Field Notes: An Upstream Journey to Brain Health

From Resistance to Response: When the Trial Fails, But the Patient Doesn't

Ted Ritter — Sat, 06 Jun 2026 14:00:59 GMT

It reads like a slam-dunk headline: “Vagus nerve implant shows lasting benefit for treatment-resistant depression, two-year study finds.” However, despite impressive durability, the trial failed to meet its primary goal on the standard depression scale. The vagus nerve, last seen in Field Note 1 as a player in mouse memory loss, returns here in a related but very different role. And it raises a tough question about whether this is a story about the benefits of vagus nerve stimulation or more about the challenge of assessing people who have spent half their lives trying depression treatments that fail them

“The vagus nerve paradoxically appears to be a major contributor to both mental illness and wellness.”

Ever since doing research for Field Note 1 on how gut bacteria, the vagus nerve, inflammation, and short-term memory interact in mice, my Facebook feed has been overflowing with ads for vagus nerve stimulators. Beware, you, too, are now destined for the same advertising purgatory!

It’s intriguing to me that the vagus nerve paradoxically appears to be a major contributor to both mental illness and wellness, leading me to this two-year study on Vagal Nerve Stimulation (VNS) for people with Treatment-Resistant Depression (TRD).

My impression has always been that one is labeled with TRD only until they find the right treatment. But what’s the right number of treatments to try? The patients in this trial went through an average of 13.5 lifetime failed antidepressant treatments. Approximately 41% had a prior suicide attempt, and had lived roughly half their lives in depression; many had also failed Transcranial Magnetic Stimulation (TMS) or Electroconvulsive Therapy (ECT). To underscore the severity of the situation, 72% of participants were unemployed.

My heart goes out to these people. Study qualification requires “failing four or more antidepressants,” which I think is backward because it places the burden on the patient. The treatments failed them, fitting into my upstream hypothesis.

The way I see it, every downstream depression treatment available today is a hammer. For most people, finding the right hammer for their nail works. With TRD, your depression is more like a screw, and, with only hammers to choose from, you are screwed.

As the authors touch on, TRD may be a totally different beast than other types of depression, which raises the question of whether the standard tools for measuring depression are the right ones for this population.

VNS has a 20-year regulatory history, originally developed for drug-resistant epilepsy. Researchers later discovered its antidepressant effects, leading the FDA to approve VNS for TRD in 2005. This VNS is not something you clip to your ear or wear on your neck. It’s a surgical procedure that, despite FDA approval, is largely unavailable because, in 2007, the Centers for Medicare & Medicaid Services (CMS) ruled that the evidence for VNS was insufficient, blocking Medicare coverage. Typically, when Medicare blocks coverage, so too do the commercial insurance companies. The RECOVER trial’s goal is to settle the coverage question, hopefully making VNS much more readily available.

Led by a team from Washington University in St. Louis, the RECOVER study was initially a one-year, double-blind study of 493 participants across 84 US sites, randomized to active VNS or a sham (unit implanted but not activated). The VNS units, made by the sponsor, LivaNova, were implanted subcutaneously in the chest with a lead wrapped around the left cervical vagus nerve.

The primary endpoint for the research was the percentage of time a participant spent “in response,” defined as a >= 50% improvement on the MADRS, a standard for measuring depression.

The disappointing news from the first-year trial was that there was no significant difference in MADRS scores between the active and sham arms. In contrast, the other measures showed a statistically significant, “modest,” difference between the groups. Conway and colleagues call this out, acknowledging that MADRS may not be the right measure for this population.

Yet the two-year follow-up study highlights impressive durability. As shown in the chart below, among patients who showed at least meaningful benefit at 12 months, 85% still had it at 24 months. The stronger responders held even better: of those with substantial benefit at 12 months, 92% still had at least meaningful benefit at 24 months. Not shown in the chart, but worth calling out, is that about a third of patients with no benefit at 12 months gained benefit during year two. Relapse was rare, and there were no safety issues.

To interpret these results, it’s important to understand the initial 12-month trial. The trial had two arms. Everyone (493) received an implant and underwent the standard interviews and screenings across four measures: clinician impression (CGI-I), patient self-report (QIDS-SR), a masked, off-site clinician rating (QIDS-C), and MADRS. Half the patients had the device turned on and calibrated over months 1-3.

At the end of the first year, all patients had their devices turned on, but the researchers only included the first-year active group scores in their durability analysis. This decision is a real limitation that we’ll return to below.

“With RECOVER, we might be seeing the flip side of the same biology from Field Note 1, though it’s impossible to verify.”

What grabbed me about the RECOVER results is both the promise of VNS and the challenges of TRD. VNS isn’t a medication targeting neurotransmitters; rather, it’s an intervention that stimulates an entire regulatory system tied to the vagus nerve. This distinction is particularly important for this population, given their lifelong challenges of being continually disappointed by medications.

