Turning down the volume: brain stimulation and neural silencing.

What does the Cochrane review say about rTMS and tDCS?

The most studied non-invasive approaches are repetitive transcranial magnetic stimulation (rTMS), which delivers magnetic pulses through the scalp, and transcranial direct current stimulation (tDCS), which applies a weak electrical current. Both aim to shift activity in brain regions involved in pain processing, most often the motor cortex.

The most comprehensive summary is the Cochrane review led by Neil O'Connell, updated in 2018 to include 94 trials with nearly 3,000 participants (O'Connell et al., 2018). Across 27 rTMS studies, stimulation reduced pain intensity by a small amount in the short term, roughly 0.4 points on a 10-point scale, or about 7 percent, which did not meet the threshold usually considered clinically important. High-frequency stimulation of the motor cortex showed a somewhat larger short-term effect, about 12 percent. The authors judged the evidence to be low or very low quality, largely because of small samples and difficulties with blinding.

Their conclusion was careful: there is very low-quality evidence that single doses of high-frequency motor cortex rTMS and tDCS may have short-term effects on chronic pain, but multiple sources of bias may have influenced those results. They called for larger, rigorous studies, especially of longer treatment courses.

Is the stimulation research improving?

Groups continue to refine targets and combinations. A 2024 analysis combined meta-analysis with brain connectivity data to map promising stimulation targets (Kong et al., 2024), and reviews have explored pairing brain stimulation with exercise (Cardenas-Rojas et al., 2020). The European Academy of Neurology has published guidelines on central neurostimulation for chronic pain (Cruccu et al., 2016).

Invasive options such as spinal cord stimulation are used in selected patients and have their own separate evidence base, which this page does not cover. Decisions about any form of stimulation belong with a pain specialist who knows your history.

What is neural silencing?

Neural silencing refers to experimental methods that make specific neurons less active. Two tools dominate:

• Chemogenetics introduces an engineered receptor into chosen neurons, usually with a harmless virus. The receptor does nothing until a specific drug is given; then it quiets those neurons. Common systems include DREADDs (designer receptors exclusively activated by designer drugs) and newer engineered ion channels.
• Optogenetics introduces light-sensitive proteins, so neurons can be switched on or off with light delivered through implanted fibers.

In animal research these tools have become essential for mapping pain circuits. A 2022 study in Science, for example, found that certain sounds reduced pain in mice by inhibiting signals from the auditory cortex to the thalamus, and that silencing those pathways with optogenetic or chemogenetic tools reproduced the effect (Zhou et al., 2022).

Researchers are also exploring silencing as a potential therapy. In 2023, a team led by John Wood at University College London used a chemogenetic channel called PSAM4-GlyR, activated by the existing drug varenicline, to silence a class of pain-sensing neurons in mice (Haroun et al., 2023). Activating the channel reversed pain behaviors in models of nerve injury and bone cancer pain without impairing motor coordination. A related study showed that a humanized version of the system reduced pain-related behavior in mice, remained effective months after delivery, and reduced hyperexcitability in human stem-cell derived sensory neurons carrying a mutation that causes an inherited pain disorder (Perez-Sanchez et al., 2023).

Has neural silencing been tried in people?

Only in the earliest safety studies. As of this writing, two early human trials are listed on ClinicalTrials.gov. One describes injecting a gene for the inhibitory hM4Di receptor into the anterior cingulate cortex, a brain region involved in the emotional side of pain, followed by oral clozapine to activate it, in people with refractory neuropathic pain (NCT06596681). Another, sponsored by Sangamo Therapeutics, is a phase 1/2 sham-controlled study of an intrathecal gene therapy designed to repress the Nav1.7 sodium channel in people with refractory pain from small fiber neuropathy (NCT06980948).

Should the goal be to switch pain off?

It is easy to be drawn to the idea of simply turning pain off. But pain is protective, and the goal of chronic pain care is not to eliminate all signaling. It is to restore a nervous system that is calibrated appropriately. Neural silencing research is valuable for understanding which circuits matter, and it may eventually yield treatments for the most severe conditions. For now, it is laboratory science with first-in-human trials just beginning.

Meanwhile, the approaches with the strongest evidence for most people with chronic pain, education, graded movement, exposure and psychological therapies, can also be thought of as ways to quiet an overprotective system, by changing what the brain has learned about threat. That is the thread running through this whole series, and through Karuna's program; see how it works.