Brain & Mind Weekly — Apr 01, 2026

Your sleeping brain replays bad memories more faithfully than good ones. A molecular switch in the hippocampus can flip fear into forgetting. And semaglutide — the drug that seemed to help everything — just failed its biggest Alzheimer's test. This was a week of uncomfortable specificity: the mechanisms behind pain that outlasts injury, social circuits that self-correct when individuals drop out, and a dose-response signal suggesting your flu shot strength might matter for dementia risk. The through-line is that the brain's defaults — what it prioritizes, what it holds onto, what it lets go — are more biased and more druggable than we assumed.

• BrainGate Typing Neuroprosthesis (Mass General Brigham / Brown University): Investigational implantable BCI using motor cortex microelectrode arrays achieved 110 characters per minute with 1.6% word error rate in two participants with paralysis — the fastest accurate BCI typing reported to date.
• Brain-OF Foundation Model (Multi-institutional): GPT-style model pretrained across fMRI, EEG, and MEG modalities performs decoding, denoising, and response prediction without task-specific retraining — open weights available on arXiv.
• Vega Voltage Indicator (Preprint): New genetically encoded green fluorescent voltage indicator with >20× improved photostability enables 15-minute continuous recordings of 50+ neurons simultaneously in brain slices.

Sleep is supposed to be restorative. Your hippocampus apparently didn't get the memo.

A new Nature Neuroscience study shows that sharp-wave ripples — brief, high-frequency electrical bursts that occur during deep sleep and are thought to consolidate memories — synchronize across the full length of the hippocampus more tightly for negative experiences than positive ones. Think of ripples as the brain's nightly backup process. The finding is that emotionally negative content gets a higher-fidelity backup: more coordinated activity across the hippocampus's front-to-back axis, which appears to be what makes a memory stick with precision.

What changes if this holds: It offers a mechanistic explanation for why traumatic memories are so vivid and persistent while pleasant ones fade. For PTSD research, the implication is direct — disrupting this asymmetric replay during sleep could become a therapeutic target. Closed-loop devices that detect sharp-wave ripples and selectively dampen the negative-biased ones are already technically feasible in rodents.

What to watch for: If follow-up studies show this bias exists in human sleep recordings (using intracranial EEG in epilepsy patients, for instance), expect a wave of clinical interest in sleep-targeted PTSD interventions. If the bias turns out to be rodent-specific, the story shrinks considerably.

Extinction — the process by which a fear memory fades after repeated safe exposure — is the basis of exposure therapy for phobias and PTSD. But the molecular machinery that actually executes it has been murky. This week's Nature Neuroscience paper names a specific actor.

Neuropeptide Y (NPY), released by a subset of inhibitory neurons in the hippocampus, acts on two distinct receptor-defined neuron populations to flip the switch from "fear this" to "it's safe now." The precision matters: it's not that NPY dampens fear generally. It engages two different receptors on two different cell types, and the combination is what converts a fear memory into an extinction memory.

What changes if this holds: NPY pathway drugs could become adjuncts to exposure therapy, helping patients who currently don't respond. MNK1/MNK2 inhibitors (already in cancer research) and NPY receptor agonists are both plausible candidates. The mechanism is now specific enough to attract pharmaceutical interest.

The signal to watch: Any announcement of a Phase 1 trial testing NPY-pathway compounds alongside exposure therapy for PTSD. The mechanistic foundation is now solid enough that the absence of such a trial within 18 months would itself be telling — it would suggest the translational path hit a pharmacokinetic wall.

Millions of people with rheumatoid arthritis know this maddening reality: the inflammation gets treated, the swelling goes down, but the pain persists. Doctors have long assumed the pain was just lagging behind the biology. A Nature Neuroscience paper this week says something more troubling is happening.

