Action Potentials for August
1: How does working memory work? In what seems like a significant advance, a new study claims to have cracked it, at least for one type of working memory in the worm C. elegans.
As background, when these worms turn around, they choose to turn in one direction or another. If they recently sensed an attractive odor in their environment on one side, they are more likely to turn to that side.
It turns out that the direction in which they turn is largely mediated by one sensory neuron, AWA. When the authors stimulate the AWA neuron, they can bias the direction in which the worm will turn, even after a delay.
This means that the worms must have some form of working memory. To try to measure this, they used confocal microscopy and calcium imaging to measure single neuron electrical activity in the worms.
The authors decompose these neural signals into the primary sources of variance, and then repeat this process on the first principal component. This statistical analysis is necessary because it’s not trivial for a human to detect these oscillations just from looking at the neurons firing.
They find one signal, which they call PC_DV, which corresponds to a stereotyped network oscillation in neurons of the head. This oscillation is seen during (fictive1) forward locomotion and also, to a lesser extent, during the corresponding reverse movement.
They found that when they stimulated the AWA neuron and combined this with the state of PC_DV, they could predict — not perfectly, but pretty well — the direction in which the worm would turn. This is despite the fact that there is up to a 100 second delay before that turn actually occurs.
They tried to find other neurons whose activity levels could predict the direction in which the worm would turn, but they couldn’t. Instead, they found a correlation between the phase of PC_DV when the AWA neuron was stimulated and the phase of the PC_DV when the (fictive) reversal behavior was initiated.
This suggests that the relative phase that PC_DV is in when a worm senses an attractive odor may be how the worm remembers which direction to turn when it comes up for its next reversal.
If storing information in the temporary phase relationships of neural oscillations is a fundamental principle, it might help explain how more complex brains, including our own, maintain and process information over short time periods.
2: Method for volumetric imaging of axons and myelin using photochemical sectioning of tissues. They compare it to electron microscopy volumetric methods:
They used it to image circuits across the entire mouse olfactory bulb, including zoomed in images from particular areas:
3: Study finds that two major types of inhibitory neurons, parvalbumin (PV) and somatostatin (SST) neurons, seem to have different strategies for integrating dendritic inputs. On a structural level, parvalbumin neurons have a higher density of synapses in proximal dendritic regions compared to distal regions, while somatostatin neurons have a more uniform distribution of synapses along their dendrites, which may account for functional differences.
4: Protocol for correlated light and electron microscopy in postmortem human brain tissue. They only studied tissue with a 6 hour postmortem window so as to maximize the preservation quality. Here is an example overlaying fluorescence staining for neurofilament on electron microscopy images:
5: Study finds that it is possible to image unstained neurons in formalin-fixed, paraffin-embedded brain tissue using the imaging beamline of Elettra, the Italian synchrotron facility. It is interesting — though perhaps not very likely — to imagine that preserved tissue will one day be imaged using massive synchrotron particle accelerators.
6: Enough about Large Language Models. Let's talk about the real LLMs — Lipid Laden Macrophages. New study finds that these cells transfer lipids scavenged from myelin to glioblastoma cells in a way that stimulates disease progression. Here on electron microscopy you can see the contact points between the myelin-containing macrophages (M) and the tumor cells (T).
7: According to a new study, the risk of recurrent stroke after an initial stroke is linked to DNA-sensing inflammation in atherosclerotic plaques. Circulating cell-free DNA, mainly from neutrophils, activates a type of inflammasome, which seems to destabilize plaques. A treatment that degrades this circulating DNA decreased the risk of recurrent stroke in mice.
8: Case reports suggest that the prevention of Alzheimer's disease may be already happening in some but certainly not all cases with the use of anti-amyloid antibodies.
9: Cognitive motor dissociation is a phenomenon where patients with disorders of consciousness show evidence of cognitive task performance on functional MRI or EEG despite lacking observable behavioral responses to commands. A new study of 241 behaviorally unresponsive adults found this phenomenon in 25% of them. It was more likely in people who were younger, had longer time since their injury, and had traumatic brain injury as the etiology of their condition.
Unsurprisingly, many of the takes about this on r/medicine are reactionary. For example: “The cynic in me, knowing NEJM history, thinks this paper was probably funded by private equity attempting to get into the LTAC space” (39 upvotes, ??). One neurologist in the comments notes that many non-neurologists are too pessimistic about the possibility of recovery after TBI.
