow within and between frontotemporal regions. The end result was rapid improvement in working-memory performance that outlasted a 50 min post-stimulation period. The results provide insight into the physiological foundations of age-related cognitive impairment and contribute to groundwork for future non-pharmacological interventions targeting aspects of cognitive decline.

Affective forecasting and partisanship

Rai summaries work by Dorison et al.:

Increasing political polarization is driven in part by voters selectively seeking views that support their preexisting beliefs and avoiding opposing views. Across several experiments, Dorison et al. found that people overestimate how upset they will be from being exposed to views from the opposing political party. For example, Clinton voters overestimated how upset they would be from watching Donald Trump's inaugural address or reading statements by Trump voters. This bias in affective forecasting occurs because voters underestimate their level of agreement with people from the opposite party. Correcting voters' affective forecasts increased their engagement with opposing views. These results have implications for fostering dialogue and reducing political polarization.

The Dorison et al. abstract:

People preferentially consume information that aligns with their prior beliefs, contributing to polarization and undermining democracy. Five studies (collective N = 2455) demonstrate that such “selective exposure” partly stems from faulty affective forecasts. Specifically, political partisans systematically overestimate the strength of negative affect that results from exposure to opposing views. In turn, these incorrect forecasts drive information consumption choices. Clinton voters overestimated the negative affect they would experience from watching President Trump's Inaugural Address (Study 1) and from reading statements written by Trump voters (Study 2). Democrats and Republicans overestimated the negative affect they would experience from listening to speeches by opposing-party senators (Study 3). People's tendency to underestimate the extent to which they agree with opponents’ views drove the affective forecasting error. Finally, correcting biased affective forecasts reduced selective exposure by 24–34% (Studies 4 and 5).

"Learned Helplessness" from constant attention to your input stream (email, etc.)?

I'm trying out a 'new rule' for myself (cf. the Real Time with Bill Maher show on HBO). I frequently wake with some new ideas that I want to develop and write about, then let that good intention to do productive generative work be blown away by glancing at and being hooked by emails and text messages that are continually running in background on the MacBook Air that I use for all my writing. The morning becomes submerged in attending to an never ending list of piddly details. I start feeling increasingly helpless and defined by reactivity to unpredictable input streams - like the experimental dogs in Seligman's classic "Learned Helplessness" experiments. My new rule - which I already violated this morning, but only once - is to carry the good ideas I wake up directly into further thinking and writing about them, completely ignoring the emails and text messages that have accumulated over the night. Going offline makes me feel powerful rather than helpless. Only after a significant period of being generative rather than reactive do I go back to glance at the input stream online. What I find is a pleasant simplification: many of the items I would have reacted to now get deleted without reading!

These sentiments are echoed by Goldfarb's recent NYTimes piece on how making yourself inaccessible from time to time is essential to boosting one's focus and effectiveness. I want to pass on clips of that essay, which contains links to the work referenced.

A 2017 survey from the American Psychological Association found that being constantly and permanently reachable on an electronic device — checking work emails on your day off; continuously cycling through social media feeds; responding to text messages at all hours — is associated with higher stress levels.

This phenomenon of always being reachable is what Linda Stone, a former Apple and Microsoft executive, calls continuous partial attention. Unlike multitasking — juggling activities of similar importance that don’t require too much cognitive processing — C.P.A. is a state of alertness during which you’re motivated by the desire not to miss out on anything.

Ms. Stone, who gives lectures and consults on issues relating to technology and attention, describes C.P.A. as an “always-on, anywhere, anytime, any place behavior that involves an artificial sense of constant crisis.” Being distractible — allowing incessant beeps, flashes and trills to shatter any semblance of concentration — contributes to a strained lifestyle, she said. Half-paying attention to everything means you’re not able to fully pay attention to anything.

This kind of task switching comes with a cost. It’s called attention residue, a term established by Sophie Leroy, a professor at the Bothell School of Business at the University of Washington. In a 2009 study, Dr. Leroy found that if people transition their attention away from an unfinished task, their subsequent task performance will suffer. For example, if you interrupt writing an email to reply to a text message, it will take time to refocus when you turn your attention back to finishing your email. That little bit of time of adjusting your focus — the residue — compounds throughout the day. As we fragment our attention, fatigue and stress increases, which negatively affects performance.

The life prospects of female co-twins are diminished by prenatal testosterone from their male twins.

