Isegoria

To pay attention, the brain uses filters, not a spotlight:

For a long time, because attention seemed so intricately tied up with consciousness and other complex functions, scientists assumed that it was first and foremost a cortical phenomenon. A major departure from that line of thinking came in 1984, when Francis Crick, known for his work on the structure of DNA, proposed that the attentional searchlight was controlled by a region deep in the brain called the thalamus, parts of which receive input from sensory domains and feed information to the cortex. He developed a theory in which the sensory thalamus acted not just as a relay station, but also as a gatekeeper — not just a bridge, but a sieve — staunching some of the flow of data to establish a certain level of focus.

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[Michael Halassa, a neuroscientist at the McGovern Institute for Brain Research at the Massachusetts Institute of Technology] was drawn to a thin layer of inhibitory neurons called the thalamic reticular nucleus (TRN), which wraps around the rest of the thalamus like a shell. By the time Halassa was a postdoctoral researcher, he had already found a coarse level of gating in that brain area: The TRN seemed to let sensory inputs through when an animal was awake and attentive to something in its environment, but it suppressed them when the animal was asleep.

In 2015, Halassa and his colleagues discovered another, finer level of gating that further implicated the TRN as part of Crick’s long-sought circuit — this time involving how animals select what to focus on when their attention is divided among different senses. In the study, the researchers used mice trained to run as directed by flashing lights and sweeping audio tones. They then simultaneously presented the animals with conflicting commands from the lights and tones, but also cued them about which signal to disregard. The mice’s responses showed how effectively they were focusing their attention. Throughout the task, the researchers used well-established techniques to shut off activity in various brain regions to see what interfered with the animals’ performance.

As expected, the prefrontal cortex, which issues high-level commands to other parts of the brain, was crucial. But the team also observed that if a trial required the mice to attend to vision, turning on neurons in the visual TRN interfered with their performance. And when those neurons were silenced, the mice had more difficulty paying attention to sound. In effect, the network was turning the knobs on inhibitory processes, not excitatory ones, with the TRN inhibiting information that the prefrontal cortex deemed distracting. If the mouse needed to prioritize auditory information, the prefrontal cortex told the visual TRN to increase its activity to suppress the visual thalamus — stripping away irrelevant visual data.

The attentional searchlight metaphor was backward: The brain wasn’t brightening the light on stimuli of interest; it was lowering the lights on everything else.

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With tasks similar to those they’d used in 2015, the team probed the functional effects of various brain regions on one another, as well as the neuronal connections between them. The full circuit, they found, goes from the prefrontal cortex to a much deeper structure called the basal ganglia (often associated with motor control and a host of other functions), then to the TRN and the thalamus, before finally going back up to higher cortical regions. So, for instance, as visual information passes from the eye to the visual thalamus, it can get intercepted almost immediately if it’s not relevant to the given task. The basal ganglia can step in and activate the visual TRN to screen out the extraneous stimuli, in keeping with the prefrontal cortex’s directive.

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Halassa’s findings indicate that the brain casts extraneous perceptions aside earlier than expected. “What’s interesting,” said Ian Fiebelkorn, a cognitive neuroscientist at Princeton University, is that “filtering is starting at that very first step, before the information even reaches the visual cortex.”

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According to his findings, the focus of the attentional spotlight seems to get relatively weaker about four times per second, presumably to prevent animals from staying overly focused on a single location or stimulus in their environment. That very brief suppression of what’s important gives other, peripheral stimuli an indirect boost, creating an opportunity for the brain to shift its attention to something else if necessary. “The brain seems to be wired to be periodically distractible,” he said.

University of Maryland School of Medicine (UMSOM) researchers have found a two-way link between traumatic brain injury (TBI) and intestinal changes:

Researchers have known for years that TBI has significant effects on the gastrointestinal tract, but until now, scientists have not recognized that brain trauma can make the colon more permeable, potentially allowing allow harmful microbes to migrate from the intestine to other areas of the body, causing infection.. People are 12 times more likely to die from blood poisoning after TBI, which is often caused by bacteria, and 2.5 times more likely to die of a digestive system problem, compared with those without such injury.

In this study, the researchers examined mice that received an experimental TBI. They found that the intestinal wall of the colon became more permeable after trauma, changes that were sustained over the following month.

It is not clear how TBI causes these gut changes. A key factor in the process may be enteric glial cells (EGCs), a class of cells that exist in the gut. These cells are similar to brain astroglial cells, and both types of glial cells are activated after TBI. After TBI, such activation is associated with brain inflammation that contributes to delayed tissue damage in the brain. Researchers don’t know whether activation of ECGs after TBI contributes to intestinal injury or is instead an attempt to compensate for the injury.

