A newly-discovered mechanism could contribute to the therapeutic effects of deep brain stimulation

Deep brain stimulation (DBS) is a surgical procedure that entails the delivery of high-frequency electrical impulses to specific regions of the brain, via surgically implanted electrodes. While it requires an invasive surgical procedure, DBS can alleviate symptoms of various psychiatric and neurological disorders, including Parkinson’s disease, epilepsy, Tourette syndrome and severe obsessive-compulsive disorder (OCD).

Due to its invasive nature, this procedure is typically reserved for patients who do not respond well to less-invasive treatment strategies. Although its therapeutic potential is well-documented, the neurobiological mechanisms through which it eases neuropsychiatric symptoms remain poorly understood.

Researchers at National Institutes of Health in Durham, N.C., U.S., recently carried out a study on mice aimed at better understanding how DBS affects the brain and shedding light on the processes that might underpin its therapeutic value.

Their findings, published in Nature Neuroscience, suggest that the selective inhibition of neurons in a specific brain area mediates the therapeutic effects of this invasive procedure, while also proposing an alternative, less-invasive strategy that might yield similar results.

“We show that high-frequency DBS of the subthalamic nucleus (STN), a common target for Parkinson’s disease (PD), activates afferent axons while inhibiting STN neurons,” wrote Jicheng Li, Jingheng Zhou and their colleagues in their paper. “These contrasting presynaptic and postsynaptic effects arise from a decrease in local neurotransmitter release with a larger decrease in glutamate than GABA, shifting the excitation/inhibition balance toward inhibition.”

As part of their study, the researchers used DBS to deliver high-frequency electrical pulses to the STN, specifically in mice that exhibited Parkinson’s disease-like symptoms. The STN is a small structure in the brain known to regulate movement, which is commonly electrically stimulated in patients with drug-resistant Parkinson’s disease.

The researchers looked at how stimulating the STN affected both incoming nerve fibers (i.e., afferent axons) and neurons within the brain region. They also measured changes in the release of specific neurotransmitters, such as glutamate and GABA.

Interestingly, they found that DBS activated afferent axons and inhibited STN neurons, while also significantly reducing the release of glutamate. Notably, the mice’s motor function appeared to improve, with a substantial reduction of Parkinson’s disease-like behaviors.

Inspired by these findings, the researchers subsequently tried to replicate the effects of DBN on STN neurons using noninvasive, chemogenetic techniques. They found that the chemogenetic inhibition of STN neurons yielded very similar results, while the activation of STN neurons did not.

“Chemogenetic inhibition, but not excitation, of STN neurons mimics the therapeutic effects of DBS in 6-OHDA-lesioned PD mice,” wrote the authors.

“Acute and chronic bilateral chemogenetic STN inhibition restores motor function in a progressive PD mouse model. These findings suggest that inhibition of STN, caused by differential depression of glutamatergic and GABAergic synapses, is a key mechanism of therapeutic DBS. ‘Chemogenetic DBS,’ direct chemogenetic inhibition of postsynaptic neurons, may offer a less invasive and more affordable alternative to electrical DBS for PD and other neurological disorders.”

In the future, the mechanism uncovered by this research team could be investigated further in studies involving rodents, primates and eventually even humans. This might eventually pave the way for the development of less-invasive and yet equally effective treatments for Parkinson’s disease, drug-resistant epilepsy and other disorders commonly treated with DBS.

© 2025 Science X Network