View article

Deep brain stimulation (DBS) to the fornix is an investigational treatment option for patients with mild Alzheimer’s Disease. Outcomes from randomized clinical trials have shown that cognitive function improved in some patients but deteriorated in others. One reason could be variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we analyzed a multi-center cohort of 46 patients with DBS to the fornix. Using normative structural and functional connectivity data, we demonstrate that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement (R = 0.45, p = 0.031). On a local level, the optimal stimulation site resided at the direct interface between these structures (R = 0.33, p = 0.016). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes (R = 0.38, p = 0.006). Findings were robust to multiple cross-validation designs and may now define an optimal network target which could subsequently guide refinement of DBS surgery and programming.