title: Fornix deep brain stimulation circuit effect is dependent on major excitatory transmission via the nucleus accumbens.
abstract: BACKGROUND
  Deep brain stimulation (DBS) is a circuit-based treatment shown to relieve symptoms from multiple neurologic and neuropsychiatric disorders. In order to treat the memory deficit associated with Alzheimer's disease (AD), several clinical trials have tested the efficacy of DBS near the fornix. Early results from these studies indicated that patients who received fornix DBS experienced an improvement in memory and quality of life, yet the mechanisms behind this effect remain controversial. It is known that transmission between the medial limbic and corticolimbic circuits plays an integral role in declarative memory, and dysfunction at the circuit level results in various forms of dementia, including AD. Here, we aimed to determine the potential underlying mechanism of fornix DBS by examining the functional circuitry and brain structures engaged by fornix DBS.
  
  
  METHODS
  A multimodal approach was employed to examine global and local temporal changes that occur in an anesthetized swine model of fornix DBS. Changes in global functional activity were measured by functional MRI (fMRI), and local neurochemical changes were monitored by fast scan cyclic voltammetry (FSCV) during electrical stimulation of the fornix. Additionally, intracranial microinfusions into the nucleus accumbens (NAc) were performed to investigate the global activity changes that occur with dopamine and glutamate receptor-specific antagonism.
  
  
  RESULTS
  Hemodynamic responses in both medial limbic and corticolimbic circuits measured by fMRI were induced by fornix DBS. Additionally, fornix DBS resulted in increases in dopamine oxidation current (corresponding to dopamine efflux) monitored by FSCV in the NAc. Finally, fornix DBS-evoked hemodynamic responses in the amygdala and hippocampus decreased following dopamine and glutamate receptor antagonism in the NAc.
  
  
  CONCLUSIONS
  The present findings suggest that fornix DBS modulates dopamine release on presynaptic dopaminergic terminals in the NAc, involving excitatory glutamatergic input, and that the medial limbic and corticolimbic circuits interact in a functional loop.
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA; Mayo Graduate School, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Erika K
authors.initials: EK
authors.lastname: Ross
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA; Department of Neurosurgery, Bundang CHA Hospital, CHA University School of Medicine, Seongnam, Korea.
authors.forename: Joo Pyung
authors.initials: JP
authors.lastname: Kim
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Settell
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA; Department of Neurosurgery, Ilsan Paik Hospital, College of Medicine, Inje University, Goyang, Korea.
authors.forename: Seong Rok
authors.initials: SR
authors.lastname: Han
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blaha
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: min.paul@mayo.edu.
authors.forename: Hoon-Ki
authors.initials: HK
authors.lastname: Min
authors.affiliation: Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: lee.kendall@mayo.edu.
authors.forename: Kendall H
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000818:Animals; D046690:Deep Brain Stimulation; D004298:Dopamine / Q000378:metabolism; D020712:Fornix, Brain / Q000502:physiology*; D006439:Hemodynamics / Q000502:physiology; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D009714:Nucleus Accumbens / Q000502:physiology*; D013552:Swine; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D004298:Dopamine
keywords: Deep brain stimulation; Dopamine; Fast scan cyclic voltammetry; Fornix; Functional magnetic resonance imaging; Nucleus accumbens