The researchers also focused on the two-way nature of the process: how gut dysfunction may worsen brain inflammation and tissue loss after TBI. They infected the mice with Citrobacter rodentium, a species of bacteria that is the rodent equivalent of E. coli, which infects humans. In mice with a TBI who were infected with this the bacteria, brain inflammation worsened. Furthermore, in the hippocampus, a key region for memory, the mice who had TBI and were then infected lost more neurons than animals without infection.

Ronald Fisher was working at an agricultural research station north of London in the 1920s, when he fixed a cup of tea for an algae biologist named Muriel Bristol:

He knew she took milk with tea, so he poured some milk into a cup and added the tea to it.

That’s when the trouble started. Bristol refused the cup. “I won’t drink that,” she declared.

Fisher was taken aback. “Why?”

“Because you poured the milk into the cup first,” she said. She explained that she never drank tea unless the milk went in second.

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“Surely,” Fisher reasoned with Bristol, “the order doesn’t matter.”

“It does,” she insisted. She even claimed she could taste the difference between tea brewed each way.

Fisher scoffed. “That’s impossible.”

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“Let’s run a test,” [chemist William Roach] said. “We’ll make some tea each way and see if she can taste which cup is which.”

Bristol declared she was game. Fisher was also enthusiastic. But given his background designing experiments he wanted the test to be precise. He proposed making eight cups of tea, four milk-first and four tea-first. They’d present them to Bristol in random order and let her guess.

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By the eighth cup Fisher was goggle-eyed behind his spectacles. Bristol had gotten every single one correct.

It turns out adding tea to milk is not the same as adding milk to tea, for chemical reasons. No one knew it at the time, but the fats and proteins in milk—which are hydrophobic, or water hating—can curl up and form little globules when milk mixes with water. In particular, when you pour milk into boiling hot tea, the first drops of milk that splash down get divided and isolated.

Surrounded by hot liquid, these isolated globules get scalded, and the whey proteins inside them—which unravel at around 160ºF—change shape and acquire a burnt-caramel flavor. (Ultra-high-temperature pasteurized milk, which is common in Europe, tastes funny to many Americans for a similar reason.) In contrast, pouring tea into milk prevents the isolation of globules, which minimizes scalding and the production of off-flavors.

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Perhaps a little petulant, Fisher wondered whether Bristol had simply gotten lucky and guessed correctly all eight times. He worked out the math for this possibility and realized the odds were 1 in 70. So she probably could taste the difference.

But even then, he couldn’t stop thinking about the experiment. What if she’d made a mistake at some point? What if she’d switched two cups around, incorrectly identifying a tea-first cup as a milk-first cup and vice versa? He reran the numbers and found the odds of her guessing correctly in that case dropped from 1 in 70 to around 1 in 4. In other words, accurately identifying six of eight cups meant she could probably taste the difference, but he’d be much less confident in her ability—and he could quantify exactly how much less confident.

Furthermore, that lack of confidence told Fisher something: the sample size was too small. So he began running more numbers and found that 12 cups of tea, with 6 poured each way, would have been a better trial. An individual cup would carry less weight, so one data point wouldn’t skew things so much. Other variations of the experiment occurred to him as well (for example, using random numbers of tea-first and milk-first cups), and he explored these possibilities over the next few months.

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Fisher published the fruit of his research in two seminal books, Statistical Methods for Research Workers and The Design of Experiments. The latter introduced several fundamental ideas, including the null hypothesis and statistical significance, that scientists worldwide still use today.

The mysterious ailments experienced by Canadian and U.S. diplomats and their families in Cuba may not have come from sonic attacks, but from poison — or, rather, pesticide:

A number of Canadians and Americans living in Havana fell victim to an unexplained illness starting in late 2016, complaining of concussion-like symptoms, including headaches, dizziness, nausea and difficulty concentrating. Some described hearing a buzzing or high-pitched sounds before falling sick.

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The symptoms experienced by the diplomats and their families, rather, are consistent with low-dose exposure, leading researchers to examine the effects of cholinesterase (ChE) blockers in commercial products.

ChE is one of the key enzymes required for the proper functioning of the nervous system. Certain classes of pesticides work by inhibiting ChE.

Cuba, like other tropical countries, regularly sprays pesticides to kill insects that carry infectious diseases.

The researchers found that since 2016, Cuba launched an aggressive campaign against mosquitoes to stop the spread of the Zika virus.

The embassies actively sprayed in offices, as well as inside and outside diplomatic residences — sometimes five times more frequently than usual. Many times, spraying operations were carried out every two weeks, according to embassy records.

Toxicological analysis of the Canadian victims confirmed the presence of pyrethroid and organophosphate — two compounds found in fumigation products.