10: Retrospective study in Southern Brazil finds that people with BMI of greater than 30 are less likely to receive the recommended intensification of medical treatment of hypertension. The authors describe this as therapeutic inertia.
11: Retrospective chart review study of 222,942 new users of antidiabetes medications finds that the prescription of semaglutide — one of the new GLP-1 receptor agonists — is associated with a lower subsequent incidence of smoking cessation medication prescriptions and counseling, suggesting that it may be beneficial for tobacco use disorders.
12: Perspective on the induction of false beliefs in people who take psychedelics. They propose that psychedelics decrease the weighting of prior beliefs and increase the weighting of new sensory inputs and insights, potentially leading to both true and false insights. In other words, psychedelics may increase the quantity and subjective intensity of insights, but not necessarily their accuracy or adaptiveness.
They create a visualization with five dimensions for thinking about insights that people experience while taking psychedelics: intensity, goodness (valence), falsifiability, accuracy (veridicality), and adaptiveness. They suggest it may be important for a therapist to help maintain epistemic hygiene so that less accurate beliefs are contained. Not always easy.
13: Public service announcement: People often do not know that 2nd generation H1 antagonists like cetirizine (Zyrtec), loratadine (Claritin), etc can affect cognition. Here is a recent systematic review on this topic. Key conclusion is that fexofenadine (Allegra) is the only oral antihistamine that does not cause impairment of cognitive function.
14: How helpful is the placebo effect in randomized trials of treatments in different psychiatric conditions? New meta analysis finds it is most helpful in MDD and GAD, and least helpful in social phobia, mania, OCD, and schizophrenia.
15: How is BMI associated with psychosomatic concerns among adolescents? New study of this in more than 1 million adolescents, using a scale that measures feeling low, irritability, nervousness, sleep difficulties, dizziness, headache, stomachache, and backache, with frequency reported as ranging from rarely/never to daily. The first three of these don’t really seem “psychosomatic” to me, but let’s ignore that.
They find there is a U-shaped curve where these concerns are more common among people with BMIs higher and lower than the average. Psychosomatic concerns increased with school grade, from primary to middle to high school, perhaps highlighting how carefree early childhood can be. Girls reported significantly higher psychosomatic concerns than boys overall, while the U-shaped association was more pronounced in boys.
16: Archaeological study uses chemical analysis to find that the altar stone in the center of Stonehenge most likely came from Scotland.
17: New high-throughput method for screening cryoprotectants:
It allows them to screen for chemicals that are both permeable to cells and non-toxic even at high concentrations:
18: The new Pixel Watch 3 has loss of pulse detection. This could be enormously useful for people interested in cryonics. It is available in several European countries, but not the US. Google says it is working with regulators in the US. Many people do not realize that the FDA is often more restrictive than their counterparts in many European countries when it comes to medical devices.
19: New publication by Andrea Sauchelli on cryonics, arguing that it incentivizes self-interested actors to care about long-term catastrophic and existential risks, which they otherwise might not be interested in due to generational egoism.
20: Agnes Callard, in a discussion with Robin Hanson, has some interesting points about cryonics. She says: “It's really hard in general to deal with the thought that death is inevitable.... We work hard to reconcile ourselves to the inevitability of death... I had to reconcile myself to the thought. My whole life I had to spend reconciling myself to the thought, 70, 80, or 90 my time would be up. And now you're tempting me with the thought that maybe that's not true. But you better be able to prove it to me, prove it's going to work, for sure, 100%, before I let myself walk down that road.” I think this is a common reason that many people don’t even want to think about cryonics.
"Fictive" because the worms in this experiment are immobilized and paralyzed for imaging, so they're not actually moving. Instead, the researchers observe neural activity patterns that would normally correspond to these behaviors in freely moving worms.
#20: I agree that avoidance of thinking about death is a powerful factor in people ignoring or rejecting even considering cryonics/biostasis. It takes time to even partly accept the inevitability of your own death. Then cryonics comes along as tells you there is a chance -- only a chance and of unknown probability -- that you can put off death indefinitely. Religion does so much better because it (falsely) promises certainty.
#8 Worth noting this was in people with familial Alzheimer's with specific mutations, which is a very small proportion of all patients. I wouldn't be surprised if it works well for them, but fails to generalise to most cases.
#13 Oh good to know! Sadly extremely relevant to me, particularly as spring is almost upon us in the Southern Hemisphere.