From Bütikofe et al.:

During sensitive periods in utero, gonadal steroids help organize biological sex differences in humans and other mammals. In litter-bearing species, chromosomal females passively exposed to prenatal testosterone from male littermates exhibit altered physical and behavioral traits as adults. The consequences of such effects are less well understood in humans, but recent near-doubling of twinning rates in many countries since 1980, secondary to advanced maternal age and increased reliance on in vitro fertilization, means that an increasing subset of females in many populations may be exposed to prenatal testosterone from their male co-twin. Here we use data on all births in Norway (n = 728,842, including 13,800 twins) between 1967 and 1978 to show that females exposed in utero to a male co-twin have a decreased probability of graduating from high school (15.2%), completing college (3.9%), and being married (11.7%), and have lower fertility (5.8%) and life-cycle earnings (8.6%). These relationships remain unchanged among the subsets of 583 and 239 females whose male co-twin died during the first postnatal year and first 28 days of life, respectively, supporting the interpretation that they are due primarily to prenatal exposure rather than to postnatal socialization effects of being raised with a male sibling. Our findings provide empirical evidence, using objectively measured nation-level data, that human females exposed prenatally to a male co-twin experience long-term changes in marriage, fertility, and human capital. These findings support the hypothesis of in utero testosterone transfer between twins, which is likely affecting a small but growing subset of females worldwide.

One mechanism of a basic life choice - to ‘go for it’ or to ‘scram’

Miller et al. use a variety of methods to find subpopulations of dopamine sensitive neurons in the amygdala of mice, projecting to different brain areas, that become active either either during explorative approach or threat-avoiding behaviors:

Avoidance of innate threats is often in conflict with motivations to engage in exploratory approach behavior. The neural pathways that mediate this approach–avoidance conflict are not well resolved. Here we isolated a population of dopamine D1 receptor (D1R)-expressing neurons within the posteroventral region of the medial amygdala (MeApv) in mice that are activated either during approach or during avoidance of an innate threat stimulus. Distinct subpopulations of MeApv-D1R neurons differentially innervate the ventromedial hypothalamus and bed nucleus of the stria terminalis, and these projections have opposing effects on investigation or avoidance of threatening stimuli. These projections are potently modulated through opposite actions of D1R signaling that bias approach behavior. These data demonstrate divergent pathways in the MeApv that can be differentially weighted toward exploration or evasion of threats.

Students of color are healthier in schools that emphasize the value of diversity

From Levine et al.:

Significance

The United States is increasingly diverse, especially among youth. At the same time, racial and ethnic gaps persist in many domains, including risk for cardiovascular disease. Here, we use a diverse sample of adolescents in a mostly urban setting to show that when schools emphasize the value of diversity, students of color are healthier. Thus, schools’ climates around diversity may have a role to play in reducing health disparities.

Abstract

As the United States becomes more diverse, the ways in which mainstream institutions recognize and address race and ethnicity will be increasingly important. Here, we show that one novel and salient characteristic of an institutional environment, that is, whether a school emphasizes the value of racial and ethnic diversity, predicts better cardiometabolic health among adolescents of color. Using a diverse sample of adolescents who attend more than 100 different schools in predominantly urban locations, we find that when schools emphasize the value of diversity (operationalized as mentioning diversity in their mission statements), students of color, but not white students, have lower values on a composite of five biomarkers of inflammation, have less insulin resistance and compensatory β-cell activity, and have fewer metabolic syndrome signs and score lower on a continuous metabolic syndrome composite. These results suggest that institutions that emphasize diversity may play an unacknowledged role in protecting the health of people of color and, thus, may be a site for future interventions to reduce health disparities.

American geography of opportunity reveals European origins

Interesting analysis from Berger and Engzell. They use microlevel Census data on self-reported ancestry to characterize the European origins of US places. They then examine whether variation in income inequality and intergenerational mobility across these places mirror differences between European countries. While parts of the Southeast contain places that are among the least mobile in the developed world, some areas in the Midwest show mobility rates similar to the Scandinavian countries. Evidence of stark regional divides that are seemingly stable over time suggests that some of this variation may be historical in origin. Their work confirms the inverse relationship between inequality and intergenerational mobility.

Significance

The United States is an immigrant nation and consists of places that differ widely in social, cultural, and economic makeup. Recent research finds striking regional variation in economic opportunity—the prospects of poor children to escape poverty as adults. Here, we show that the dominant European ancestry of a place does much to explain such differences: Levels of income equality and mobility across US communities with different European heritage mirror those across corresponding European countries. This finding sheds light on the historical roots of the American geography of opportunity.

Abstract

A large literature documents how intergenerational mobility—the degree to which (dis)advantage is passed on from parents to children—varies across and within countries. Less is known about the origin or persistence of such differences. We show that US areas populated by descendants to European immigrants have similar levels of income equality and mobility as the countries their forebears came from: highest in areas dominated by descendants to Scandinavian and German immigrants, lower in places with French or Italian heritage, and lower still in areas with British roots. Similar variation in mobility is found for the black population and when analyzing causal place effects, suggesting that mobility differences arise at the community level and extend beyond descendants of European immigrant groups. Our findings indicate that the geography of US opportunity may have deeper historical roots than previously recognized.

Infants and toddlers expect different third party punishment behaviors from ingroup and outgroup members.

Yet another example of how our brains are wired to distinguish ingroup and outgroup at a very early age...Ting et al. find sophisticated social analysis performed by 1- and 2.5-year-olds, who show different expectations of the behavior of a third party who has viewed an ingroup-outgroup versus an ingroup-ingroup transgression:

Significance

Adults are more likely to punish transgressions that do not affect them when these transgressions victimize ingroup members. Such third-party punishment (TPP) often takes an indirect form, such as the withholding of help. Building on these results, we showed 2.5- and 1-year-olds scenarios involving a wrongdoer, a victim, and a bystander, and we manipulated the minimal-group memberships of the wrongdoer and the victim relative to that of the bystander. When the victim belonged to the bystander’s group, children expected TPP: They detected a violation when the bystander chose to help the wrongdoer. When the victim did not belong to the bystander’s group, however, children no longer expected TPP. Young children thus selectively expect indirect TPP for harm to ingroup members.

Abstract

Adults and older children are more likely to punish a wrongdoer for a moral transgression when the victim belongs to their group. Building on these results, in violation-of-expectation experiments (n = 198), we examined whether 2.5-year-old toddlers (Exps. 1 and 2) and 1-year-old infants (Exps. 3 and 4) would selectively expect an individual in a minimal group to engage in third-party punishment (TPP) for harm to an ingroup victim. We focused on an indirect form of TPP, the withholding of help. To start, children saw a wrongdoer steal a toy from a victim while a bystander watched. Next, the wrongdoer needed assistance with a task, and the bystander either helped or hindered her. The group memberships of the wrongdoer and the victim were varied relative to that of the bystander and were marked with either novel labels (Exps. 1 and 2) or novel outfits (Exps. 3 and 4). When the victim belonged to the same group as the bystander, children expected TPP: At both ages, they detected a violation when the bystander chose to help the wrongdoer. Across experiments, this effect held whether the wrongdoer belonged to the same group as the bystander and the victim or to a different group; it was eliminated when the victim belonged to a different group than the bystander, when groups were not marked, and when either no theft occurred or the wrongdoer was unaware of the theft. Toddlers and infants thus expect individuals to refrain from helping an ingroup victim’s aggressor, providing further evidence for an early-emerging expectation of ingroup support.

Yet another longevity predictor?

The NYTimes and WaPo must have a substantial number of readers in my 75-80 year old demographic, an age interval during which physical capabilities are rapidly diminishing. Strout offers yet another article pointing to research on physical tests that measure life expectancy:

The test requires you to lower yourself to the floor, crisscross style, without bracing yourself with your hands, knees, arms, or sides of your legs. If you can stand back up, again without the aid of those body parts, you’ve scored a perfect 10 (five points for sitting, five points for standing). You lose a point every time you support yourself with a forbidden joint or appendage...The researchers tested 2,002 adults 51 to 80 years old, and then followed them until a participant died or until the study concluded, which was a median of 6.3 years. In that time, 159 people died — only two of whom had scored a perfect 10. Those who had the lowest score of zero to three points had a risk of death that was five to six times higher than those who scored eight to 10 points.

...more variables apply to our health (and our longevity) than those this particular test focuses on. It’s important to remember that the study results are most relevant to those the same age as the subjects in the testing group, who were ages 51 and up — a point often lost in discussion. Most of the people who scored the lowest on the test were in the 76-to-80 age range, a group that generally experiences decreased mobility and coordination. The research also didn’t reveal the causes of the 159 deaths during the follow-up period. Should we assume they all died of complications from falling, instead of cardiovascular disease or cancer? We don’t know.

The article points to other work showing correlations between physical performance and health. Men who can complete 40 push-ups over a ten year period have a 96% lower risk of cardiovascular disease. People over 65 who walk one meter per second or faster live longer than those who can't.

Using artificial intelligence for medical billing scams.