For me, the obvious question is, given that VNS shows some benefit, what is it doing? Surprisingly, the researchers did not investigate this question. They only speculate on this, with likely candidates including changes in neurotransmitter signaling, neuroplasticity, and the vagus nerve’s anti-inflammatory effects.

The inflammation angle aligns with my first Field Note, where I discussed its role in altering vagal nerve signaling and driving cognitive decline in mice. I understand why RECOVER didn’t measure any inflammatory markers. Its design focused not on how VNS works, but how well it works.

This thread led me to a very small Canadian study by Lespérance et. al. that measured inflammatory markers in TRD patients receiving VNS. This trial comes with two key disclaimers: it involved only 6 patients, and the patients’ level of depression was less severe than that of the RECOVER group.

The Lespérance team found a reduction in inflammatory markers, but not those typically associated with damaging inflammation and depression: TNF-α and IL-6. Neither marker moved noticeably. What changed were other inflammation markers related to signaling pathways that recruit immune cells into the brain, as well as proteins that govern the blood-brain barrier.

The authors interpreted this (pure speculation) to mean that VNS may not directly reduce inflammation; rather, it influences the underlying inflammatory machinery. For example, augmenting the blood-brain barrier and reducing the signals that summon immune cells to cross it.

In Field Note 1, we saw how bacterial metabolites suppressed vagal nerve signaling, leading to neuroinflammation and downstream memory loss in mice. With RECOVER, we might be seeing the flip side of the same biology, though it’s impossible to verify because RECOVER didn’t measure any inflammatory markers, and Lespérance included only 6 patients.

From an upstream perspective, aspects of both depression and cognitive decline might overlap at the intersection of the vagus nerve, the blood-brain barrier, and inflammation. And certainly, there is strong evidence that midlife depression associates with cognitive decline later in life. But does having depression in midlife cause later cognitive decline, or are they both symptoms of the same upstream dysfunction? It’s a question worth revisiting.

“This trial may be telling us more about the limits of how we measure TRD, than how well VNS treats it.”

Plausible isn’t proven, and this section is where I work through the gap with three concerns about how to interpret these results.

First, we don’t know why VNS is triggering the results the authors found. Their best guesses are:

Changes in neurotransmitter signaling would involve the locus coeruleus, a small brainstem nucleus that’s a principal source of norepinephrine and one of the structures that project to the hippocampus, a structure I wrote about in Field Note 1.
Neuroplasticity, which seems to be a catch-all these days for both brain dysfunction and its potential recovery.
The anti-inflammatory pathway.

Second, because there was no control arm in year two, there is no way to tell if durability is due to VNS. Certainly, scores (non-MADRS) remained high and even rose in some cases, but without a sham-control group, we don’t know whether VNS was the reason.

Third, the relationship between the responses of the sham and active stimulation groups is odd. The sham group's scores increased in the last three months of the first-year trial, and the authors speculate that sham participants became more optimistic as the activation date approached. There's clearly much more going on than just vagal stimulation, and even the authors noted that the sham group scored higher than in comparable trials.

On the surface, this research looks like a story about whether VNS works for severe depression, and according to the standard depression scale (MADRS), it doesn’t. My take is that the researchers chose the wrong primary endpoint for patients with TRD. For the meaningful subset of patients who responded on the other three measures, the vast majority maintained that response two years out. Again, these were people who had spent half their lives with treatments failing them. So, while this trial suggests some benefit from VNS, it clearly highlights the challenge of measuring TRD in the first place.

For my next Field Note, I want to further look into the blood-brain barrier and its possible role in cognitive decline and depression. Suffice it to say, it’s time to take out the trash.

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From Gut to Brain: A Fast Track to Memory Loss

Ted Ritter — Mon, 11 May 2026 19:31:28 GMT

A new mouse study suggests some memory decline may begin in the gut—not the brain—with inflammation disrupting communication along the gut-to-brain pathway. This same inflammatory pathway may help explain why GLP-1 drugs like Ozempic are associated with a lower risk of dementia, even though major human trials have failed to slow cognitive decline in people already suffering from Alzheimer’s disease. To me, the most important takeaway is that brain aging may be more modifiable than we assume. Rather than focusing only on downstream symptoms after cognitive decline has emerged, this research points upstream—toward earlier biological drivers such as inflammation, metabolism, and gut-to-brain signaling.

Here it is! My inaugural Field Note. After 25 years in cybersecurity analysis—learning to explain upstream risks before they became crises—I’m now applying that same mindset to brain health. I’ve often written for clients about “shifting left” to find vulnerabilities at the source before they reach production. Brain health needs the same rethink: many current treatments target downstream effects such as low serotonin levels and amyloid plaques rather than root causes. We need to focus upstream!

In this first Field Note, I’m writing about a new study in mice that links gut bacteria to memory loss, and potential ways to reverse that loss. BTW, my interest in the gut-to-brain connection started a few years ago after reading about a patient who developed depression following a poop transplant (it’s a thing!) from a donor with undisclosed depression.

