I am terrified of cognitive decline. I’ve built my life and identity around creative problem solving and story telling. Who am I if that goes away. Cognitive health isn’t just a problem facing modern medicine, in the form of dementia and Alzheimer's, it is the erasure of self. Medically, we can see the devastating symptoms, trace the accumulation of plaques and tangles, yet truly effective, widely applicable interventions elude us. We round up the usual suspects—Amyloid-β (Aβ) & Tau—like detectives focusing on a single clue at a complex crime scene. But perhaps our tendency to seek “simple” explanations is clouding a messy problem: not one faulty component but a breakdown in the intricate, dynamic system of the brain itself. Preserving cognitive health requires tuning the very symphony of neural activity.

At Optoceutics, we're pursuing a path guided by this systemic view, using targeted light stimulation to engage fundamental brain processes. Recent research from disparate fields paints a picture that makes our approach seem slightly less "mad science" and perhaps even…plausible. (Though let's be honest, a healthy dose of hubris is probably required to think one can untangle something as complex as the aging brain.)

Consider the brain's essential housekeeping. We now know the brain isn't static; it has its own plumbing, the glymphatic system, working alongside meningeal lymphatics, crucial for clearing metabolic waste. Fascinatingly, recent work shows this isn't just passive drainage. Neural networks themselves actively orchestrate this clearance through synchronized activity, creating large-scale ionic waves that drive fluid flow. Flatten these waves, and clearance stalls. Synthetically boost them with optogenetics, and clearance improves. Neurons, it seems, are the conductors of their own cleaning crew—a highly interdependent system.

Even more directly relevant to our work, non-invasive 40 Hz gamma stimulation—the frequency both associated with active cognitive engagement and which our device employs—specifically promotes this glymphatic clearance in Alzheimer's models, dilating lymphatic vessels, increasing fluid exchange, and demonstrably helping remove amyloid, partly via specialized interneurons.

So, part one of the story: the specific brain rhythms associated with cognitive engagement actively drive waste clearance, and 40 Hz stimulation seems to enhance this critical process.

But clearance is likely only half the equation. Why does the waste build up excessively in the first place, and why do cognitive functions decline? Another thread of research highlights the delicate balance of excitation and inhibition (E/I) in cortical circuits. A new study (below) links impaired meningeal lymphatics—a breakdown in that cleaning system—not just to behavioral deficits but directly to altered E/I balance in the cortex, driven by microglia releasing inflammatory signals like IL-6. This suggests a potential feedback loop: impaired clearance triggers an immune response that further disrupts neural communication.

If you'll permit me to nerd out on some information theory, things get particularly interesting from here. I suspect the finely tuned E/I balance in a healthy cortex isn't just about preventing seizures; it's about maximizing coding efficiency and communication efficacy. Coherent neural firing patterns, likely reflected in specific brain rhythms like gamma (local) and theta (global coupling) (as shown in the Aβ/Tau abstract linking oscillations to cognition, see below), allow the brain to represent and transmit information effectively. As we age, or as pathology emerges, and neuronal firing slows, this fine-tuning degrades. Coordination decreases. When the coherence of the neural code drops, the system needs more overall activity—more neurons firing more often—just to convey the same amount of information. This is what some call "toxic hyperactivity", but perhaps it's misleadingly named. It might simply be the brain inefficiently shouting to be heard over increasing internal noise—a natural consequence of degraded coding, not necessarily a disease process per se.

This inefficient "shouting", however, likely puts metabolic stress on the system, triggering precisely the kind of microglial activation and IL-6 release seen in the lymphatic dysfunction study, further disrupting synaptic balance and exacerbating the problem. Cognitive decline ensues not just from accumulated waste but from this escalating cycle of inefficient coding and detrimental immune responses.

Now the potential role of 40 Hz stimulation comes into sharper focus. We know from the glymphatic studies that it directly aids clearance. But could it also be addressing the upstream problem? While direct proof requires more work, my madness finds the hypothesis compelling. Gamma rhythms are deeply implicated in cognitive processes like working memory, and studies using other forms of non-invasive stimulation (like tACS, highlighted in the Memory Modulation Maps abstract, see below) have shown that causally modulating specific rhythms can indeed enhance cognitive function. Could our 40 Hz light stimulation be helping to restore or reinforce gamma coherence in cortical circuits? By driving activity at this specific, functionally relevant frequency, perhaps we're helping the brain return to a more efficient coding state, reducing the need for that energetically costly "hyperactivity" and thereby lessening the inflammatory stress response driven by microglia.

If this admittedly grand, multi-part hypothesis holds water, 40 Hz stimulation isn't just mopping the floor (enhancing clearance); it's helping fix the leaky faucet (improving neural coding efficiency). It addresses both the symptom (waste buildup) and a potential underlying cause (information processing inefficiency leading to stress and damage).

