A first-of-its-kind study conducted as part of a randomized controlled clinical trial (ClinicalTrials.gov: NCT03642522) reported in the American Journal of Psychiatry on May 18, 2022, uncovers largescale changes in functional connectivity in the brain in patients with treatment-resistant depression who were administered targeted magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is used to treat patients with depression who do not respond to antidepressants, which is nearly 40% patients with major depression. In such patients, rTMS is directed at the right or left DLPFC (dorsolateral prefrontal cortex), which activates local and distant neurons, and affects symptoms related to depression such as mood, suicidal tendencies, social withdrawal, and anxiety.

The magnetic therapy involves delivering a painless magnetic pulse at a frequency of one Hertz using an electromagnetic coil placed against the patient’s scalp. Although found to be effective, the mechanistic underpinnings remain unclear.

In the research article titled,”Predictive value of acute neuroplastic response to rTMS in treatment outcome in depression: A concurrent TMS-fMRI trial,” a team of scientists including members from the Djavad Mowafaghian Centre for Brain Health (DMCBH) and the University of British Columbia (UBC), conducted functional magnetic resonance imaging (fMRI) on 26 female and 12 male outpatients with treatment-resistant depression to measure changes in functional connectivity upon rTMS. The goal of the study was to determine the value of fMRI-detected changes in predicting clinical response to treatment in these patients.

Fidel Vila-Rodriguez, MD, PhD, is senior author of the study.

“We wanted to know what happens to the brain when rTMS treatment is being delivered,” said Fidel Vila-Rodriguez, MD, PhD, an assistant professor in UBC’s department of psychiatry, researcher at DMCBH and senior author of the study. “Our findings suggest that rTMS might rely on the brain’s capacity for change (neuroplasticity) to be effective. It also suggests that the effects of rTMS on the brain are widespread beyond the focal area stimulated (functional network effects). This work provides a mechanistic explanation of what rTMS does to treat depression and supports the notion that for rTMS to treat depressive symptoms a distributed change in brain activity (network or circuit base) is necessary.”

Vila-Rodriguez and his team delivered one round of rTMS to the patients while they were inside an MRI scanner. MRI, a medical application of nuclear magnetic resonance (NMR), uses strong magnetic field gradients and radio waves to acquire high-contrast images of brain activity, enabling the researchers to record real time responses to rTMS.

Upon stimulating the DLPFC, the team found widespread, sharp and transient changes in functional connectivity, particularly in regions of the brain involved in regulating emotional responses to memory and motor control.

Following rTMS treatment for four weeks, the team again conducted fMRI on the participants and recorded regions that showed changes in functional connectivity. The team then assessed whether the activated regions recorded at the end of the treatment were associated with patients having fewer symptoms of depression. This analysis involved functional connectome-based predictive modeling to test their association with changes in the score on the Montgomery-Åsberg Depression Rating Scale (MADRS) after rTMS treatment.

Vila-Rodriguez said, “We found that regions of the brain that were activated during the concurrent rTMS-fMRI were significantly related to good outcomes.” He hopes mapping regions of the brain stimulated by rTMS could help determine how well a patient responds to rTMS treatments.

The team found strongest predictive associations in connections between prefrontal regions and motor, parietal, and insular cortices and between bilateral regions of the thalamus.

“By demonstrating this principle and identifying regions of the brain that are activated by rTMS, we can now try to understand whether this pattern can be used as a biomarker,” he said.

With financial support from the DMCBH, the Alzheimer’s Disease Research Competition, and the Canadian Institutes of Health Research (CIHR), Vila-Rodriguez’ team is now exploring how rTMS can be used to treat different neuropsychiatric disorders, including the use of rTMS to enhance memory in patients with early-onset Alzheimer’s disease, and whether the rTMS brain activation patterns is reflected in changes in heart rate.

“We are about start a study where we will use fMRI to guide where in the brain we treat patients with depression at the individual level (personalized targeting). These [locations in the brain] are called individualized functional targets,” said Vila-Rodriguez.

“How does rTMS work’ is one of the most frequent questions I get in clinic. Providing an accurate explanation and narrative to patients is critical,” added Vila-Rodriguez.