Friday, July 19, 2019

It’s never simple...The tidy textbook story about the primary visual cortex is wrong.

When I was a postdoc in the Harvard Neurobiology department in the mid-1960’s I used to have afternoon tea with the Hubel and Weisel group. These are the guys who got a Nobel prize for, among other things, finding that the primary visual cortex is organized into cortical columns of cells that responded to lines that prefer different orientations. Another grouping of columns, called ‘blobs’ responded selectively to color and brightness but not orientation. These two different kinds of groups sent their outputs to higher visual areas that were supposed to integrate the information. My neurobiology course lectures and my Biology of Mind book showed drawings illustrating these tidy distinctions.

Sigh… now Garg et al. come along with two-photon calcium imaging to probe a very large spatial and chromatic visual stimulus space and map functional microarchitecture of thousands of neurons with single-cell resolution. They show that processing of orientation and color is combined at the earliest stages of visual processing, totally challenging the existing model. Their abstract:
Previous studies support the textbook model that shape and color are extracted by distinct neurons in primate primary visual cortex (V1). However, rigorous testing of this model requires sampling a larger stimulus space than previously possible. We used stable GCaMP6f expression and two-photon calcium imaging to probe a very large spatial and chromatic visual stimulus space and map functional microarchitecture of thousands of neurons with single-cell resolution. Notable proportions of V1 neurons strongly preferred equiluminant color over achromatic stimuli and were also orientation selective, indicating that orientation and color in V1 are mutually processed by overlapping circuits. Single neurons could precisely and unambiguously code for both color and orientation. Further analyses revealed systematic spatial relationships between color tuning, orientation selectivity, and cytochrome oxidase histology.

Wednesday, July 17, 2019

An anti-aging pill with some credibility....

An AARP article points to studies on the new drug RTB101, which boosts immune function in older people and lowers risk for respiratory diseases. By virtue of it's inhibition of the multiprotein complex TORC1, which mediates temporal control of cell growth, it is also a potential anti-aging drug. Below is text from the anti-aging website lifespan.io:
resTORbio, Inc. is developing RTB101, an oral medication that inhibits target of rapamycin complex 1 (TORC1). Using a combination of RTB101 and everolimus, another TORC1 inhibitor, the company is testing a comprehensive immunotherapy program to fight respiratory tract infections in the elderly, improving the immune system rather than attempting to target individual infectious agents.
The mammalian target of rapamycin (mTOR) pathway uses the multiprotein complexes TORC1 and TORC2 to conduct signaling. While inhibiting TORC2 has been observed to decrease lifespan, TORC1 inhibition has been shown to have multiple positive effects, including enhanced brain functions, reduction of adipose tissue, and delaying the onset of age-related pathology. Inhibiting TORC1 with both RTB101 and everolimus decreases S6K while increasing 4EBP1 and Atg; affecting each of these downstream products in this way is reported to enhance lifespan.
In 2018, the company reported that a phase 2b trial of RTB101 has returned positive results for boosting the immune system to respond better to respiratory infections. The trial saw 652 aged people with increased risk of RTIs enroll and compared to the control group, there were significantly fewer patients treated with RTB101 who suffered from one or more RTIs during a 16-week trial period. The next step for resTORbio is to conduct a study of its effects on other infections, heart failure, or autophagy-related diseases later in 2018.
Concluding the successful Phase 2 and 2b studies the company has agreed with the FDA to proceed to a large scale phase 3 clinical trial scheduled to begin later in 2019...resTORbio has licensed the worldwide rights for its product from Novartis Limited, a major pharmaceutical company...Website: resTORbio

Monday, July 15, 2019

Correlating our our physical and mental experiences of stress linked to psychological and physical well-being

