Transcranial magnetic stimulation (TMS) is a non-invasive, FDA-approved therapy that uses brief magnetic pulses to treat depression, particularly in patients who do not respond to medication. Yet scientists have long struggled to understand how it works at the level of brain cells and circuits.
Now, researchers at UCLA Health have opened that black box.
In a study published in Cell, a collaborative team out of the UCLA Neuromodulation Division reported the first preclinical model showing how a fast-acting form of TMS physically repairs brain circuits disrupted by stress to produce antidepressant effects. Remarkably, TMS selectively targeted specific brain cells to restore a disrupted communication channel in the brains of mice. The findings could lead to brain stimulation therapies that are more effective, precise and longer lasting, not only for depression, but potentially for a wide range of neurological and psychiatric disorders.
The study was co-led by Dr. Scott Wilke, assistant professor of psychiatry and the Penske Family Chair in Neuromodulation at UCLA Health, and Dr. Laura DeNardo, associate professor of physiology in the David Geffen School of Medicine at UCLA
"This work brings together what we see in the clinic with the kind of cellular-level insight you can only get from advanced neuroscience tools", said Wilke, who is also a psychiatrist with the UCLA TMS Clinical and Research Service. "For the first time, we can see exactly which brain cells are changed by this rapid treatment and how that restoration supports recovery of depression-related behaviors.
In repetitive transcranial magnetic stimulation (rTMS), pulsed electromagnetic fields are delivered through a coil placed on the scalp to focally stimulate brain activity. While effective, standard rTMS protocols typically require daily treatments over 6 weeks or longer.
In recent years, clinicians have developed accelerated intermittent theta burst stimulation (aiTBS), which compresses treatment into just five days and can produce rapid relief of depressive symptoms. Despite growing clinical use, the biological basis of these fast and long-lasting effects remained largely unknown.
To investigate this, the UCLA team collaborated with scientists at the National Institutes of Health to invent a novel method that enables them to stimulate the mouse brain in a way that is similar to how patients are treated in the clinic. Using mice exposed to chronic stress to simulate depression, the researchers were able to stimulate awake animals while monitoring brain activity in real time.
The researchers discovered that chronic stress caused neurons in the prefrontal cortex to lose dendritic spines, which are tiny protrusions that support synaptic communication between brain cells. This loss of synaptic structures was observed across multiple neuron types.
They found just one day of aiTBS restored these lost connections and led to enhanced activity during depression-related behaviors but only in a specific class of neurons known as intratelencephalic (IT) neurons. Other neighboring neuron types were largely unaffected.
"We initially thought TMS might broadly affect the prefrontal cortex, but instead the effects were surprisingly precise," said Michael Gongwer, the study's first author and an MD-PhD student at UCLA Health. "Seeing lost synaptic structures re-emerge and then seeing those same neurons regain activity during behavior was incredibly exciting"
When the researchers selectively blocked IT neuron activity during stimulation, the antidepressant effects disappeared, demonstrating that these neurons are essential for the therapy's behavioral benefits.
"Stress disrupts the structural scaffolding neurons rely on to communicate," said DeNardo. "By restoring those structures in IT neurons, the stimulation re-engages circuits that support adaptive behavior."
The researchers observed rapid improvements in stress-related behaviors within 24 hours of treatment. Importantly, these therapeutic effects on behavior persisted for at least one week after only a single day of stimulation and were accompanied by stable structural changes in IT neurons.
"What's striking is that this isn't just a temporary shift in activity," Wilke said. "The treatment restores neuronal structure in a way that allows normal circuit function and behavior to recover."
While animal models cannot fully capture the complexity of human depression, the study provides some of the strongest evidence to date for how brain stimulation can rapidly produce therapeutic effects at the cellular and circuit level.
Beyond depression, TMS is being used for disorders including chronic pain, OCD, PTSD, and tinnitus, which are all conditions which arise from dysfunction in specific brain circuits. This research points towards opportunities to make neuromodulation treatments even more effective.
"Every patient is unique," Wilke said. "By studying these treatments in mice, we can systematically test how different stimulation parameters reshape brain circuits, which may ultimately help us tailor neuromodulation therapies to individual patients."
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Journal reference:
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