M Mallar Chakravarty1, Clement Hamani2, Alonso Martinez-Canabal3, Jacob Ellegood4, Christine Laliberté4, José N Nobrega5, Tejas Sankar6, Andres M Lozano7, Paul W Frankland8, Jason P Lerch9. 1. 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. 2. Division of Neurosurgery, Toronto Western Hospital, Canada; Behavioural Neurobiology Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada. 3. Program in Neuroscience and Mental Health, The Hospital for Sick Children, Canada. 4. Mouse Imaging Centre (MICe), The Hospital for Sick Children, Canada. 5. Department of Psychiatry, University of Toronto, Canada; Behavioural Neurobiology Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Canada. 6. Division of Neurosurgery, Toronto Western Hospital, Canada; Division of Neurosurgery, University of Alberta, Canada. 7. Division of Neurosurgery, Toronto Western Hospital, Canada. 8. 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. 9. 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.
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.
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: Nicholas J Michelson; James R Eles; Alberto L Vazquez; Kip A Ludwig; Takashi D Y Kozai Journal: J Neurosci Res Date: 2018-12-26 Impact factor: 4.164
Authors: Colleen P E Rollins; Daniel Gallino; Vincent Kong; Gülebru Ayranci; Gabriel A Devenyi; Jürgen Germann; M Mallar Chakravarty Journal: Neuroimage Clin Date: 2018-11-20 Impact factor: 4.881