Davidson and colleagues at the Univ. of Wisconsin show that individual differences in the ability to associate subjective stress and heart rate are related to psychological and physical well being. Here is a description of the work from a newsletter, followed by the abstract from Psychological Sciences. They:
...analyzed data from 1,065 participants in the Midlife in the United States (MIDUS) study, a longitudinal effort looking at well-being as adults age. Participants completed a series of stressful computer tasks, including a mental math task and a color identification task.
Before, during and after the tasks, researchers measured participants’ heart rate and asked them to rate their stress on a scale of one to 10 throughout the study.
After the participants completed the stress tests, researchers compared each person’s heart rate to the stress levels they reported — a measure called “stress-heart rate coherence”— and found that some people’s stress levels aligned with their heart rate better than others.
To examine the link between stress-heart rate coherence and people’s emotional well-being, researchers used psychological questionnaires focused on well-being, depression, anxiety and coping as well as blood samples measuring inflammation markers. Researchers found that people with greater stress-heart rate coherence had fewer symptoms of anxiety and depression, greater overall psychological well-being and lower levels of inflammation.
Here is the journal article's abstract:
The physiological response to stress is intertwined with, but distinct from, the subjective feeling of stress, although both systems must work in concert to enable adaptive responses. We investigated 1,065 participants from the Midlife in the United States 2 study who completed a self-report battery and a stress-induction procedure while physiological and self-report measures of stress were recorded. Individual differences in the association between heart rate and self-reported stress were analyzed in relation to measures that reflect psychological well-being (self-report measures of well-being, anxiety, depression), denial coping, and physical well-being (proinflammatory biomarkers interleukin-6 and C-reactive protein). The within-participants association between heart rate and self-reported stress was significantly related to higher psychological well-being, fewer depressive symptoms, lower trait anxiety, less use of denial coping, and lower levels of proinflammatory biomarkers. Our results highlight the importance of studying individual differences in coherence between physiological measures and subjective mental states in relation to well-being.
And here is a PDF of the article.

Friday, July 12, 2019

The Problem With ‘Sharenting’

An article in the NYTimes 'Privacy Project' by Kamenetz resonates with my own experience of very mixed reactions to viewing some of what I consider the most private and intimate details of the lives of my 5 and 7 year old grandsons occasionally revealed in some of the Facebook posts by their parents. I feel embarrassed for the boys, and sometimes how they would feel in their 20s and 30s if they were to look back at these posts on their childhood. (A pre-facebook version of the situation from my childhood is a photograph of two legs - five year old Deric - protruding from under a newspaper sitting on the toilet...how cute!). Some clips from the Kamenetz piece:
Today, many children’s social media presence starts with a sonogram, posted, obviously, without consent. One study from Britain found that nearly 1,500 images of the average child had been placed online by their fifth birthday. Parents get a lot of gratification from telling kids’ stories online...It’s less clear what our children have to gain from their lives being broadcast in this way. ..parents’ rights to free speech and self-expression are at odds with children’s rights to privacy when they are young and vulnerable...This is especially true when the information is potentially damaging. Imagine a child who has behavior problems, learning disabilities or chronic illness. Mom or Dad understandably want to discuss these struggles and reach out for support. But those posts live on the internet, with potential to be discovered by college admissions officers and future employers, friends and romantic prospects. A child’s life story is written for him before he has a chance to tell it himself.
Even if you confine your posts about your children to sunny days and birthday parties, any information you provide about them — names, dates of birth, geographic location — could be acquired by data brokersClose X, companies that collect personal information and sell it to advertisers.
Finally, there’s display and commodification. In 2018, the top earner on YouTube, according to Forbes, was a 7-year-old boy who brought in $22 million by playing with toys. It’s never seemed more accessible to become famous at a wee age, and the type of children who used to sing into a hairbrush in the mirror are often clamoring to start their own channels today.
The most egregious abuses are just the tip of the iceberg, though. For every moneymaking influencer, there are millions of less-successful stage parents and wannabes scratching for followers on YouTube and Instagram. They’re out there shoving cameras in children’s faces, using up their free time, killing spontaneity, warping the everyday rituals of childhood into long working shoots.
When it comes to childhood and technology, we adults are the horror show.

