Grant: Project Grant

Major depressive disorder is a common and disabling illness. Although many people improve with medication or psychotherapy, a substantial group continues to experience significant symptoms despite multiple treatments. This condition, known as treatment-resistant depression (TRD), causes major personal suffering and places a high burden on families and the health-care system. There is a clear need for new and more precise treatment approaches. Brain imaging research suggests that TRD may involve abnormal communication within large brain networks. One network of particular interest is the salience network, which helps the brain detect and respond to important emotional and environmental information. Recent studies using advanced, longer-duration brain scans have shown that in some people with depression, this network appears enlarged and overly connected. This measurable brain feature may help identify a subgroup of patients who could benefit from targeted brain stimulation. This study will test a personalized, non-invasive brain stimulation technique called low-intensity focused ultrasound (FUS). FUS can reach deeper brain regions than other non-invasive methods and may help reduce abnormal over-connection within the salience network. Participants will first undergo advanced brain imaging to determine whether they have the salience-network pattern. Those who meet this criterion will be randomly assigned to receive either active FUS or a carefully matched sham (placebo) procedure, with neither participants nor evaluators knowing which was given. We will examine whether FUS changes brain network connectivity and whether these changes are associated with improvement in depression symptoms. This pilot study will also evaluate safety and feasibility, informing a larger future clinical trial.