If these mouse study results prove relevant to humans, treatment strategies for cognitive decline could fundamentally change. Below, I explain why understanding this pathway is essential.

“What we call ‘brain aging’ may partly stem from a breakdown in gut-to-brain communication.”

Age-related memory decline is top of mind. My family history makes me extra sensitive. For example, recently, when I couldn’t immediately recall the name of the Canadian singer who went to school with my Uncle (Leonard Cohen), I freaked! Friends told me, “Happens to me all the time.” But why do our memories fade and become harder to reach with age?

Researchers at the University of Pennsylvania suggest that what we call “brain aging” may partly stem from a breakdown in gut-to-brain communication. The gut bacterium Parabacteroides goldsteinii in mice produces medium-chain fatty acids. These activate receptors on peripheral immune cells, triggering inflammation. This inflammation damages vagal nerve impulses to the hippocampus (where new memories are made).

What’s intriguing is that this finding is consistent with another area of research in humans: peripheral inflammation is linked to cognitive decline, and may cause it. Two large meta-analyses found that higher levels of inflammatory markers significantly increase the risk of cognitive decline in older adults. Even more striking, a long-term study found that people with higher inflammation in their 20s performed worse on cognitive tests in middle age. However, while these studies suggest an association, they do not confirm causation or the exact mechanisms involved. Still, inflammation is increasingly hard to ignore.

What excites me about this paper is the level of detail in the biological pathway. This isn’t just generic advice about “gut health” — it’s a description of a specific molecular pathway.

The researchers tackled causation versus correlation head-on using multiple approaches. Young mice developed memory problems after exposure to aged mice and their gut bacteria. Germ-free mice receiving microbiomes from older mice showed a similar decline. Researchers also isolated specific bacterial species to test their direct effects.

Researchers linked cognitive decline to reduced activation of hippocampal neurons. They identified medium-chain fatty acids as an active molecule that could reproduce memory deficits when given directly.

Further, they tested specific interventions. A bacteriophage targeting bacteria improved memory in aged mice. Inhibiting a specific cell-surface receptor involved in inflammation triggered by the medium-chain fatty acids restored cognitive function. Finally, Vagal nerve stimulation with capsaicin restored memory performance.

The mouse research is quite interesting to me because it relates to drugs that millions of people already take. Researchers showed that liraglutide (similar to Ozempic and Wegovy) improved memory in aged mice. This finding may relate to human findings. Strikingly, observational studies have linked GLP-1 drugs for diabetes to lower dementia risk. Impressive, right, though this may be correlation more than causation.

Late last year, Novo Nordisk announced that its EVOKE trials, the largest GLP-1 studies conducted in Alzheimer’s, did not slow cognitive decline, prompting Novo to end the program. This doesn’t kill the GLP-1 hypothesis, but it complicates it significantly.

“Inflammation, metabolism, and neurodegeneration may be parts of the same upstream process.”

I’m intrigued by the way GLP-1 drugs sit at the intersection of metabolism, inflammation, and cognitive decline. Researchers increasingly suspect that insulin resistance, impaired glucose metabolism, and chronic inflammation may all contribute to cognitive decline and Alzheimer’s disease. This is one reason some researchers describe aspects of Alzheimer’s as “Type III diabetes,” since many Alzheimer’s brains show disrupted glucose utilization.

It’s important to note that the observational studies tracked people taking GLP-1 drugs before dementia onset. The EVOKE trials tested the drugs in people who already had early-stage Alzheimer’s. In other words, the drugs may still have value for prevention even though they don’t reverse existing damage. This difference—between prevention and treatment, and between causation and correlation—highlights a research gap that will require more targeted trials to resolve.

What makes this worth paying attention to is that brain aging may be driven in part by modifiable factors. Aged, germ-free mice experience delayed cognitive decline. This makes the upstream focus personally urgent. And by targeting defined actors along the pathway, researchers suggest a possible route to truly tackle the causes—not just the symptoms—of cognitive decline, at least in mice. Interestingly, the researchers did not find increased intestinal permeability (“leaky gut”) in the mice experiencing cognitive decline, suggesting the effects may be more closely tied to inflammation and vagal signaling.

How cool is it that specific approaches can restore memory function in aged mice? This could open a path toward new treatments targeting inflammation and gut-to-brain pathways in humans.

“Mickey ain’t me!”

Despite all the Facebook videos we see, plausible isn’t the same as proven. This study shows a clear mechanism in mice, but at the same time, Mickey ain’t me! Whether this gut-brain pathway is the same in humans, whether bacterial changes occur similarly across species, and whether the tested interventions would prove safe and effective in people are the essential unknowns I will follow closely.

I’m intrigued by the possibility that the gut-to-brain pathway has an impact beyond memory and cognition. This investigation will continue as I explore the vagus nerve’s role in treatment-resistant depression. If it turns out that high inflammation and vagal signaling suppression contribute to both cognitive decline and mood disorders, these pathways may prove more relevant than we currently understand.

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