Wednesday, July 10, 2019

Looking for a dose of optimism?

I want to point to a recent NYTimes Op-Ed piece by David Brooks that is a bit more upbeat than his frequent hand wringing over the dissolution of old verities. A few clips from its later paragraphs:
The reality and challenge is that America has become radically pluralistic. We used to be unipolar — one dominant majority culture and a lot of minority groups that defined themselves against it. Now we’re multipolar. We’re all minorities now.
That could blow us to smithereens. But who knows? We could learn to be minorities together, to be what Rabbi Jonathan Sacks calls creative minorities. In a brilliant 2013 lecture, Sacks noted that when Solomon’s temple was destroyed and the Jews were cast into exile, the prophet Jeremiah had a surprising message: Go to new lands. Build houses. Plant gardens. Seek the peace and prosperity of the cities in which you settle.
In a world of radical pluralism, we are all Jews. We have no choice but to build a mass multicultural democracy, a society that has no dominant center but is a collection of creative minorities...Nearly 200 years ago, Tocqueville wrote that democracy was creating a new sort of man. Pluralism today is creating a new sort of person, especially among the young. They don’t just relish diversity; they embody it. Many have mixed roots — say, half-French/half-Dominican. Many are border stalkers; they live between cultures, switch back and forth, and work hard to build a multiplicity of influences into a single coherent life. They’re Whitmanesque, containing multitudes, holding opposite ideas in their minds at the same time.
Radical pluralism also necessitates retelling the nation’s history. We’ve always been a universal nation, a crossroads nation, a nation whose very identity is defined by the fact that it is a hub for a dense network of minorities and subgroups, and the distinct way of life they fashion to interact and flourish together.
I used to think that America had to find a new unifying national narrative. Now I wonder if not having a single national narrative will become our national narrative.

Monday, July 08, 2019

Subgroups of gay men correspond to different biodevelopmental pathways

Swift-Gallant et al. consider three established biomarkers of sexual orientation and suggest they reflect distinct biodevelopmental pathways influencing same-sex sexual orientation in men. They describe these biomarkers in their introduction:
A well-established biomarker of sexual orientation is familiality of male same-sex sexual orientation. Same-sex sexual orientation clusters in families, twin studies show greater sexual orientation concordance among monozygotic than dizygotic twins, and molecular genetic studies have identified candidate genes associated with sexual orientation.
A second well-studied biomarker of sexual orientation is handedness. Although the biological underpinnings of handedness are not yet clear, increasing evidence suggests that handedness is a marker of cerebral lateralization determined prenatally by genetic, immunological, and endocrine mechanisms and/or by developmental instability... it is estimated that men have 20% greater odds of non−right-handedness than women, and gay men have 34% greater odds of being non−right-handed than heterosexual men.
A third well-established biomarker of sexual orientation is the fraternal birth order effect). Across a diverse range of cultures and sample types, studies have shown that older brothers increase the odds of androphilia in later-born males. The maternal immune hypothesis is the best-developed explanation of the fraternal birth order effect. It argues that male antigens enter maternal circulation during the gestation and birthing of male offspring, promoting an immune response to these male-specific antigens that increases with each successive male fetus gestated; thus, with each successive pregnancy with a male fetus, the odds increase that these maternal antibodies will affect sexual differentiation of the brain and behavior, including sexual preferences.
Their Significance and Abstract statements:  