Sustained non-canonical type 1 interferon signaling — interferons are immune proteins best known for fighting viruses — is keeping peripheral sensory neurons in a permanently sensitized state, even after the original inflammatory trigger is gone. Specifically, interferon-driven MNK1/MNK2–eIF4E signaling in the nerve fibers that carry pain signals from joints to spinal cord maintains hypersensitivity independently of joint inflammation. Blocking this pathway didn't just reduce pain — it reversed it.

What changes: MNK1/MNK2 inhibitors already exist in oncology pipelines. Repurposing them for chronic inflammatory pain is now a mechanistically grounded proposition, not a fishing expedition. If this translates, it could help the substantial fraction of RA patients whose pain doesn't respond to anti-inflammatory treatment.

Failure looks like: The pathway being redundant in humans — other signaling cascades maintaining sensitization even when MNK is blocked. Watch for human dorsal root ganglion transcriptomic studies confirming the same interferon signature.

The GLP-1 drug story has been one of medicine's most exciting narratives — weight loss, kidney protection, cardiovascular benefit, and a growing list of organs that seem to respond. Alzheimer's was the next frontier. This week, the frontier pushed back.

In the Phase 3 EVOKE and EVOKE+ trials, semaglutide — sold as Ozempic and Wegovy — did not slow clinical progression of Alzheimer's disease. The trials were large, randomized, and placebo-controlled: the definitive test. Overall, the trials did not show a clinical benefit.

What this means: GLP-1 drugs' remarkable cross-organ track record has a limit, and the brain's amyloid pathology may be it. The observational data suggesting dementia protection may have reflected confounding, amid healthier people taking the drug and weight loss reducing vascular risk, rather than a direct neuroprotective effect.

The silver lining to watch: Subgroup analyses from EVOKE+ could still reveal whether semaglutide helps a specific Alzheimer's subtype — vascular-dominant, early-stage, or APOE4-negative patients. If those analyses show a signal, the GLP-1/dementia question reopens rather than closes. If they don't, the field moves on.

When you're cold, you move closer to other people. Simple enough. But how does your brain decide to do that — and what happens in a group when some individuals stop cooperating?

A Nature Neuroscience study found that the prefrontal cortex — usually associated with planning and self-control — encodes decisions to huddle in mice during cold exposure. Unique cortical populations drive individual huddling decisions. But the genuinely surprising finding is what happens when researchers silenced those neurons in some animals: the remaining group members compensated, increasing their own huddling to maintain group warmth. The compensation was driven by measurable changes in the neural activity of the non-silenced mice.

What changes: This is a rare window into how individual brain states aggregate into collective behavior — and how groups self-correct when members disengage. The model extends well beyond thermoregulation to any social system where individual opt-outs force group-level adjustment.

The signal: If follow-up work identifies the specific prefrontal cell types driving compensation (some evidence points to "initiator" neurons), it would create a tractable model for studying social resilience — and its breakdown in conditions like autism or social anxiety.

Place cells fire when you're at a location. That's been known since the 1970s. But what happens when you're sitting still? A Nature Neuroscience paper shows that a neighboring region is doing something stranger.

Neurons in the medial entorhinal cortex — home to grid cells, which create a coordinate system for navigation — collectively represent discrete nonlocal positions during immobility. They're mentally "visiting" task-relevant locations the animal isn't currently at. Meanwhile, CA1 (the hippocampus's main output) temporarily disconnects from this signal.

What changes: This reframes the entorhinal cortex from a passive spatial relay to an active simulation engine — generating representations of places that matter for planning. It's a potential substrate for prospective thinking and mental navigation, and it connects to the broader question of how the brain constructs and uses internal models of the world.

Failure looks like: The nonlocal representations being epiphenomenal — correlated with planning but not causally necessary. Optogenetic disruption experiments during the nonlocal coding periods would be the decisive test.

If you want to study psilocybin or DMT for depression, you first have to get some. That's a bigger hurdle than it sounds — complex chemical synthesis or extraction from organisms that are difficult to cultivate. A team engineered Nicotiana benthamiana (a lab-friendly tobacco relative) to produce five different psychedelic tryptamines — psilocybin, DMT, 5-MeO-DMT, and others — by inserting biosynthetic genes from fungi, plants, and animals.

