Psychedelics & Neurostimulation for Brain Rewiring | Dr. Nolan Williams

Andrew Huberman opens by situating the conversation in Dr. Nolan Williams's Stanford laboratory and clinic, which focuses on depression and other mood disorders and on transcranial magnetic stimulation (TMS), a brain-stimulation technique that can activate or quiet specific brain circuits. What distinguishes the group, in Huberman's framing, is combining TMS with cutting-edge, still-experimental compounds including ibogaine, psilocybin, MDMA, cannabis and DMT, and coupling brain stimulation with neuroplasticity learning protocols. He also flags a counterintuitive theme carried into the discussion: the antidepressant effects of ketamine may not arise from its dissociative effects, and that the Brain Stimulation Laboratory is recruiting for clinical trials at bsl.stanford.edu.

Huberman sets the agenda by invoking Williams's claim that depression is perhaps the most debilitating condition worldwide, that the field has a fairly limited number of tools compared with something like cancer, but that the number and potency of those tools is growing. Williams's answer develops three distinct arguments. First, depression is not one phenomenological thing: it spans a presentation dominated by loss of interest, an anxious and overactive form, and an underactive form with no anxiety and low motivation. This is why his group works with Conor Liston at Cornell on neuroimaging-based biotypes to parse out different depression presentations clinically and in the brain. Second, depression is both a risk factor for other illnesses and a condition that makes other medical and psychiatric illnesses worse, with the American Heart Association recently adding it as a fourth major risk factor for coronary artery disease alongside hypertension (high blood pressure), hyperlipidemia (high cholesterol) and diabetes (high blood sugar). Third, the relationship runs both ways: after a heart attack the risk of depression is higher than in the normal population, which motivates the lab's direct measurement of brain-heart connections.

Depression is the most disabling condition worldwide.

Williams quantifies the disability in deliberately stark comparisons: moderate depression is about as disabling as acutely having a heart attack, and severe depression as disabling as having, and dying from, untreated cancer. He then identifies the specific gap his lab targets: the highest-acuity, emergency and inpatient settings. Drawing on his dual training as a neurologist and psychiatrist, he contrasts the rest of medicine, where escalating acuity from a primary care office to the emergency room to the ICU or cath lab brings more tests and more treatments, with psychiatry, where moving from depressed to suicidal on average brings fewer treatments and no tests. These patients end up receiving the same standard oral antidepressants they had been getting as outpatients, and the field has not developed a consistent way to treat the acute escalation.

the number of treatments actually go down on average

An important qualification runs through this opening: Williams explicitly notes that work on treating depression to reduce future heart-attack risk is being pursued but that there is not yet a complete solution. The interview therefore frames the rest of the discussion as an attempt to engineer new brain-based solutions for a problem that is simultaneously enormous in burden and under-instrumented at its most severe end.

Huberman presses on the brain-heart claim partly because, as he puts it, many people treat the heart-mind relationship as woo or soft biology. He wants to know whether Williams is describing an actual physical connection and which brain area is involved. Williams answers with a concrete anatomical chain, and the exchange is notable for converting a vague mind-body intuition into a specified circuit that can be probed experimentally.

It's the sense of control governor of the brain.

The first stimulation target is the dorsolateral prefrontal cortex (DLPFC). Williams explains the mechanism through Faraday's law: a magnetic pulse induces an electrical current in electrically conducting substances, here brain tissue but not skull, scalp or hair, producing direct depolarization of cortical neurons at the surface of the DLPFC. When this is done inside a scanner, the signal distributes into the anterior cingulate, the insula and the amygdala, then into the nucleus tractus solitarius and ultimately down the vagus nerve to the heart. On this account the heart very consistently seems to be the end organ of the DLPFC, and the circuit is offered as a direct probe of the brain-heart connection rather than a metaphor.

The evidence is a time-locked physiological effect. Stimulating over the left DLPFC produces a deceleration of heart rate measured the way cardiologists measure it, within a two-second train of stimulation: the deceleration appears at one second, the heart rate drops, drifts back up during an eight-second break, and drops again with the next train. The effect does not appear with stimulation over visual cortex or motor cortex, which grounds the claim of regional specificity. Williams adds that the finding has been replicated roughly four or five times, citing work by Martin Arens and colleagues in Europe and the Netherlands, so the result is presented as a reproducible phenomenon rather than a single lab's observation.