Significance
Studying individual differences in gender and sexual orientation provides insight into how early-life biology shapes brain and behavior. The literature identifies multiple biodevelopmental influences on male sexual orientation, but these influences are generally studied individually, and the potential for association or interaction between them remains largely unexplored. We hypothesized that distinct biodevelopmental pathways correspond to specific subgroups of nonheterosexual men. We present evidence that nonheterosexual men can be categorized into at least four subgroups based on established biomarkers, and these biodevelopmental pathways differentially relate to gender expression and personality traits. These findings indicate individual differences in biodevelopmental pathways of male sexual orientation. They also illustrate the value of latent profile analyses for studying individual differences.
Abstract
Several biological mechanisms have been proposed to influence male sexual orientation, but the extent to which these mechanisms cooccur is unclear. Putative markers of biological processes are often used to evaluate the biological basis of male sexual orientation, including fraternal birth order, handedness, and familiality of same-sex sexual orientation; these biomarkers are proxies for immunological, endocrine, and genetic mechanisms. Here, we used latent profile analysis (LPA) to assess whether these biomarkers cluster within the same individuals or are present in different subgroups of nonheterosexual men. LPA defined four profiles of men based on these biomarkers: 1) A subgroup who did not have these biomarkers, 2) fraternal birth order, 3) handedness, and 4) familiality. While the majority of both heterosexual and nonheterosexual men were grouped in the profile that did not have any biomarker, the three profiles associated with a biomarker were composed primarily of nonheterosexual men. We then evaluated whether these subgroups differed on measures of gender nonconformity and personality that reliably show male sexual orientation differences. The subgroup without biomarkers was the most gender-conforming whereas the fraternal birth order subgroup was the most female-typical and agreeable, compared with the other profiles. Together, these findings suggest there are multiple distinct biodevelopmental pathways influencing same-sex sexual orientation in men.

Friday, July 05, 2019

Social Media - no effect on adolescent life satisfaction?

Orben et al. (open source article) provide a study whose results contest a common opinion, reinforced by several previous studies, that adolescents who use social media extensively are more likely to be depressed and have low self esteem. They used...
...large-scale representative panel data to disentangle the between-person and within-person relations linking adolescent social media use and well-being. We found that social media use is not, in and of itself, a strong predictor of life satisfaction across the adolescent population. Instead, social media effects are nuanced, small at best, reciprocal over time, gender specific, and contingent on analytic methods.
They note limitations of current published research:
Focused on cross-sectional relations, scientists have few means of parsing longitudinal effects from artifacts introduced by common statistical modeling methodologies. Furthermore, the volume of data under analysis, paired with unchecked analytical flexibility, enables selective research reporting, biasing the literature toward statistically significant effects. Nevertheless, trivial trends are routinely overinterpreted by those under increasing pressure to rapidly craft evidence-based policies.
The UK study examined data on 12,672 10-15 year old. Two summary graphics are provided. One clip:
...the importance of gender was apparent: Only 16% of significant models arose from male data.
The last two paragraphs:
The relations linking social media use and life satisfaction are, therefore, more nuanced than previously assumed: They are inconsistent, possibly contingent on gender, and vary substantively depending on how the data are analyzed. Most effects are tiny—arguably trivial; where best statistical practices are followed, they are not statistically significant in more than half of models. That understood, some effects are worthy of further exploration and replication: There might be small reciprocal within-person effects in females, with increases in life satisfaction predicting slightly lower social media use, and increases in social media use predicting tenuous decreases in life satisfaction.
With the unknowns of social media effects still substantially outnumbering the knowns, it is critical that independent scientists, policymakers, and industry researchers cooperate more closely. Scientists must embrace circumspection, transparency, and robust ways of working that safeguard against bias and analytical flexibility. Doing so will provide parents and policymakers with the reliable insights they need on a topic most often characterized by unfounded media hype. Finally, and most importantly, social media companies must support independent research by sharing granular user engagement data and participating in large-scale team-based open science. Only then will we truly unravel the complex constellations of effects shaping young people in the digital age.

Wednesday, July 03, 2019

Think twice about metformin as an anti-aging drug.

