Poster No:
16
Submission Type:
Abstract Submission
Authors:
Satoka Fujimoto1, Atsushi Fujimoto2, Catherine Elorette1, Davide Folloni1, Lazar Fleysher1, Ki Sueng Choi1, Brian Russ3, Helen Mayberg1, Peter Rudebeck1
Institutions:
1Icahn School of Medicine at Mount Sinai, New York, NY, 2Icahn School of Medicine at Mount Sinai, New york, NY, 3Nathan Kline Institute, Orangeburg, NY
First Author:
Co-Author(s):
Ki Sueng Choi
Icahn School of Medicine at Mount Sinai
New York, NY
Helen Mayberg
Icahn School of Medicine at Mount Sinai
New York, NY
Introduction:
Deep brain stimulation targeting subcallosal anterior cingulate cortex (SCC-DBS) and adjacent white matter (WM) is a promising therapy for treatment resistant depression (TRD) [1,2]. The neural mechanisms through which SCC-DBS facilitates recovery from TRD are, however, not fully characterized, making it difficult to optimize treatment for all patients. While white matter abnormality is reported to relevant with depression severity [3], it remains unclear how DBS stimulation of white matter alters brain-wide circuits even in healthy brains, an essential first step in determining the therapeutic mechanisms of SCC-DBS. The aim of the current study was to establish how SCC-DBS works in the healthy brain, focusing on determining the brain-wide network-level functional and anatomical effects of white matter stimulation.
Methods:
To model the approach used to successfully treat TRD patients, we implanted SCC-DBS electrodes in two male rhesus macaques. The organization and differentiation of gray matter and the white matter in the macaque brain, especially the frontal and temporal cortex, are highly similar to humans making them the best available animal model [4]. Diffusion-weighted imaging (DWI) (Siemens Skyra 3T, human head 32ch coil, b=1000 s/mm2, 1.5mm isotropic resolution, 8 b0s per scan, two opposite phase encoding = AP/PA) and whole brain resting-state functional MRIs (rs-fMRIs, echo planar image, custom-built 4-channel monkey coil, 1.5mm isotropic) were acquired before electrode implantation. Using probabilistic diffusion tractography analysis (FSL, FMRIB), we identified the confluence of the cingulum bundle (CB), forceps minor (FM), and uncinate fasciculus (UF) [5]. We then unilaterally implanted a single miniaturized DBS lead in this location in one hemisphere. The other hemisphere serves as a control. One month after electrode implantation, stimulation (5mA, 130Hz, 90μsec) began and was maintained for 6 weeks. Following 6 weeks of SCC-DBS stimulation and explantation of the electrode, we acquired functional and diffusion scans to match the pre-electrode scans to investigate the functional and anatomical changes induced by SCC-DBS. Fractional anisotropy (FA), calculated from the DWI, was used to investigate anatomical changes in WM, and rs-fMRI data were analyzed using a seed-based comparative-connectome approach to determine where SCC-DBS stimulation induced changes in functional connectivity (FC), using AFNI, FSL, and MRtrix3. Seed ROI was set in the stimulated area 25 where the artifact was minimized by the absence of the DBS lead. Multiple comparison analyses were conducted to confirm the statistical differences.
Results:
Diffusion tractography reconstruction of the CB, FM, and UF revealed a close homology between humans and monkeys. The confluence of the 3 WM tracts was located in the WM adjacent to area 25, and the location was highly similar to humans. Thus, we were able to accurately model the anatomical target that is used in human TRD patients. After 6 weeks of SCC-DBS stimulation, FA was significantly increased in the CB in the stimulated hemisphere. The midcingulate portion of CB carries fibers connecting the anterior and posterior cingulate cortex (PCC), and this specific part showed a significant increase in FA. FC between the stimulated ROI (Area 25) and DMN hubs (medial prefrontal cortex and PCC) and limbic system hubs (cingulate cortex, hippocampus, amygdala) were significantly decreased following 6-weeks of stimulation.
Conclusions:
Chronic SCC-DBS changes brain-wide structures and functional networks connected to the SCC. Specifically, WM changes were prominent in the stimulated CB, especially MCC portion, and functional changes were predominant in the DMN. Our data reveal the specific effects of SCC-DBS on brain-wide anatomical and functional connectivity, information essential for establishing the neural mechanisms of DBS for TRD, as well as the biological bases of pathologically depressed mood.
Brain Stimulation:
Deep Brain Stimulation 1
Disorders of the Nervous System:
Psychiatric (eg. Depression, Anxiety, Schizophrenia)
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Anatomy and Functional Systems
White Matter Anatomy, Fiber Pathways and Connectivity 2
Keywords:
Affective Disorders
ANIMAL STUDIES
FUNCTIONAL MRI
Psychiatric Disorders
WHITE MATTER IMAGING - DTI, HARDI, DSI, ETC
1|2Indicates the priority used for review
Provide references using author date format
1. Mayberg, HS et al. (2005). ‘Deep brain stimulation for treatment-resistant depression.’ Neuron, 45(5), 651–660.
2. Crowell, AL et al. (2019). ‘Long-Term Outcomes of Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression.’ The American journal of psychiatry, 176(11), 949–956.
3. Alagapan S et al. (2023). ‘Cingulate dynamics track depression recovery with deep brain stimulation.’ Nature, 622(7981), 130–138.
4. Rudebeck PH et al. (2019). ‘From bed to bench side: Reverse translation to optimize neuromodulation for mood disorders.’ Proceedings of the National Academy of Sciences of the United States of America, 116(52), 26288–26296.
5. Riva-Posse P et al. (2018). ‘A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression.’ Molecular psychiatry, 23(4), 843–849.