As a 76 year old Medicare beneficiary, I am frequently annoyed by the blatant ploys that medical care providers use to game the 'fee for services' system: notably scheduling unnecessary appointments and procedures. Metz and Smith describe how this behavior could be enhanced by a dark side of the use of A.I. in health care, as A.I. image analysis technology spreads across medicine, and systems are developed that can detect diabetic retinopathy, as well as lung and brain diseases.

Similar forms of artificial intelligence are likely to move beyond hospitals into the computer systems used by health care regulators, billing companies and insurance providers. Just as A.I. will help doctors check your eyes, lungs and other organs, it will help insurance providers determine reimbursement payments and policy fees.

Ideally, such systems would improve the efficiency of the health care system. But they may carry unintended consequences, a group of researchers at Harvard and M.I.T. warns. In a paper published on Thursday in the journal Science, the researchers raise the prospect of “adversarial attacks” — manipulations that can change the behavior of A.I. systems using tiny pieces of digital data. By changing a few pixels on a lung scan, for instance, someone could fool an A.I. system into seeing an illness that is not really there, or not seeing one that is.

...doctors, hospitals and other organizations could manipulate the A.I. in billing or insurance software in an effort to maximize the money coming their way...If an insurance company uses A.I. to evaluate medical scans, for instance, a hospital could manipulate scans in an effort to boost payouts. If regulators build A.I. systems to evaluate new technology, device makers could alter images and other data in an effort to trick the system into granting regulatory approval.

In their paper, the researchers demonstrated that, by changing a small number of pixels in an image of a benign skin lesion, a diagnostic A.I system could be tricked into identifying the lesion as malignant. Simply rotating the image could also have the same effect, they found.

Small changes to written descriptions of a patient’s condition also could alter an A.I. diagnosis: “Alcohol abuse” could produce a different diagnosis than “alcohol dependence,” and “lumbago” could produce a different diagnosis than “back pain."

In turn, changing such diagnoses one way or another could readily benefit the insurers and health care agencies that ultimately profit from them. Once A.I. is deeply rooted in the health care system, the researchers argue, business will gradually adopt behavior that brings in the most money.

Inflam-aging

Leucht and collaborators show that injured bones do not heal as well with age because of the increases in chronic inflammation that occur with aging.

Significance

As we age, our capacity for tissue repair and regeneration in response to injury declines. Accordingly, bone repair is delayed and impaired in older patients. At the cornerstone of bone healing is the skeletal stem/progenitor cell (SSPC), whose function and number diminishes with age. However, the mechanisms driving this decline remain unclear. Here, we identify age-associated inflammation (“inflamm-aging”) as the main culprit of SSPC dysfunction and provide support for a central role of NF-κB as a mediator of inflamm-aging. Our results show that modification of the inflammatory environment may be a translational approach to functionally rejuvenate the aged SSPC, thereby improving the regenerative capacity of the aged skeleton.

Abstract

Aging is associated with impaired tissue regeneration. Stem cell number and function have been identified as potential culprits. We first demonstrate a direct correlation between stem cell number and time to bone fracture union in a human patient cohort. We then devised an animal model recapitulating this age-associated decline in bone healing and identified increased cellular senescence caused by a systemic and local proinflammatory environment as the major contributor to the decline in skeletal stem/progenitor cell (SSPC) number and function. Decoupling age-associated systemic inflammation from chronological aging by using transgenic Nfkb1KO mice, we determined that the elevated inflammatory environment, and not chronological age, was responsible for the decrease in SSPC number and function. By using a pharmacological approach inhibiting NF-κB activation, we demonstrate a functional rejuvenation of aged SSPCs with decreased senescence, increased SSPC number, and increased osteogenic function. Unbiased, whole-genome RNA sequencing confirmed the reversal of the aging phenotype. Finally, in an ectopic model of bone healing, we demonstrate a functional restoration of regenerative potential in aged SSPCs. These data identify aging-associated inflammation as the cause of SSPC dysfunction and provide mechanistic insights into its reversal.

Affect theory and the new age of anxiety.

Hua Hsu, in the March 25, 2019, issue of The New Yorker, does a fascinating presentation of the work and ideas of Lauren Berlant, whose writing is an example of new field of literary criticism, termed "affect theory", that focuses on nonlinguistic feelings and emotions. Here are a few clips from the article:

In October, 2011, the literary scholar and cultural theorist Lauren Berlant published “Cruel Optimism,” a meditation on our attachment to dreams that we know are destined to be dashed...We like to imagine that our life follows some kind of trajectory, like the plot of a novel, and that by recognizing its arc we might, in turn, become its author. But often what we feel instead is a sense of precariousness—a gut-level suspicion that hard work, thrift, and following the rules won’t give us control over the story, much less guarantee a happy ending. For all that, we keep on hoping, and that persuades us to keep on living...The persistence of the American Dream, Berlant suggests, amounts to a cruel optimism, a condition “when something you desire is actually an obstacle to your own flourishing.”