Gretchen Reynolds points to work suggesting that use of metformin (the most commonly used Type 2 diabetes drug) as an anti-aging agent by healthy active people (because it reduces inflammation and causes other cellular effects that alter aging) may have a downside. Konopka et al. report that it suppresses the anti-aging effects of exercise, notably exercise-related gains in muscle-cell mitochondrial respiration. There is the usual caveat that this is a single study with a relatively small number of subjects (53). Here is their technical abstract:
Metformin and exercise independently improve insulin sensitivity and decrease the risk of diabetes. Metformin was also recently proposed as a potential therapy to slow aging. However, recent evidence indicates that adding metformin to exercise antagonizes the exercise‐induced improvement in insulin sensitivity and cardiorespiratory fitness. The purpose of this study was to test the hypothesis that metformin diminishes the improvement in insulin sensitivity and cardiorespiratory fitness after aerobic exercise training (AET) by inhibiting skeletal muscle mitochondrial respiration and protein synthesis in older adults (62 ± 1 years). In a double‐blinded fashion, participants were randomized to placebo (n = 26) or metformin (n = 27) treatment during 12 weeks of AET. Independent of treatment, AET decreased fat mass, HbA1c, fasting plasma insulin, 24‐hr ambulant mean glucose, and glycemic variability. However, metformin attenuated the increase in whole‐body insulin sensitivity and VO2max after AET. In the metformin group, there was no overall change in whole‐body insulin sensitivity after AET due to positive and negative responders. Metformin also abrogated the exercise‐mediated increase in skeletal muscle mitochondrial respiration. The change in whole‐body insulin sensitivity was correlated to the change in mitochondrial respiration. Mitochondrial protein synthesis rates assessed during AET were not different between treatments. The influence of metformin on AET‐induced improvements in physiological function was highly variable and associated with the effect of metformin on the mitochondria. These data suggest that prior to prescribing metformin to slow aging, additional studies are needed to understand the mechanisms that elicit positive and negative responses to metformin with and without exercise.

Monday, July 01, 2019

Your professional decline.

