title: Deep brain stimulation of the ventromedial prefrontal cortex causes reorganization of neuronal processes and vasculature.
abstract: BACKGROUND
  Chronic high-frequency electrical deep brain stimulation (DBS) of the subcallosal cingulate region is currently being investigated clinically as a therapy for treatment of refractory depression. Experimental DBS of the homologous region, the ventromedial prefrontal cortex (VMPFC), in rodent models has previously demonstrated anti-depressant-like effects. Our goal was to determine if structural remodeling accompanies the alterations of brain function previously observed as a result of chronic DBS.
  
  
  METHODS
  Here we applied 6h of high-frequency bilateral VMPFC DBS daily to 8 9-week old C57Bl/6 mice for 5days. We investigated the "micro-lesion" effect by using a sham stimulation group (8 mice) and a control group (8 mice with a hole drilled into the skull only). Whole brain anatomy was investigated post-mortem using high-resolution magnetic resonance imaging and areas demonstrating volumetric expansion were further investigated using histology and immunohistochemistry.
  
  
  RESULTS
  The DBS group demonstrated bilateral increases in whole hippocampus and the left thalamus volume compared to both sham and control groups. Local hippocampal and thalamic volume increases were also observed at the voxel-level; however these increases were observed in both DBS and sham groups. Follow-up immunohistochemistry in the hippocampus revealed DBS increased blood vessel size and synaptic density relative to the control group whereas the sham group demonstrated increased astrocyte size.
  
  
  CONCLUSIONS
  Our work demonstrates that DBS not only works by altering function with neural circuits, but also by structurally altering circuits at the cellular level. Neuroplastic alterations may play a role in mediating the clinical efficacy of DBS therapy.
authors.affiliation: Cerebral Imaging Centre, Douglas Mental Health University Institute, Canada; Department of Psychiatry, McGill University, Canada; Department of Biomedical Engineering, McGill University, Canada. Electronic address: mallar@cobralab.ca.
authors.forename: M Mallar
authors.initials: MM
authors.lastname: Chakravarty
authors.affiliation: Division of Neurosurgery, Toronto Western Hospital, Canada; Behavioural Neurobiology Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada.
authors.forename: Clement
authors.initials: C
authors.lastname: Hamani
authors.affiliation: Program in Neuroscience and Mental Health, The Hospital for Sick Children, Canada.
authors.forename: Alonso
authors.initials: A
authors.lastname: Martinez-Canabal
authors.affiliation: Mouse Imaging Centre (MICe), The Hospital for Sick Children, Canada.
authors.forename: Jacob
authors.initials: J
authors.lastname: Ellegood
authors.affiliation: Mouse Imaging Centre (MICe), The Hospital for Sick Children, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Laliberté
authors.affiliation: Department of Psychiatry, University of Toronto, Canada; Behavioural Neurobiology Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada.
authors.forename: José N
authors.initials: JN
authors.lastname: Nobrega
authors.affiliation: Division of Neurosurgery, Toronto Western Hospital, Canada; Division of Neurosurgery, University of Alberta, Canada.
authors.forename: Tejas
authors.initials: T
authors.lastname: Sankar
authors.affiliation: Division of Neurosurgery, Toronto Western Hospital, Canada.
authors.forename: Andres M
authors.initials: AM
authors.lastname: Lozano
authors.affiliation: Program in Neuroscience and Mental Health, The Hospital for Sick Children, Canada; Department of Psychology, University of Toronto, Toronto, Canada; Department of Physiology, University of Toronto, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Frankland
authors.affiliation: Program in Neuroscience and Mental Health, The Hospital for Sick Children, Canada; Mouse Imaging Centre (MICe), The Hospital for Sick Children, Canada; Department of Medical Biophysics, University of Toronto, Canada.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Lerch
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000502:physiology*; D046690:Deep Brain Stimulation / Q000379:methods*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL