Late-life treatment resistant depression (LL-TRD) is a public health and clinical dilemma.~Older patients with TRD are: 1) at greater risk for morbidity from medications and ECT, and 2) more likely to require maintenance ECT (which carries risks of cognitive impairment and repeated exposure to general anesthesia), compared to younger depressed patients. There is great need to develop targeted and safe treatments for those with LLTRD.~Deep brain stimulation (DBS) is a neurosurgical intervention with potential to become a treatment option for appropriately selected patients with LL-TRD. To date, the subcallosal cingulate white matter (SCCWM) is the DBS target with the most clinical, safety, and neurophysiologic data supporting therapeutic efficacy. The SCC is considered a governor for a network implicated in the processing of negative emotions and symptoms of depression. Furthermore, structural and functional impairments of the SCC and connected network structures are associated with LLD, supporting its potential as a target for DBS in older adults.~The overarching aim for this project is to develop DBS of the SCCWM for LL-TRD using an experimental medicine approach in which the investigators will program the device based both on 1) a neurophysiologic measure of target engagement and 2) safety (defined as lack of neuropsychiatric worsening and stable neurocognition). The proposed biomarker of target engagement is theta cordance (TC), a composite of absolute and relative theta power that is strongly correlated with regional neural metabolism. The hypothesis is that TC will increase during DBS is based on the observation of increased frontal TC during DBS in combination with PET data, which showed increased metabolism in frontal cortical structures in responders to DBS.~The investigators will use magnetoencephalography to measure TC during DBS and then will adjust stimulation settings to optimize target engagement over the course of the study, in response to observed increases in TC. Adding to the novelty of the project is use of personalized tractography to guide precise electrode placement in the area of the SCCWM which contain white matter tracts to mood-relevant frontal and subcortical nuclei.~During the two years of this open-label project the investigators will implant 6 patients. For each subject, over the course of 6 months, the investigators will ascertain the dose range effect of escalating DBS stimulation parameters on both TC and measures of safety.
This is an open label study with a sample size of 6 to develop deep brain stimulation of the subcallosal cingulate white matter(SCCWM) for late life depression using an experimental medicine approach in which the investigators will program the device based both on 1) a neurophysiologic measure of target engagement and 2) safety (defined as lack of neuropsychiatric worsening and stable neurocognition).