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Background: Humans routinely shift their sleepiness and wakefulness levels in response to emotional factors. The diversity of emotional factors that modulates sleep-wake levels suggests that the ascending arousal network may be intimately linked with networks that mediate mood. Indeed, while animal studies have identified select limbic structures that play a role in sleep-wake regulation, the breadth of corticolimbic structures that directly modulates arousal in humans remains unknown., Objective: We investigated whether select regional activation of the corticolimbic network through direct electrical stimulation can modulate sleep-wake levels in humans, as measured by subjective experience and behavior., Methods: We performed intensive inpatient stimulation mapping in two human participants with treatment resistant depression, who underwent intracranial implantation with multi-site, bilateral depth electrodes. Stimulation responses of sleep-wake levels were measured by subjective surveys (i.e. Stanford Sleepiness Scale and visual-analog scale of energy) and a behavioral arousal score. Biomarker analyses of sleep-wake levels were performed by assessing spectral power features of resting-state electrophysiology., Results: Our findings demonstrated three regions whereby direct stimulation modulated arousal, including the orbitofrontal cortex (OFC), subgenual cingulate (SGC), and, most robustly, ventral capsule (VC). Modulation of sleep-wake levels was frequency-specific: 100Hz OFC, SGC, and VC stimulation promoted wakefulness, whereas 1Hz OFC stimulation increased sleepiness. Sleep-wake levels were correlated with gamma activity across broad brain regions., Conclusions: Our findings provide evidence for the overlapping circuitry between arousal and mood regulation in humans. Furthermore, our findings open the door to new treatment targets and the consideration of therapeutic neurostimulation for sleep-wake disorders., Competing Interests: Declaration of competing interest A.D.K. consults for Angelini, Eisai, Evecxia Therapeutics, Ferring Pharmaceuticals, Galderma, Harmony Biosciences, Idorsia, Jazz Pharmaceuticals, Janssen Pharmaceuticals, Lundbeck, Merck, Neurocrine Biosciences, Pernix Pharma, Sage Therapeutics, Takeda Pharmaceutical Company, Big Health, Millennium Pharmaceuticals, Otsuka Pharmaceutical and Neurawell Therapeutics. A.D.K. acknowledges support from Janssen Pharmaceuticals, Jazz Pharmaceuticals, Neurocrine, Axsome Therapeutics (no. AXS-05-301) and Reveal Biosensors. K.W.S. receives salary and equity options from Neumora Therapeutics. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)