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Background: Deep brain stimulation (DBS) and other neuromodulatory techniques are being increasingly utilized to treat refractory neurologic and psychiatric disorders., Objective: /Hypothesis: To better understand the circuit-level pathophysiology of treatment-resistant depression (TRD) and treat the network-level dysfunction inherent to this challenging disorder, we adopted an approach of inpatient intracranial monitoring borrowed from the epilepsy surgery field., Methods: We implanted 3 patients with 4 DBS leads (bilateral pair in both the ventral capsule/ventral striatum and subcallosal cingulate) and 10 stereo-electroencephalography (sEEG) electrodes targeting depression-relevant network regions. For surgical planning, we used an interactive, holographic visualization platform to appreciate the 3D anatomy and connectivity. In the initial surgery, we placed the DBS leads and sEEG electrodes using robotic stereotaxy. Subjects were then admitted to an inpatient monitoring unit for depression-specific neurophysiological assessments. Following these investigations, subjects returned to the OR to remove the sEEG electrodes and internalize the DBS leads to implanted pulse generators., Results: Intraoperative testing revealed positive valence responses in all 3 subjects that helped verify targeting. Given the importance of the network-based hypotheses we were testing, we required accurate adherence to the surgical plan (to engage DBS and sEEG targets) and stability of DBS lead rotational position (to ensure that stimulation field estimates of the directional leads used during inpatient monitoring were relevant chronically), both of which we confirmed (mean radial error 1.2±0.9 mm; mean rotation 3.6±2.6°)., Conclusion: This novel hybrid sEEG-DBS approach allows detailed study of the neurophysiological substrates of complex neuropsychiatric disorders., Competing Interests: Declaration of competing interest SAS is a consultant for Boston Scientific, Neuropace, Koh Young, Zimmer Biomet, Varian, Sensoria Therapeutics, and co-founder of Motif Neurotech. NP is a consultant for Boston Scientific and Abbott. WG has received donated devices from Medtronic and is a consultant for Biohaven Pharmaceuticals. SJM has served as a consultant for Alkermes, Allergan, Axsome Therapeutics, Clexio Biosciences, Engrail Therapeutics, Intra-Cellular Therapies, Janssen, Neurocrine, Perception Neurosciences, Praxis Precision Medicines, and Sage Therapeutics. CCM is a consultant for Boston Scientific; receives royalties from Hologram Consultants, Neuros Medical, and Qr8 Health; and is a shareholder in the following companies: Hologram Consultants, Surgical Information Sciences, CereGate, Autonomic Technologies, Cardionomic, Enspire DBS. All other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)