Intense magnetic pulses used on the scalp to activate the mind can swiftly alleviate numerous deeply despondent individuals unresponsive to typical therapies. However, the mechanism through which transcranial magnetic stimulation, the name given to this procedure, counteracts depression has long remained an enigma. Presently, a study overseen by Stanford Medicine researchers has revealed that the treatment operates by reversing the flow of atypical brain signals.
Moreover, the discoveries imply that retrograde patterns of neural functioning amid crucial brain regions might serve as a biomarker for aiding in the diagnosis of depression.
"The primary conjecture has been that TMS has the potential to modify the trajectory of neural activity within the brain," remarked Anish Mitra, MD, PhD, a postdoctoral fellow in psychiatry and behavioral sciences. "However, to be candid, I held a fair amount of skepticism. I was eager to put it to the test."
Mitra possessed the perfect instrument for the task. During his time as a graduate student at Washington University in Saint Louis, working under the guidance of Mark Raichle, MD, he devised a mathematical tool capable of scrutinizing functional magnetic resonance imaging (fMRI) data, which is frequently employed to identify active regions within the brain. The novel analysis technique hinged on detecting subtle temporal disparities in the activation of various brain areas, thereby unveiling the direction of said activity.
In the study published on May 15 in the Proceedings of the National Academy of Sciences, Mitra and Raichle joined forces with Nolan Williams, MD, an associate professor of psychiatry and behavioral sciences. Dr. Williams and his team have been at the forefront of utilizing personalized magnetic stimulation tailored to the unique brain anatomy of each patient in order to address severe depression. This innovative treatment, known as Stanford Neuromodulation Therapy (SNT), incorporates cutting-edge imaging technologies to guide the application of high-dose magnetic pulses that can modulate brain activity associated with major depression. In comparison to traditional TMS, which typically involves daily sessions spanning several weeks or months, SNT follows an accelerated schedule with 10 daily sessions over a period of just five days. This accelerated approach aims to expedite the therapeutic process.
"This was the ideal examination to ascertain whether TMS possesses the capacity to alter the dynamics of signal propagation within the brain," expressed Mitra, who serves as the lead author of the study. "If this experiment fails to demonstrate it, then it is unlikely that anything else will."
Raichle and Williams are senior authors of the study.
Timing is everything
The research team enlisted the participation of 33 individuals diagnosed with treatment-resistant major depressive disorder. Out of these, 23 patients underwent SNT treatment, while the remaining 10 underwent a sham treatment that replicated SNT but without the actual magnetic stimulation. The data from these patients were then compared to the data of 85 healthy individuals without depression, serving as the control group.
Upon analyzing the fMRI data encompassing the entire brain, a particular connection emerged as significant. In a healthy brain, there exists a connection between the anterior insula, a region responsible for integrating bodily sensations, and the anterior cingulate cortex, which governs emotions.
Mitra explained, "One way to conceptualize it is that the anterior cingulate cortex receives this information regarding the body, such as heart rate or temperature, and then makes decisions on how to feel based on this amalgamation of signals."
However, in approximately 75% of the participants with depression, there was a notable reversal in the usual pattern of activity: the anterior cingulate cortex exhibited a tendency to send signals to the anterior insula. Furthermore, the severity of the depression correlated with a higher proportion of signals traveling in this reversed direction.
Mitra remarked, "What we observed is that the roles of sender and receiver in this relationship appear to hold significant importance when it comes to determining whether someone is experiencing depression."
"It's as if you have already predetermined how you will feel, and then all your sensory perceptions are filtered through that predetermined mood," he explained. "The mood becomes the primary factor influencing your perception."
"That aligns with the perspective of many psychiatrists regarding depression," he added. "Even experiences that would typically bring joy to a patient no longer elicit any pleasure."
When depressed patients underwent SNT treatment, the flow of neural activity within their brains transitioned back to the normal direction within a week. Remarkably, this shift in neural activity coincided with a notable improvement in their depressive symptoms, signifying a lifting of their depression.
The individuals who experienced the most severe depression, characterized by the highest degree of misdirected brain signals, were found to be the ones most likely to benefit from the treatment.
"We are capable of reversing the abnormal spatio-temporal patterns, resulting in individuals' brains resembling those of normal, healthy controls," stated Williams.
A biomarker for depression
One of the challenges in treating depression has been the limited understanding of its underlying biological mechanisms. When a patient presents with a fever, various tests can be conducted to identify the cause, such as bacterial or viral infections, enabling appropriate treatment options. However, when it comes to patients with depression, there are no equivalent diagnostic tests available to determine the underlying factors and guide treatment decisions.
"This is the first instance in the field of psychiatry where this specific alteration in biology, referring to the flow of signals between these two brain regions, can predict the corresponding change in clinical symptoms," explained Williams.
Williams pointed out that not all individuals with depression exhibit this abnormal flow of neural activity, and it may be infrequent in cases of less severe depression. Nevertheless, it holds significant potential as an essential biomarker for guiding the selection of appropriate treatments for the disorder. He explained, "The fMRI data, which enables precise treatment with SNT, can be utilized both as a biomarker for depression and as a means of personalized targeting to address its underlying cause."
"When we encounter a person with severe depression, we can examine this biomarker to determine the likelihood of their positive response to SNT treatment," stated Mitra.
"Behavioral conditions such as depression have posed challenges in terms of capturing them through imaging techniques because they involve the intricate dynamics and relationships between different brain regions," expressed Raichle, a researcher with over four decades of experience in brain imaging. "It is remarkably promising that the current technology is advancing towards addressing the complexity of the problems we seek to comprehend."
The researchers intend to replicate the study using a larger cohort of patients. Additionally, they encourage others to adopt their analytical technique to unveil further insights into the direction of brain activity concealed within fMRI data. Mitra remarked, "As long as you possess high-quality, pristine fMRI data, you can investigate this characteristic of the signals."