In their efforts to understand the beneficial effects of SAINT, an important new fast-acting brain stimulation treatment for refractory major depression, researchers now think they understand why it works, and for whom. Remarkably, they propose, the treatment works because it helps to reverse the direction of signaling within an important brain network that is likely out of synch in major depression. The finding has potentially significant implications for fitting patients to the treatment and for understanding depression more generally.

Last September, the U.S. Food and Drug Administration approved commercialization of SAINT for people with severe major depressive disorder who have not responded to multiple conventional antidepressant therapies.

Developed by a team led by Nolan R. Williams, M.D., of Stanford University, a 2018 and 2016 BBRF Young Investigator and 2019 winner of BBRF’s Klerman Prize for exceptional clinical research, SAINT has been impressive in three clinical trials. It has provided rapid remission for about 80 percent of the several dozen severely depressed, treatment-resistant individuals involved in the trials. SAINT is an accelerated and intensified form of rTMS (repetitive transcranial magnetic stimulation), which has been widely used to treat depression since its approval in 2008. Unlike conventional rTMS, SAINT is individually targeted for each patient. Patients also receive stimulation in much shorter treatment sessions, lasting only a few minutes, compared with 37 minutes in conventional rTMS. One of the chief innovations of SfaAINT is to deliver 10 stimulation sessions per day over just 5 days (vs. one session for 5 days a week over 4-6 weeks in rTMS). SAINT sessions are separated by an interval of 50 minutes “to build upon one another to amplify the antidepressant effect,” Dr. Williams has explained.

Now, Anish Mitra, Ph.D., a postdoctoral investigator in the Stanford laboratory of BBRF Scientific Council member and two-time grantee Karl Deisseroth, M.D., Ph.D., and a team that includes his Stanford co-mentor Dr. Williams and Marcus E. Raichle, M.D., 2004 BBRF Goldman-Rakic Prize winner, have used Dr. Mitra’s innovative method of analyzing data from fMRI functional brain scans to probe how, why, and for whom SAINT works.  

As a doctoral student in Dr. Raichle’s lab at Washington University, St. Louis, Dr. Mitra developed a mathematical tool to analyze fMRI scans, which show areas of the brain in which large numbers of neurons are being activated. In the new study, resting-state fMRI (rs-fMRI) was used, which shows activity when the brain is not burdened with any specific task.  Dr. Mitra’s analytical tool makes it possible to identify tiny differences in timing between the activation of different brain areas. Conventional analysis is not designed to reveal this temporal dimension. Differences in the timing of activation can reveal the direction in which information is flowing between brain regions.  

The team used rs-fMRI scans of 33 severely depressed patients who took part in SAINT clinical trials—scans made before treatment began and after it ended. The same kind of scans from 85 healthy controls were used for comparative purposes. These latter scans revealed that in the undepressed brain, an area called the anterior insula, which has the role of integrating information about bodily sensations, sends signals to the anterior cingulate cortex (ACC), one of the regions that regulates emotions.  

But analysis of the SAINT patient scans showed that in about three-fourths of patients, this “normal” information flow was reversed. The ACC was sending signals to the anterior insula. The more severe an individual’s depression symptoms, the greater the proportion of signals between the two areas that were flowing the wrong way.

When SAINT patients were treated, the flow of neural activity changed—now moving from the anterior insula to the ACC—as is seen in undepressed people. The team also was able to determine that those patients with the highest depression scores pre-treatment were those who were most likely to benefit from SAINT.  

In a paper in Proceedings of the National Academy of Sciences reporting their results, the team was careful to note that the biomarker they discovered regarding the flow and timing of signaling applies specifically to signaling within the brain’s “salience network”—a large network spanning the ACC, the anterior insula, the lateral prefrontal cortex, and the tempoparietal junction. This network is involved in processing emotions and evaluating one’s internal state. The team’s analysis points to the dorsal portion of the ACC as a “major hub” in the salience network, whose ”early signaling,” i.e.,  prior to signaling it should be receiving from the anterior insula, appears to be directly tied to major depression symptoms. 

It is important to recognize that not every patient receiving SAINT has a remission, although in those helped most dramatically, the direction of information flow between the ACC and anterior insula was reversed, the evidence indicated. Equally important, the scans used in the new analysis were those of individuals with severe and treatment-resistant depression. Depression is “heterogeneous”—it affects patients in a large number of ways, with symptoms varying widely over the total population of depressed people. It is likely that there are multiple mechanisms involved in depression symptoms, involving other brain regions. SAINT may be more or less effective in a broader population of patients with varying manifestations of major depression.

The research can proceed in many different directions, the team notes. Since stimulation of other brain areas has been found to relieve depression symptoms in some patients (SAINT is applied directly over a part of the cortex called the dorsolateral prefrontal cortex, or DLPFC), it will be necessary to determine if other mechanisms in addition to the “ACC-salience network” mechanism are involved. In other words, have they pinpointed a unique subtype of severe, refractory major depression? Or is the finding more generally applicable in depression?

Another of the interesting questions to be explored in future research is whether noninvasive stimulation of other areas—for example, the insula—might also have the effect of reversing the “wrong-way” flow of information discovered in the current analysis.