It goes down about 10 beats per minute

Asked why the left DLPFC specifically, Williams ties the heart finding to a broader literature on mood lateralization. The left DLPFC is thought to be the side where excitatory, potentiating stimulation reduces depressive symptoms. He cites Mike Fox at Harvard: stroke lesions that cause depression, mapped onto the human connectome, are all functionally connected to the left DLPFC, while lesions that cause mania converge on the right DLPFC. Experimentally, exciting the left or inhibiting the right are both antidepressant, and exciting the right can be anti-manic in some studies, which motivates the idea of a hemispheric balancing of mood between the two regions.

there seems to be a hemispheric balancing of mood between these two brain regions

Huberman articulates the puzzle that makes this more than a mapping exercise. He explains that a connectome is built on the model of genomes and proteomes, i.e. large collections mapping connections between neurons, and that the Human Connectome Project reveals right-versus-left regularities even though, by his own inspection of human brains, the layers, cell types and neurochemicals (which cells express or receive dopamine or serotonin) do not look that different on the two sides. He therefore asks how what appears to be basically the same parts list yields an accelerator and a brake on depression and mania, and whether the difference lies in inputs, in learning during development, or in innate hemispheric biases.

Williams's reply is a candid statement of the limits of the current evidence. The mechanism has not been worked out. On the handedness question he notes that about 25 percent of left-handed individuals have right-brain dominance and about 1 percent of right-handed people do when the pattern is flipped, and that the study that would help tease this apart still has not been done at the needed level. The phenomenon is nonetheless described as empirically true in the sense that TMS can be used as a probe to push and pull on the systems, and that causal evidence from stroke locations and brain images points to the asymmetry. This is a useful distinction in the interview: a robust, manipulable effect coexisting with an unresolved explanation for why the asymmetry exists.

Huberman asks whether the circuit runs in the opposite direction, i.e. whether slowing the heart by other means helps depression, and whether behavioral approaches such as exhale-emphasized breathing or deliberately slow cadence breathing feed back to the DLPFC. Williams first answers with vagus nerve stimulation: an implanted vagus nerve stimulator's afferent fibers project up to the DLPFC through the cingulate and anterior insula, the same tract, and stimulating there can alleviate depression. The surprising fact that stimulating a cranial nerve in the neck improves mood is offered as further evidence that this is a whole track and system, where stimulating one part of the system can improve mood.

On behavioral interventions, Williams says there are a number of small but fairly well-designed studies implicating the DLPFC in meditation and mindfulness suggesting these work quite well in mild depression. He introduces the concept of a volitional threshold for depression: at some point a person moves from total volition to semi-volition, with thoughts that are hard to control, beyond which such interventions become harder to engage, the extreme being catatonia in severe depression where people are stuck motorically with little or no control. Exercise is named as a good treatment for mild depression that may work through a lower resting heart rate, though he explicitly says he is not aware of studies looking at DLPFC physiology pre- and post-exercise and calls that a study worth doing. On heart rate variability, he notes that not every study is positive, but quite a few associate lower heart rate variability with moderate to severe depression.

Williams then issues the interview's most important correction, which guards against a naive reading of earlier segments. The deceleration of heart rate occurs in the moment of stimulation and is not necessarily maintained chronically; it is more an indicator of being in the right network than being central to the mechanism. The amount of variance in mood explained by the heart rate deceleration is not huge, only a small percentage, and he notes that propranolol and similar drugs were for years implicated in causing depression, an idea since debunked. He concludes it is unlikely that simply decelerating the heart rate improves depression; rather, reaching the mood-regulatory area triggers a parasympathetic cortical process that causes the deceleration, a process independent of mood that can be demonstrated in a normal healthy individual. This reframes the earlier heart-rate discussion from a candidate treatment mechanism to a validation signal for target engagement.

the actual deceleration seems to be much more of a marker that you're in the right system

Huberman absorbs this by recasting depression as a lack of control over inner state, using his image of the autonomic nervous system as a seesaw of alertness and calmness whose hinge has never been defined. He proposes that the DLPFC-cingulate circuit might be the first candidate for that hinge, and Williams agrees. A further asymmetry detail closes the thread: the identical stimulation over the right DLPFC can produce acceleration of heart rate, but the right-side finding is more variable across studies while the left is very consistent, reinforcing both the lateralization claim and the caution about effect reliability.