Arthur Brooks, former president of the conservative American Enterprise Institute think tank and New York Times Op-Ed writer, does an essay in the Atlantic in which he contemplates his professional decline, making points that are universally relevant. Some clips:
...happiness of most adults declines through their 30s and 40s, then bottoms out in their early 50s...Almost all studies of happiness over the life span show that, in wealthier countries, most people’s contentment starts to increase again in their 50s, until age 70 or so. That is where things get less predictable, however. After 70, some people stay steady in happiness; others get happier until death. Others—men in particular—see their happiness plummet. Indeed, depression and suicide rates for men increase after age 75...A few researchers have looked at this cohort to understand what drives their unhappiness. It is, in a word, irrelevance.
This is especially an issue in gifted and accomplished people.
...accomplishment is a well-documented source of happiness. If current accomplishment brings happiness, then shouldn’t the memory of that accomplishment provide some happiness as well?...Though the literature on this question is sparse, giftedness and achievements early in life do not appear to provide an insurance policy against suffering later on...abundant evidence suggests that the waning of ability in people of high accomplishment is especially brutal psychologically...Call it the Principle of Psychoprofessional Gravitation: the idea that the agony of professional oblivion is directly related to the height of professional prestige previously achieved, and to one’s emotional attachment to that prestige...the memory of remarkable ability, if that is the source of one’s self-worth, might, for some, provide an invidious contrast to a later, less remarkable life.
In some professions, early decline is inescapable. No one expects an Olympic athlete to remain competitive until age 60. But in many physically nondemanding occupations, we implicitly reject the inevitability of decline before very old age. Sure, our quads and hamstrings may weaken a little as we age. But as long as we retain our marbles, our quality of work as a writer, lawyer, executive, or entrepreneur should remain high up to the very end, right? ...The data are shockingly clear that for most people, in most fields, decline starts earlier than almost anyone thinks...if you start a career in earnest at 30, expect to do your best work around 50 and go into decline soon after that...the most common age for producing a magnum opus is the late 30s...the likelihood of a major discovery increases steadily through one’s 20s and 30s and then declines through one’s 40s, 50s, and 60s. Are there outliers? Of course. But the likelihood of producing a major innovation at age 70 is approximately what it was at age 20—almost nonexistent.
In sum, if your profession requires mental processing speed or significant analytic capabilities—the kind of profession most college graduates occupy—noticeable decline is probably going to set in earlier than you imagine...Whole sections of bookstores are dedicated to becoming successful. The shelves are packed with titles like The Science of Getting Rich and The 7 Habits of Highly Effective People. There is no section marked “Managing Your Professional Decline.”
Brooks contrasts the declines of Charles Darwin, who became embittered and inactive after his younger most creative period had passed, with Johann Sebastian Bach, who redesigned his life - as baroque music was being replaced by the "classical" style - moving from being an innovator to being a teacher and instructor.
The lesson for you and me, especially after 50: Be Johann Sebastian Bach, not Charles Darwin...How does one do that? A potential answer lies in the work of the British psychologist Raymond Cattell, who in the early 1940s introduced the concepts of fluid and crystallized intelligence. Cattell defined fluid intelligence as the ability to reason, analyze, and solve novel problems—what we commonly think of as raw intellectual horsepower. ...It is highest relatively early in adulthood and diminishes starting in one’s 30s and 40s...Crystallized intelligence, in contrast, is the ability to use knowledge gained in the past. Think of it as possessing a vast library and understanding how to use it. It is the essence of wisdom. Because crystallized intelligence relies on an accumulating stock of knowledge, it tends to increase through one’s 40s, and does not diminish until very late in life...poets—highly fluid in their creativity—tend to have produced half their lifetime creative output by age 40 or so. Historians—who rely on a crystallized stock of knowledge—don’t reach this milestone until about 60...No matter what mix of intelligence your field requires, you can always endeavor to weight your career away from innovation and toward the strengths that persist, or even increase, later in life...teaching is an ability that decays very late in life, a principal exception to the general pattern of professional decline over time...the most profound insights tend to come from those in their 30s and early 40s. The best synthesizers and explainers of complicated ideas—that is, the best teachers—tend to be in their mid-60s or older, some of them well into their 80s.
Most Eastern philosophy warns that focusing on acquisition leads to attachment and vanity, which derail the search for happiness by obscuring one’s essential nature. As we grow older, we shouldn’t acquire more, but rather strip things away to find our true selves—and thus, peace.
At some point, writing one more book will not add to my life satisfaction; it will merely stave off the end of my book-writing career. The canvas of my life will have another brushstroke that, if I am being forthright, others will barely notice, and will certainly not appreciate very much. The same will be true for most other markers of my success.
What I need to do, in effect, is stop seeing my life as a canvas to fill, and start seeing it more as a block of marble to chip away at and shape something out of. I need a reverse bucket list. My goal for each year of the rest of my life should be to throw out things, obligations, and relationships until I can clearly see my refined self in its best form.
Hindu philosophy—and indeed the wisdom of many philosophical traditions—suggests that you should be prepared to walk away from the rewards of success before you feel ready. Even if you’re at the height of your professional prestige, you probably need to scale back your career ambitions in order to scale up your metaphysical ones.
David Brooks talks about the difference between “résumé virtues” and “eulogy virtues,”...Résumé virtues are professional and oriented toward earthly success. They require comparison with others. Eulogy virtues are ethical and spiritual, and require no comparison. Your eulogy virtues are what you would want people to talk about at your funeral. As in He was kind and deeply spiritual, not He made senior vice president at an astonishingly young age and had a lot of frequent-flier miles....To move from résumé virtues to eulogy virtues is to move from activities focused on the self to activities focused on others.
..an abundance of research strongly suggests that happiness—not just in later years but across the life span—is tied directly to the health and plentifulness of one’s relationships. Pushing work out of its position of preeminence—sooner rather than later—to make space for deeper relationships can provide a bulwark against the angst of professional decline.
The aspen tree is an excellent metaphor for a successful person—but not, it turns out, for its solitary majesty. Above the ground, it may appear solitary. Yet each individual tree is part of an enormous root system, which is together one plant...The secret to bearing my decline—to enjoying it—is to become more conscious of the roots linking me to others. If I have properly developed the bonds of love among my family and friends, my own withering will be more than offset by blooming in others.