Scientists Pinpoint the Brain Cells Behind TMS Rapid Antidepressant Effects

Depression affects hundreds of millions globally, and many patients do not respond to standard antidepressants. Repetitive transcranial magnetic stimulation has emerged as an effective alternative, with accelerated protocols like aiTBS producing antidepressant effects within days rather than weeks. Yet the biological mechanism behind these rapid effects has remained poorly understood, limiting further optimization of the therapy.

Researchers at UCLA developed a mouse model of rTMS designed to closely replicate the clinical aiTBS protocol, then exposed chronically stressed mice — which display depression-like behavioral deficits — to the treatment. Using fiber photometry, a technique that measures real-time neural activity in specific cell types, the team tracked two populations of prefrontal cortex neurons: intratelencephalic (IT) neurons, which connect within the cortex, and pyramidal tract (PT) neurons, which project to subcortical targets.

The key finding was a striking divergence between these two neuron types. During aiTBS and afterward, IT neurons showed persistently elevated activity, while PT neurons did not. Structural analysis confirmed that aiTBS reversed the stress-induced loss of dendritic spines — the physical connection points between neurons — specifically in IT neurons. No such recovery was observed in PT neurons.

To test causality, the researchers used chemogenetics to selectively silence IT or PT neurons during rTMS sessions. Blocking IT neuron activity completely abolished the antidepressant-like behavioral effects of aiTBS, while blocking PT neurons had no such impact. This demonstrates that IT neurons are not merely active bystanders but essential mediators of the therapeutic effect.

For clinicians and researchers, these findings offer a clear cellular target for refining brain stimulation therapies. Future interventions could be designed to selectively engage IT neuron circuits, potentially improving response rates and shortening treatment timelines. Caveats include the mouse model context and the abstract-only nature of the available data.