Intracranial electrical stimulation of corticolimbic sites modulates arousal in humans

Joline M Fan; A Moses Lee; Kristin K Sellers; Kai Woodworth; Ghassan S Makhoul; Tony X Liu; Catherine Henderson; Daniela A Astudillo Maya; Rebecca Martinez; Hashem Zamanian; Benjamin A Speidel; Ankit N Khambhati; Vikram R Rao; Leo P Sugrue; Katherine W Scangos; Edward F Chang; Andrew D Krystal

doi:10.1016/j.brs.2023.06.017

Intracranial electrical stimulation of corticolimbic sites modulates arousal in humans

Brain Stimul. 2023 Jul-Aug;16(4):1072-1082. doi: 10.1016/j.brs.2023.06.017. Epub 2023 Jun 28.

Authors

Joline M Fan¹, A Moses Lee², Kristin K Sellers³, Kai Woodworth², Ghassan S Makhoul², Tony X Liu², Catherine Henderson², Daniela A Astudillo Maya², Rebecca Martinez², Hashem Zamanian², Benjamin A Speidel⁴, Ankit N Khambhati³, Vikram R Rao⁴, Leo P Sugrue⁵, Katherine W Scangos², Edward F Chang³, Andrew D Krystal²

Affiliations

¹ Department of Neurology, University of California, San Francisco, CA, USA; Weill Institute for Neurosciences, University of California, San Francisco, CA, USA. Electronic address: Joline.Fan@ucsf.edu.
² Weill Institute for Neurosciences, University of California, San Francisco, CA, USA; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA, USA.
³ Weill Institute for Neurosciences, University of California, San Francisco, CA, USA; Department of Neurosurgery, University of California, San Francisco, CA, USA.
⁴ Department of Neurology, University of California, San Francisco, CA, USA; Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
⁵ Weill Institute for Neurosciences, University of California, San Francisco, CA, USA; Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA, USA; Department of Radiology, University of California, San Francisco, CA, USA.

Abstract

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.

Keywords: Arousal; Human electrophysiology; Neurostimulation; Sleepiness; Ventral capsule.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Arousal* / physiology
Electric Stimulation
Humans
Sleep / physiology
Sleepiness*
Wakefulness / physiology

Abstract

Publication types

MeSH terms

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