Study shows how rTMS treatments alter brain-wide neural connectivity in treatment-resistant depressed patients, a clue to predict who will benefit

Over the past decade, rTMS (repetitive transcranial magnetic stimulation), a form of noninvasive brain stimulation, has become a first-line treatment option for depressed patients, including those with dementia. major depressive disorder (MDD) who have not responded to several cycles of other antidepressant treatments.

rTMS helps reduce symptoms of depression in a significant percentage of patients with treatment-resistant MDD – estimates range from one-third to one-half. This has enormous beneficial impacts, as treatment-resistant MDD patients are often handicapped by their condition and have a high risk of suicide.

Why does rTMS help reduce symptoms of depression and is there a way to determine before treatment who is most likely to benefit? The answer about its mechanism of action is uncertain, but experts have long believed that the magnetic pulses that rTMS delivers just below the scalp to an area of ​​the brain called the dorsolateral prefrontal cortex (DLPFC) have the effect of altering the plasticity of neurons in this brain. region and possibly in other regions to which it is linked.

Generally speaking, altering plasticity means altering the strength of connections between brain regions, making them stronger or weaker. (Depending on the context, either is potentially therapeutic.) If rTMS works by altering neuroplasticity, it would support an important theory about the causes of depression. The “neuroplasticity hypothesis” of depression proposes that dysfunction of neuronal plasticity is at least one of the important underlying mechanisms that cause illness.

A research team led by Fidel Vila-Rodriguez, MD, Ph.D., of the University of British Columbia, wanted to learn more about the therapeutic action of rTMS and its relationship to plasticity. They investigated how a single rTMS application alters neuroplasticity, inferred from alterations in functional connectivity, both at the level of the processing target, the DLPFC, but also at the brain scale. They also sought to discover whether these patterns of connectivity after a single session of rTMS can be used to predict which patients with MDD are most helped by a subsequent 4-week course of rTMS.

They reported their results in the American Journal of Psychiatry. Sophia Frangou, MD, Ph.D., 2019 BBRF Colvin Prize Winner, 2008 BBRF Independent Researcher and 2002 BBRF Young Investigator; And Sean Nestor, MD, Ph.D., a young BBRF 2022 researcher, were part of the team. Ruiyang Ge, Ph.D., was the first author of the article.

The researchers recruited 52 patients with treatment-resistant MDD for a trial to measure the impact of a 4-week course of rTMS. Among them, 38 patients (26 women; mean age 42 years) agreed to participate in a separate survey involving a single rTMS session before the start of treatment. These patients received this first session of rTMS inside a scanner that generates functional MRI images of brain activity in real time. The patients then underwent a 4-week rTMS treatment.

The researchers found that rTMS stimulation of the right DLPFC “induced acute generalized alterations in functional connectivity” and that these changes “predicted clinical outcomes after 4 weeks of rTMS treatment”.

The team made a number of interesting observations in addition to this conclusion. They found “widespread connectivity changes even in [brain] regions without known functional or anatomical connections” with the site targeted in the treatments, the DLPFC. Importantly, they noted, “it adds to the evidence that rTMS has the potential to influence the functional organization of the brain beyond what is predicted” by the DLPFC’s already known connectivity model.

This, in turn, suggests to the team that one of the reasons for rTMS’s effectiveness in depression is its ability to alter connectivity at the “macro level”, i.e. in sites widely dispersed throughout the brain that may be implicated in depression in different ways. various symptoms (eg, low mood, suicidal tendencies, difficulty experiencing pleasure). In general, the changes in connectivity noted after rTMS were reductions in baseline connectivity, not increases.

It was also interesting to note that the connectivity changes observed after an initial rTMS session, although significant, were not long-lasting. This suggests to the team why repeated stimulation sessions, longer sessions, or sessions delivering a greater number of magnetic pulses are necessary to generate clinical improvement from rTMS therapy.

Finally, the team commented on the predictive value of the functional connectivity changes they observed after the first rTMS session. There was an association between the level of connectivity changes at this first session and treatment response after 4 weeks of treatment. Patients with the most pronounced changes in the initial session tended to benefit more from the full treatment. For this reason, the team proposes that preliminary fMRI reading of how rTMS alters plasticity in the brain could be used as an indicator of a patient’s ability to respond to comprehensive treatment.

The results of this study now need to be replicated in larger cohorts including a control group and in trials comparing the results of targeting the right DLPFC with other rTMS targets, the team noted.