The plant becomes a light-powered bioreactor. The pathway currently requires transient expression (not yet heritable), which the authors frame as a built-in biosafety feature.

What changes if yields hold: The cost and regulatory friction of producing research-grade psychedelic compounds drops dramatically. Clinical trials that are currently bottlenecked on compound supply could accelerate. It reframes "natural product" sourcing as something farmable and controllable.

The test: Independent labs reproducing the reported yields and purities. If the method scales to greenhouse cultivation, it changes the economics of psychedelic-assisted therapy research within a year or two.

Brain-computer interfaces keep getting smaller. This week's entry, published in Nature Biomedical Engineering, is genuinely striking: a flexible, wireless device roughly 100 microns wide — injectable by needle — that maintained stable single-neuron recordings for a full year in animal experiments. The device uses soft materials and a bio-dissolving outer shell to minimize inflammation, and it recorded neural spikes during behavior without the scarring typical of rigid probes.

What changes: Chronic, low-inflammation neural monitoring has been a major barrier for clinical BCIs and epilepsy implants. A device that stays put and records reliably for a year without provoking tissue responses makes long-term monitoring and closed-loop therapies practical in ways they weren't before.

Failure looks like: The device working in rodents but not scaling to primate cortex, where tissue mechanics and immune responses differ. Watch for non-human primate data as the next validation step.

A resource-scale study in Nature Neuroscience mapped how stimulating different deep brain stimulation targets and frequencies echoes through whole-brain networks. The key finding: identical stimulation can normalize some distributed networks while simultaneously pushing others further from healthy patterns.

This explains a clinical puzzle — why DBS can help movement while sometimes worsening mood or cognitive control. The brain isn't a set of independent switches; it's a network where pulling one lever tugs on everything else.

What changes: Device design should shift toward whole-brain readouts and closed-loop adjustments, not just optimizing a single local target. If regulators start seeing adaptive DBS submissions that monitor distributed network states, that's the signal the field is acting on this evidence.

The observable test: Whether next-generation DBS trials include whole-brain fMRI or EEG monitoring as secondary endpoints, rather than relying solely on motor scores.

Vega Voltage Indicator — A new genetically encoded green fluorescent voltage indicator, described in a bioRxiv preprint, claims >20× improved photostability over existing tools, enabling continuous 15-minute recordings of 50+ neurons in brain slices. If other labs confirm the performance, it removes a fundamental bottleneck for long-duration, high-speed voltage imaging experiments.

NeuroGNN Seizure Classifier — Demonstrated at SBMT 2026, this dynamic graph neural network trained on multimodal EEG reportedly improves classification of rare seizure types by about 29% in conference test datasets by modeling how epileptic activity spreads through cortical networks. Conference demo stage — awaiting peer-reviewed validation.

TurboFIRE Intraoperative fMRI — Also shown at SBMT 2026, this real-time fMRI processor streams millimeter-precise activation maps during surgery, revealing speech and movement zones live. Paired with diffusion tensor imaging for tract visualization — promising for reducing post-op deficits in eloquent cortex resections.

A tobacco plant quietly synthesizing five psychedelics at once, a grain-of-salt implant eavesdropping on single neurons for a year, and your sleeping hippocampus running a biased highlight reel that favors the worst day of your life.

Somewhere a semaglutide molecule is looking at the blood-brain barrier and whispering, "I thought we had something."

Until next week — stay curious, stay skeptical.

If someone you know would enjoy learning that their brain is literally replaying their worst memories in higher definition than their best ones, forward this their way.

Social media addiction just became a legal liability — a Los Angeles jury found Meta and YouTube liable in a bellwether trial that turns "design defect" into a litigation template. Read → Two Verdicts in Two Days