Subgenual Cingulate Deep Brain STIMulation for Apathetic Behavioral Variant FRONtotemporal Dementia

Frontotemporal dementia (FTD), the most common dementia in individuals younger than 60 years of age, has no disease-modifying treatment. Neuroimaging studies have revealed salience and default mode network dysfunction, frontotemporal atrophy and hypometabolism as pathophysiological hallmarks of behavioral variant FTD (bvFTD). A key brain structure affected by bvFTD is the subgenual cingulate (SGC), which serves as a hub for multi-axonal projections to and from the ventromedial prefrontal, dorsal anterior cingulate, orbitofrontal, and dorsolateral frontal cortices, and limbic structures.The disruption of these SGC projections in bvFTD result in the core clinical features of apathy, disinhibition, loss of empathy, compulsivity, hyperorality and loss of executive function. The central goal of this proposal is to use deep brain stimulation (DBS) for modulation of the SGC downstream projections to treat bvFTD. We hypothesize that SGC DBS will drive activity in the dysfunctional networks, reverse hypometabolism, and potentially improve symptoms. To determine the physiologic effects and mechanisms of SGC DBS, we will assess cerebral metabolism by FDG-PET, connectivity by rsfMRI and MEG, atrophy by volumetric MRI, and neurodegenerative and neuroinflammatory biomarkers. The safety and preliminary efficacy data obtained in these patients will inform the possible future role of DBS in apathetic bvFTD.

Inclusion Criteria:Men and women aged 40-85 yearsDiagnosis of image-supported behavioral variant frontotemporal dementia according to NIC-FTD and NACC FTLD guidelinesApathy as one of the symptomsStable dose of baseline FTD medications for at least 3 monthsThe patient has an available caregiver or other appropriate knowledgeable informant who can reliably report on daily activities and function. The patient must also have a substitute decision maker, if different from caregiver, to sign the informed consent for participation in the study.Exclusion Criteria:Meets diagnostic criteria for other psychiatric diagnosisHas other major Central Nervous System (CNS) disease that impairs motor, sensory or cognitiveAlcohol or illegal substance dependence within last 12 monthsOther medical conditions which render anesthesia and surgery as unsafe as determined by neurosurgeonContraindications for MRI scanning, including implanted metallic devices (e.g., non-MRI-safe cardiac pacemaker or neurostimulator; some artificial joints metal pins; surgical clips; or other implanted metal parts), or claustrophobia or discomfort in confined spaces.Has a medical condition requiring a repetitive MRI body scanRequires chemotherapy for the treatment of malignancy or requiring chronic oral or intravenous (immunosuppressive or) steroid therapyIs unable to comply with study visit schedule and timelinePast significant intracranial surgeryA female lactating or of child-bearing potential, with a positive pregnancy test or not using adequate contraception.