Longitudinal assessment of the neuroanatomical consequences of deep brain stimulation: Application of fornical DBS in an Alzheimer's mouse model.

ABSTRACT

Following its success in the treatment of refractory movement disorders, deep brain stimulation (DBS) is currently under clinical investigation as a possible treatment for several neuropsychiatric disorders, including Alzheimer's disease (AD). DBS's mechanism of action, delivery regimen, optimal brain target, and timeline of behavioural and neuroanatomical outcomes are all open fields of investigation. There is a critical need to develop methodologies that allow us to examine the time course of both behavioural changes and neuroanatomical remodelling in response to DBS. Here we present a proof-of-concept methodology for DBS experiments which incorporates both brain imaging and behaviour in a longitudinal fashion. We implanted triple transgenic AD mouse models (expressing mutations for both amyloid and tau) with custom magnetic resonance imaging (MRI)-compatible, carbon based electrodes. Mice received DBS or sham stimulation to the fornix (a critical white matter node in the brain's memory circuit) for 1 h (100 Hz, 100 µs pulses, 100 µA). Treatment was followed with an adapted Morris water maze (to test learning and memory; performed weekly) and structural MRI (to assess neuroanatomy; 3 days before and 3 days after DBS with a 6 week follow-up). The acute DBS treatment improved learning and long term memory in a delayed, sex specific, and transient manner relative to sham-stimulated controls. Significant, persistent, volumetric changes were seen in diverse brains structures, also heavily mediated by sex. We believe this methodology may be used as a template for DBS-related experimentation and will encourage preclinical studies to use longitudinal designs.