It is known that damage to certain brain circuits can cause specific neuropsychiatric symptoms. But can targeting those particular circuits with therapeutic stimulation modulate the symptoms? A recent study led by Brigham and Women’s Hospital’s Michael D. Fox, MD, PhD, principal investigator and director of the Center for Brain Circuit Therapeutics, and Shan H. Siddiqi, MD, MBBS, corresponding author and a neuropsychiatrist at the center, answers that crucial question in the affirmative.
Dr. Fox believes the center’s interdisciplinary makeup — with faculty from neurology, psychiatry, neurosurgery and neuroradiology — gives it a strong foundation for tackling complex neuropsychiatric challenges.
“This paper exemplifies what you can do when you collaborate across disciplines, departments and even institutions,” he says. “I think the Brigham is doing that better than pretty much anybody else.”
In the study, published in Nature Human Behaviour, the team looked at depression severity after brain lesions, transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) across a total of 14 datasets. The investigators showed it is possible to map out depression based on the location of disease-causing lesions, TMS sites that relieve depression and DBS sites that either cause or relieve depression. They also found that all of these sites converge on one common circuit.
“That gives us a very, very strong link between the circuit that we identified and depression,” Dr. Fox says. “Also, it showed, for the first time, that you can use lesions that cause a symptom to identify a brain circuit that is an effective therapeutic target across multiple different types of brain stimulation.”
Collaboration Crossing Institutions and Countries
This paper was the product of a wide-ranging collaboration spanning 14 teams at multiple institutions across six countries. The researchers’ aim was to discover viable therapeutic targets for neuropsychiatric disorders. Meeting this goal has proven difficult, especially for psychiatric conditions. For instance, looking for imaging correlates of depression on MRI scans is problematic because these correlates may not be causally involved in the disease.
“This issue of causality is critical,” Dr. Fox says. “If the correlate is causing the disease, that’s great — maybe you have the right target. But if it’s compensating for the disease, it could be the worst possible target. You could intervene on that spot in the brain but make no progress in treating the disease or even make symptoms worse.”
The top causal source of information for mapping out symptoms is a brain lesion, according to Dr. Fox. With lesions, there is a causal link between the location of brain damage and the resulting symptom. TMS and DBS are other important sources — i.e., there is a causal link between the location of brain stimulation and symptom change.
Based on their analysis of brain lesions (n=461, five datasets), TMS (n=151, four datasets) and DBS (n=101, five datasets), the researchers found all three of these causal sources of information triangulate on a single brain circuit for depression.
“We showed that a) you can identify a circuit based on lesions causing a symptom, and b) brain stimulation sites that hit that circuit are the ones that best improve that symptom,” Dr. Fox says. “This convergent causal mapping lets you target the circuit in question in a very powerful way. For example, we can now take the circuit we identified, determine the exact spot of the brain that’s part of that circuit and hold our TMS coil over it to treat depression.”
Another key takeaway concerns the nature of brain stimulation treatment. A controversial, longstanding hypothesis has offered that TMS and DBS are radically different in nature and should be used to target different parts of the brain. Dr. Fox has had a contrasting hypothesis: You can target the same circuit with different forms of brain stimulation, whether that’s a non-invasive modality like TMS or an invasive modality like DBS.
“This is our strongest evidence to date showing that TMS and DBS really do converge on the same brain circuit, and no matter what neuromodulation technology or treatment you’re using, you’ve got to hit that circuit to have therapeutic benefit,” Dr. Fox says.
Finding New Targets for Other Neuropsychiatric Disorders
Moving forward, Dr. Fox and his colleagues plan to use these results to improve brain stimulation treatments and apply the same causal mapping approach to find better treatment targets for other neuropsychiatric symptoms and disorders.
For example, one ongoing effort involves studying patients who received DBS for Parkinson’s disease. Based on the circuit to which the electrodes are connected, investigators may be able to pinpoint patients who are having depression as a side effect of their brain stimulation. They may also be able to identify patients at risk of DBS-induced depression and then reprogram the electrodes to treat the depression. This work is currently in the validation phase, but clinical trials could start soon.