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A new study published in the Journal of Nature Human Behaviour looked at how brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease.

“The study is about brain circuitry in depression,” study author, Dr. Shan H. Siddiqi told us. “We were hoping to find if modulating specific brain circuits (with brain damage or brain stimulation) can causally modify depression severity.”

Researchers hypothesized that they would find a common “depression circuit” that is connected to lesions that cause depression, transcranial magnetic stimulation (TMS) sites that improve depression, and deep brain stimulation (DBS) sites that modify depression, across 14 different datasets.

“I chose this topic because it helps us learn about cause and effect in the brain, rather than just looking at incidental correlations,” Dr. Siddiqi told us. “By studying causality, we can identify better treatment targets.”

Across 14 existing datasets (713 patients), researchers looked at the connectivity of lesions, TMS sites, and DBS sites using the human connectome, a normative “wiring diagram” of the human brain. They compared the connectivity of sites that modify depression versus sites that don’t modify depression.

“As hypothesized, we found a common circuit that is connected to lesions that cause depression, transcranial magnetic stimulation (TMS) sites that improve depression, and deep brain stimulation (DBS) sites that modify depression,” Dr. Siddiqi told us. “This was true across multiple neuropsychiatric disorders that can cause depression (primary major depression, stroke, brain injury, Parkinson’s, and epilepsy). Stimulation sites connected to the circuit led to greater improvement in depression.”

Dr. Siddiqi was surprised by the consistency of the results across different datasets and different diagnoses. He explained that in the past, neuroimaging research has yielded very inconsistent and unreliable results, especially in psychiatric illnesses. This has led to a so-called “reproducibility crisis” which makes it hard for researchers to translate their results to the real world.

It’s unheard of to find consistency across 14 datasets and three different modalities (TMS, DBS, and lesions). In fact, he didn’t expect it to work, but was convinced to try it.

“When we found such consistent results, I was so astonished that I literally didn’t believe it,” Dr. Siddiqi told us. “I spent countless late nights trying to poke holes, until my wife told me that I have to sleep. Fortunately, we had a remarkable team of collaborators who provided 24 second opinions to confirm that it’s not only real, but also reveals better treatment targets in patients with depression and Parkinson’s, and possibly also other disorders.”

Perhaps the most interesting surprise was that clinical outcomes depended more on the target circuit than the underlying diagnosis. Researchers found a similar depression circuit whether the patient’s symptom change was caused by a brain lesion (due to traumatic brain injury, ischemic stroke, or brain bleed), therapeutic effects of brain stimulation in patients with depression, or adverse effects of brain stimulation in patients with epilepsy or Parkinson’s disease.

“We have a new approach to identify therapeutic targets for different neuropsychiatric disorders based on the location of brain lesions that can cause similar disorders,” Dr. Siddiqi told us. “We also showed quite conclusively that the effects of brain stimulation are not just due to placebo. Stimulating the right circuit is more effective than stimulating the wrong circuit.”