...our Sisyphean pursuit of the good life has high stakes, and its amalgam of fantasy and futility is something that we process as experience before we rationalize it in thought. These feelings, Berlant says, are the “body’s response to the world, something you’re always catching up to.”...We dream of swimming toward a beautiful horizon, but in truth, Berlant evocatively observed, we are constantly “dogpaddling around a space whose contours remain obscure.” What stories do we tell ourselves in order to stay afloat?

“The Hundreds” (Duke), Berlant’s latest book, co-written with Kathleen Stewart, an anthropologist at the University of Texas at Austin, grows out of ... short writing exercises. Each entry is an experiment in “following out the impact of things” in a hundred words, or a multiple of a hundred words...The result is a strange and captivating book.

In Berlant and Stewart’s hands, affect theory provides a way of understanding the sensations and resignations of the present, the normalized exhaustion that comes with life in the new economy. It is a way of framing uniquely modern questions: Where did the seeming surplus of emotionality that we see on the Internet come from, and what might it become? What new political feelings were being produced by the rudderless drift of life in the gig economy? What if millennials were unintelligible to their parents simply because they have resigned themselves to precariousness as life’s defining feature?

Berlant’s work can feel strangely and kindly optimistic...Maybe relinquishing or recalibrating our fantasies of the good life doesn’t lead to absolute darkness. It can simply be a matter of coming to grips with different possibilities of communion, figuring out who benefits from our collective weariness...But attentiveness to affect encourages us to imagine ourselves beyond the present: even if feelings of exhaustion, indifference, or disillusionment may have been naturalized, that doesn’t mean they’re natural...

“No one wants to be a bad or compromised kind of force in the world, but the latter is just inevitable,” Berlant once wrote in a short essay on her personal credos. “The question is how to develop ways to accentuate those contradictions, to interrupt their banality and to move them somewhere.” We can build worlds out of these small ambitions. We continue to write, even if it occasionally feels as though we were spinning our wheels, and we continue to live, even if it means giving up the certainty that our story is going to end the way we want it to. Writing on her blog a few years ago, Berlant issued what she described as her collective’s secret motto: “We refuse to be worn out.”

More green space in childhood, fewer psychiatric disorders in adulthood.

From Engemann et al.:

Urban residence is associated with a higher risk of some psychiatric disorders, but the underlying drivers remain unknown. There is increasing evidence that the level of exposure to natural environments impacts mental health, but few large-scale epidemiological studies have assessed the general existence and importance of such associations. Here, we investigate the prospective association between green space and mental health in the Danish population. Green space presence was assessed at the individual level using high-resolution satellite data to calculate the normalized difference vegetation index within a 210 × 210 m square around each person’s place of residence (∼1 million people) from birth to the age of 10. We show that high levels of green space presence during childhood are associated with lower risk of a wide spectrum of psychiatric disorders later in life. Risk for subsequent mental illness for those who lived with the lowest level of green space during childhood was up to 55% higher across various disorders compared with those who lived with the highest level of green space. The association remained even after adjusting for urbanization, socioeconomic factors, parental history of mental illness, and parental age. Stronger association of cumulative green space presence during childhood compared with single-year green space presence suggests that presence throughout childhood is important. Our results show that green space during childhood is associated with better mental health, supporting efforts to better integrate natural environments into urban planning and childhood life.

Neural signal diversity is increased by psychedelics

From Carhart-Harris and collaborators:

What is the level of consciousness of the psychedelic state? Empirically, measures of neural signal diversity such as entropy and Lempel-Ziv (LZ) complexity score higher for wakeful rest than for states with lower conscious level like propofol-induced anesthesia. Here we compute these measures for spontaneous magnetoencephalographic (MEG) signals from humans during altered states of consciousness induced by three psychedelic substances: psilocybin, ketamine and LSD. For all three, we find reliably higher spontaneous signal diversity, even when controlling for spectral changes. This increase is most pronounced for the single-channel LZ complexity measure, and hence for temporal, as opposed to spatial, signal diversity. We also uncover selective correlations between changes in signal diversity and phenomenological reports of the intensity of psychedelic experience. This is the first time that these measures have been applied to the psychedelic state and, crucially, that they have yielded values exceeding those of normal waking consciousness. These findings suggest that the sustained occurrence of psychedelic phenomenology constitutes an elevated level of consciousness - as measured by neural signal diversity.