Stanford Accelerated Neuromodulation

a significant technical advancement over conventional TMS

I enjoy the challenge of trying to understand, and sometimes trying to help others understand complex technologies. Stanford Accelerated Neuromodulation or SAINT, the very powerful treatment for severe depression, is one technology that is worthwhile explaining to others. If I get it right in this essay, you will have a practical understanding that is not superficial but at the same time does not get into distracting details. In taking on this project, I discovered that this brief essay needs to be bookended- marked on one side by the devoted mother of a child with treatment resistant depression who I worked with, and on the other side, by a remarkable scientist who was instrumental in bringing SAINT into clinical practice. We will encounter our bookend at the conclusion.

As most of us know, the brain consists of networks of neurons communicating through electrical activity — activity that was originally observed using older technologies such as EEG, and more elegantly with functional MRI, one of the most advanced research tools available today that emerged in the early 2000s. With the latter, one can see in real time two seemingly remote areas of the brain light up simultaneously establishing that they share a functional connection. In order to understand how we can take advantage of the brain's neuronal interconnectivity it will be helpful to step back and look at how things evolved historically.

For decades, clinicians have observed that injury to the frontal lobes — particularly following stroke or trauma — often affects mood, frequently producing a flattening or depressive state.

In the 1970s and 1980s, these observations were added to by EEG studies that showed that individuals suffering from depression had characteristic asymmetries in frontal brain activity, particularly reduced activity in the left frontal cortex.

Further advances in brain imaging during the 1990s and early 2000s, especially positron emission tomography (PET), allowed researchers to observe metabolic activity within deeper brain regions. These studies demonstrated that a discrete area known as the subgenual anterior cingulate cortex (sgACC) was often overactive in depressed individuals.

The latest imaging technology, functional MRI, has made it possible to visualize not just isolated brain regions, but interacting networks. Researchers have discovered abnormal communication between surface regions of the frontal cortex and deeper emotional centers such as the sgACC.

An exciting new therapeutic technology, TMS, is a non invasive method that allows clinicians to manipulate the brain's electrical networks as a method of treatment. Let’s look more closely at how TMS works, and then consider how SAINT refines that approach.

As we have stated above, we know that electrical activity in the frontal cortex on the surface of the brain is functionally connected to deeper emotional circuitry, including the key region known as the subgenual anterior cingulate cortex (sgACC). This deeper structure has repeatedly been shown to be overactive in many patients suffering from severe depression. In landmark psychiatric research with dramatic treatment in the early 2000s, neurosurgeons reached the sgACC directly with implanted stimulators and provided startling relief to some patients with otherwise intractable symptoms.

TMS offers a non-invasive way to influence this deeper circuitry. By applying carefully patterned magnetic stimulation to the frontal cortex, clinicians can modulate activity in the sgACC through established network connections. Because the treatment does not require surgery or anesthesia, it can be administered safely in an outpatient setting. For patients whose depression has not responded to standard medication trials, remission rates with TMS are at least comparable to, and in many cases exceed, further attempts at treatment with medications alone.

SAINT constitutes a refinement of currently established TMS techniques. The most elegant refinement SAINT offers is the recognition that individual brains differ subtly in their organization. At the time of treatment, using functional MRI, clinicians identify in a given patient the specific region within that patient's dorsolateral prefrontal cortex (DLPFC) that allows for the strongest connection with that patient's sgACC. Because of individual differences in patients, even a shift of a few centimeters can mean the difference between successful stimulation and failure. In effect, SAINT personalizes the stimulation target. Adding to refinements in localizing stimulation, the SAINT protocol applies multiple spaced sessions per day, substantially increasing the total applied dose of TMS in a brief time period. This allows for the compression of treatment into days rather than the weeks with typical TMS protocols.

The results of these refinements have been striking. In the initial controlled trial of SAINT, remission rates were so high that the study was stopped early for ethical reasons. It made no sense to further randomize patients into a sham arm when it became known that the treatment was so effective. Subsequent investigations in broader samples suggest that approximately 50–60 percent of highly treatment-resistant patients achieve remission. In the landscape of psychiatric research these figures are remarkable. I hope the above description clarifies some of the dry science behind SAINT. It's time to visit the two bookends that came about as I prepared for this essay: my young patient's mother and the remarkable scientist who developed SAINT. A few years ago I was struggling to help a young patient with severe depressive symptoms. She had a remarkable mother who was steadfast in her devotion and resilience in dealing with her child's difficult symptoms. One day the mother contacted me and asked had if I heard of SAINT, I had not, and she requested that I check out its plausibility and credibility. The research I turned up with was encouraging and given that we were at wit's end in helping her daughter I endorsed the family give it a try.

The patient ended up being followed by another clinic, but recently we heard that the young girl is off of all medicines, is doing well, and is applying to college. At the time of this essay, delving into SAINT, I encountered Nolan Williams, MD, the young researcher at Stanford who was instrumental in bringing SAINT to fruition. Nolan's credentials were remarkable, including numerous prizes in psychiatry, considerable public recognition including TED talks, and articles about his work in the New York Times.

He is a man who invites curiosity and as I looked into his biography, I saw photos of this young, good-looking man surrounded by a wife and small children. Related biographical information revealed not only his academic accomplishments but the fact that he was an active athlete, particularly kite surfing.

So it was shocking to read that at the age of 43 he died by his own hand. Discovering this, I was confronted my with my bookends: a young patient likely saved by Nolan's technology and a brilliant medical scientist lost to the same illness he devoted his career to understanding and treating.

There is a very human element to the bookends around this essay that transcends biological psychiatry. Who can say to what extent a mother's love for her daughter might be no less powerful than the profound biological treatment we have been examining here. And is it not natural in reacting to the sadness one feels in learning of Nolan's death to wonder to what extent the very personal and private experience he was going through might have responded to the human touch of a psychotherapeutic relationship?