Scientists from Stanford Medicine have made a breakthrough in understanding how transcranial magnetic stimulation (TMS) relieves severe depression in patients who haven’t responded to standard treatments. Their research, published in the Proceedings of the National Academy of Sciences, reveals that TMS works by reversing abnormal brain signals, thereby altering the flow of neural activity in the brain.
The study was led by Anish Mitra, MD, Ph.D., in collaboration with Mark Raichle, MD, and Nolan Williams, MD. Mitra, who developed a mathematical tool to analyze functional magnetic resonance imaging (fMRI) during his time as a graduate student at Washington University in Saint Louis, applied this technique to investigate the effects of TMS on brain activity.
The researchers utilized a personalized TMS approach called Stanford neuromodulation therapy (SNT), which involves delivering high-dose patterns of magnetic pulses tailored to each patient’s brain anatomy. Unlike traditional TMS, which requires daily sessions over an extended period, SNT utilizes an accelerated timeline of 10 daily sessions for five consecutive days.
By analyzing the timing and direction of neural activity in different brain regions, the team found that TMS with SNT has the capacity to change the flow of signals in the brain. This discovery challenges previous hypotheses and provides new insights into the mechanism behind TMS’s effectiveness in treating depression.
Moreover, the study suggests that the backward streams of neural activity between key brain areas could serve as a potential biomarker for diagnosing depression. This finding could have significant implications for the development of diagnostic tools and personalized treatments for patients with depression.
The researchers believe that their findings could lead to further advancements in TMS therapy and improve outcomes for individuals with severe depression.
Timing is everything
The research team recruited 33 participants diagnosed with treatment-resistant major depressive disorder for their study. Out of these, 23 individuals underwent Stanford neuromodulation therapy (SNT) treatment, while the remaining 10 received a sham treatment as a control group. The fMRI data of these patients were then compared with data from 85 healthy individuals without depression.
During the analysis of fMRI data across the entire brain, the researchers identified a significant connection. In a normal brain, the anterior insula, responsible for integrating bodily sensations, sends signals to the anterior cingulate cortex, which regulates emotions.
However, in 75% of the participants with depression, the usual flow of activity was reversed, with the anterior cingulate cortex sending signals to the anterior insula instead. The severity of the depression correlated with a higher proportion of signals traveling in the wrong direction.
This reversal of signals implies that individuals with depression have already determined how they will feel, and all sensory inputs are interpreted through that predetermined mood. As a result, even enjoyable experiences may fail to bring them pleasure.
However, when depressed patients received SNT treatment, the direction of neural activity shifted back to the normal pattern within one week, coinciding with an alleviation of their depression. Notably, those with more severe depression and a higher degree of misdirected brain signals were the ones who benefited the most from the treatment.
According to Nolan Williams, the treatment allowed them to reverse the abnormality in space and time, making the patients’ brain activity resemble that of healthy individuals.
Overall, these findings provide valuable insights into the mechanism of depression and the effects of SNT treatment. They suggest that by correcting the abnormal flow of neural activity, SNT can effectively alleviate depression in patients who have not responded to standard treatments.
A biomarker for depression
One of the challenges in treating depression has been the lack of understanding regarding its biological mechanisms. Unlike other medical conditions where specific tests can be performed to determine the appropriate treatment, there are no equivalent tests for depression.
However, the recent study conducted by the Stanford Medicine scientists has shed light on a potential breakthrough. They discovered that the abnormal flow of signals between two specific brain regions serves as a predictive biomarker for the change in clinical symptoms of depression. This finding has never been observed before in psychiatry and represents a significant advancement in understanding the biology of depression.
It is important to note that not all individuals with depression exhibit this abnormal flow of neural activity. It may be more prevalent in severe cases of depression and less common in milder forms. Nonetheless, it holds promise as a biomarker for triaging treatment options for depression.
The fMRI data, which allows for precise treatment using Stanford neuromodulation therapy (SNT), can be used both as a biomarker for diagnosing depression and as a means of personalized targeting to address the underlying causes of the disorder. By identifying this biomarker, clinicians can assess the likelihood of a positive response to SNT treatment in individuals with severe depression.
Traditional imaging techniques have struggled to capture behavioral conditions like depression due to the complexity of the relationships between different parts of the brain. However, advancements in technology are now enabling a deeper understanding of these complex problems.
The researchers aim to replicate their study with a larger group of patients and encourage other scientists to adopt their analytical technique to uncover further insights into the direction of brain activity hidden within fMRI data. By utilizing high-quality fMRI data, researchers can investigate this property of brain signals and gain a better understanding of depression and its treatment.