There was also a correlation between the individuals most affected by the symptoms and the number of fumigations that were performed at their residence.

(Hat tip to our Slovenian Guest.)

A small clinical study suggests that it might be possible to reverse the body’s epigenetic clock, which measures a person’s biological age:

For one year, nine healthy volunteers took a cocktail of three common drugs — growth hormone and two diabetes medications — and on average shed 2.5 years of their biological ages, measured by analysing marks on a person’s genomes. The participants’ immune systems also showed signs of rejuvenation.

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The latest trial was designed mainly to test whether growth hormone could be used safely in humans to restore tissue in the thymus gland. The gland, which is in the chest between the lungs and the breastbone, is crucial for efficient immune function. White blood cells are produced in bone marrow and then mature inside the thymus, where they become specialized T cells that help the body to fight infections and cancers. But the gland starts to shrink after puberty and increasingly becomes clogged with fat.

Evidence from animal and some human studies shows that growth hormone stimulates regeneration of the thymus. But this hormone can also promote diabetes, so the trial included two widely used anti-diabetic drugs, dehydroepiandrosterone (DHEA) and metformin, in the treatment cocktail.

Tim Ferriss has put aside many of his other projects to advance psychedelic medicine:

“It’s important to me for macro reasons but also deeply personal ones,” Mr. Ferriss, 42, said. “I grew up on Long Island, and I lost my best friend to a fentanyl overdose. I have treatment-resistant depression and bipolar disorder in my family. And addiction. It became clear to me that you can do a lot in this field with very little money.”

Mr. Ferriss provided funds for a similar center at Imperial College London, which was introduced in April, and for individual research projects at the University of San Francisco, California, testing psilocybin as an aide to therapy for distress in long-term AIDS patients.

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Experiments using ecstasy and LSD, for end-of-life care, were underway by the mid-2000s. Soon, therapists began conducting trials of ecstasy for post-traumatic stress, with promising results. One of the most influential scientific reports appeared in 2006: a test of the effects of a strong dose of psilocybin on healthy adults. In that study, a team led by Roland Griffiths at Johns Hopkins found that the volunteers “rated the psilocybin experience as having substantial personal meaning and spiritual significance and attributed to the experience sustained positive changes in attitudes and behavior.”

At least as important as the findings, which were exploratory, was the source, Johns Hopkins, with all its reputational weight, and no history of institutional bias toward alternative treatments. “I got interested through meditation in altered states of consciousness, and I came into this field with no ax to grind,” said Dr. Griffiths, the director of the new center.

By late 2018, the Hopkins group had reported promising results using psilocybin for depression, nicotine addiction and cancer-related distress. Others around the world, including Dr. David Nutt at Imperial College London, were producing similar results.

Mr. Ferriss, who organized half the $17 million in commitments and contributed more than $2 million of his own for the new Hopkins center, said he approached wealthy friends who he knew had an interest in mental health. The new venture, he said he told them, “truly has the chance to bend the arc of history, and I’ve spent nearly five years looking at and testing options in this space to find the right bet. Would you have any interest in discussing?”

Mr. Ferriss said he met Dr. Griffiths in 2015, became intrigued with the research, and began thinking about the Hopkins group as he might an investment bet. He launched a crowdfunding campaign for a small depression study, to see how efficiently the Hopkins team used the money. “Essentially it was a seed investment,” Mr. Ferriss said. “I ran a beta test, and they really delivered.”

Craig Nerenberg, one of those friends and the founder of the hedge fund Brenner West Capital Partners, quickly agreed to contribute. “I have lost a family member to addiction and have felt the pain of loved ones who struggled through depression,” Mr. Nerenberg said by email. “It’s hard for me to imagine a contribution that I can make which — if the research data continues to bear out — will have a greater impact over the next decade.”

The remaining half of the commitments for the center came from the Steven & Alexandra Cohen Foundation and is earmarked for treatment of Lyme disease. Mr. Cohen is a billionaire investor; the foundation focuses on eduction, veterans issues, Lyme disease and children’s health, among other things. In an email, Ms. Cohen wrote, “I strongly believe that we must dare to change the minds of those who think this drug is for recreational purposes only and acknowledge that it is a miracle for many who are desperate for relief from their symptoms or for the ability to cope with their illnesses. It may even save lives.”

Investigators at the Hopkins center, its counterpart at Imperial College London and elsewhere still have an enormous amount of work to do to learn which mind-altering substances are beneficial for whom, at what doses, and when such treatment is dangerous. The same concerns that shut down similar research in the 1970s are audible in the caution expressed by many psychiatrists today: These are powerfully mind-altering substances, and administering them to people who are already unstable is uncertain work, to put it mildly. One scary adverse event could cripple the whole enterprise.