Of course, this is a complex biological puzzle, and claiming to have the whole picture would be foolish. The interactions between neural rhythms, glial cells, vascular dynamics, and waste clearance are extraordinarily intricate. But the convergence of evidence from these diverse studies is exciting. It suggests that targeting fundamental brain dynamics— the rhythms of neural communication and the processes they orchestrate—offers a powerful, systemic approach to promoting cognitive health and resilience. It’s still mad science, perhaps, but it’s science increasingly grounded in a symphony of converging biological evidence.

Follow me on LinkedIn or join my growing Bluesky!

Research Roundup

When the Janitor Quits

You do not want your brain’s janitor to quit. Astrocytes (non-neuronal cells in your brain) facilitate removal of “junk” (please forgive the technical language) via the meningeal lymphatic system. When this system breaks down so does your cognitive health.

Cognitive health depends on finely tuned balance between neuronal excitation and inhibition, producing highly synchronized waves of activity in the cortex. Recent research shows that “prolonged impairment of meningeal lymphatics alters [this] balance” leading to deficits like memory loss.

Too much “junk” (again, you’ll just have to bear with the arcane language) throws off your microglia, which in turn alters immunometabolic processes in the brains, leading to over-expression of “inhibitory synapse phenotypes”.

Good news: “Restoring meningeal lymphatic function in aged mice reverses age-associated synaptic and behavioral alterations”. OK, that’s mainly good news for research mice (who at present have a better healthcare infrastructure than most humans). But it does point to how to improve cognitive health.

Does increased gamma and/or theta activity—via cognitive effort or external stimulation—induce good glial-mediated lymphatic function leading to better cognitive health?

Information Theoretic Alzheimer's

Cortical oscillations pop up in my work on cognitive health, interbrain synchrony, and applied neuromodulation. What links these “brain waves” to brain anatomy and disease?

Studying individuals without symptoms of cognitive decline via MEG reveals that Alzheimer's associated Amyloid-β (Aβ) depositions “colocalize with accelerated neurophysiological activity”. While those already showing symptoms (Aβ + tau deposits, also known as “junk”) show a “shift toward slower neurophysiological activity…linked to cognitive decline.”

This pattern in cortical neurons of hyper-activity followed by pronounced slowing is the MO of pathological cognitive decline. But rather than thinking of the hyperactivity from amyloid-β deposits as “toxic” and mysterious, I see information theory explaining both shifts.

Memory Modulation Maps

Optoceutics uses noninvasive stimulation of neural oscillations (specifically, 40 Hz Gamma). As a board member and scientific advisor, I love seeing new research on why this improves cognitive health. Enter “Causal functional maps of brain rhythms in working memory”.

The findings tell a nuanced story (the best kind!) in which “stimulating anterior frontal and medial temporal theta oscillations and occipitoparietal gamma rhythms leads to significant dose-dependent improvement in working memory task performance”.

In other words, targeting the specific cortical regions with the specific modulation does causally improve cognition. In fact, theta effects vary by region: orbitofrontal boosts with higher frequency while medial temporal responses are lower. And prefrontal gamma can even disrupt performance.

Further, “all these results are driven by changes in working memory accuracy rather than processing time”. This last doesn’t surprise me if the function of these oscillations is to increase coding efficiency of coupling rather than speeding inter-regional propagation.

<<Support my work: book a keynote or briefing!>>

Want to support my work but don't need a keynote from a mad scientist? Become a paid subscriber to this newsletter and recommend to friends!

SciFi, Fantasy, & Me

Why isn't Jimmi Simpson in everything? In fairness, he almost already is: It's Always Sunny In Philadelphia, Westworld, The Newsroom , Psych, and of course Lyle the Intern on Letterman. He's the master of the so-wrong-it's-right line delivery. I just watched him again on Black Mirror, in the Callister episodes. Add in Jesse Plemons, Cristin Milioti, Jimmi Simpson, Billy Magnussen—it's easy to see why the original and the sequel are among the best of Black Mirror.

Stage & Screen

• May 7, Chicago: Innovation, Collective Intelligence, and the Information-Exploration Paradox
• May 8, Porto: Talking about entrepreneurship at the SIM conference in Portugal
• May 14, London: it time for my semi-annual lecture at UCL.
  • And more is in the works for London, including talks, interviews, and ...standup?
• June 12, SF: Golden Angels
• June 9, Philadelphia: "How to Robot-Proof Your Kids" with Big Brothers, Big Sisters!
• June 18, Cannes: Cannes Lyons
• Late June, South Africa: Finally I can return. Are you in SA? Book me!
• October, UK: More med school education

If your company, university, or conference just happen to be in one of the above locations and want the "best keynote I've ever heard" (shockingly spoken by multiple audiences last year)?

Vivienne L'Ecuyer Ming