Review

. 2023 May 16;20(1):64.

doi: 10.1186/s12984-023-01187-8.

Manipulating facial musculature with functional electrical stimulation as an intervention for major depressive disorder: a focused search of literature for a proposal

Ilya Demchenko^{1

2}, Naaz Desai^{3

4}, Stephanie N Iwasa^{4

5}, Fatemeh Gholamali Nezhad¹, José Zariffa^{4

5

6

7

8}, Sidney H Kennedy^{1

2

9}, Nicholas O Rule¹⁰, Jeffrey F Cohn¹¹, Milos R Popovic^{2

4

5

7

8}, Benoit H Mulsant^{9

12}, Venkat Bhat^{13

14

15

16

17

18}

Affiliations

¹ Interventional Psychiatry Program, Mental Health and Addictions Service, St. Michael's Hospital - Unity Health Toronto, Toronto, ON, M5B 1M4, Canada.
² Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
³ Krembil Research Institute - University Health Network, Toronto, ON, M5T 0S8, Canada.
⁴ KITE, Toronto Rehabilitation Institute - University Health Network, Toronto, ON, M5G 2A2, Canada.
⁵ CRANIA, University Health Network, Toronto, ON, M5G 2C4, Canada.
⁶ Rehabilitation Sciences Institute, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5G 1V7, Canada.
⁷ Institute of Biomedical Engineering, Faculty of Applied Science & Engineering, University of Toronto, Toronto, ON, M5S 3E2, Canada.
⁸ The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, Faculty of Applied Science & Engineering, University of Toronto, Toronto, ON, M5S 3G8, Canada.
⁹ Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5T 1R8, Canada.
¹⁰ Department of Psychology, Faculty of Arts & Science , University of Toronto, Toronto, ON, M5S 3G3, Canada.
¹¹ Department of Psychology, Kenneth P. Dietrich School of Arts & Sciences, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
¹² Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M6J 1H4, Canada.
¹³ Interventional Psychiatry Program, Mental Health and Addictions Service, St. Michael's Hospital - Unity Health Toronto, Toronto, ON, M5B 1M4, Canada. venkat.bhat@utoronto.ca.
¹⁴ Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada. venkat.bhat@utoronto.ca.
¹⁵ Krembil Research Institute - University Health Network, Toronto, ON, M5T 0S8, Canada. venkat.bhat@utoronto.ca.
¹⁶ KITE, Toronto Rehabilitation Institute - University Health Network, Toronto, ON, M5G 2A2, Canada. venkat.bhat@utoronto.ca.
¹⁷ CRANIA, University Health Network, Toronto, ON, M5G 2C4, Canada. venkat.bhat@utoronto.ca.
¹⁸ Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5T 1R8, Canada. venkat.bhat@utoronto.ca.

PMID: 37193985
PMCID: PMC10190013
DOI: 10.1186/s12984-023-01187-8

Review

Manipulating facial musculature with functional electrical stimulation as an intervention for major depressive disorder: a focused search of literature for a proposal

Ilya Demchenko et al. J Neuroeng Rehabil. 2023.

. 2023 May 16;20(1):64.

doi: 10.1186/s12984-023-01187-8.

Authors

Affiliations

¹ Interventional Psychiatry Program, Mental Health and Addictions Service, St. Michael's Hospital - Unity Health Toronto, Toronto, ON, M5B 1M4, Canada.
² Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
³ Krembil Research Institute - University Health Network, Toronto, ON, M5T 0S8, Canada.
⁴ KITE, Toronto Rehabilitation Institute - University Health Network, Toronto, ON, M5G 2A2, Canada.
⁵ CRANIA, University Health Network, Toronto, ON, M5G 2C4, Canada.
⁶ Rehabilitation Sciences Institute, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5G 1V7, Canada.
⁷ Institute of Biomedical Engineering, Faculty of Applied Science & Engineering, University of Toronto, Toronto, ON, M5S 3E2, Canada.
⁸ The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, Faculty of Applied Science & Engineering, University of Toronto, Toronto, ON, M5S 3G8, Canada.
⁹ Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5T 1R8, Canada.
¹⁰ Department of Psychology, Faculty of Arts & Science , University of Toronto, Toronto, ON, M5S 3G3, Canada.
¹¹ Department of Psychology, Kenneth P. Dietrich School of Arts & Sciences, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
¹² Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, M6J 1H4, Canada.
¹³ Interventional Psychiatry Program, Mental Health and Addictions Service, St. Michael's Hospital - Unity Health Toronto, Toronto, ON, M5B 1M4, Canada. venkat.bhat@utoronto.ca.
¹⁴ Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada. venkat.bhat@utoronto.ca.
¹⁵ Krembil Research Institute - University Health Network, Toronto, ON, M5T 0S8, Canada. venkat.bhat@utoronto.ca.
¹⁶ KITE, Toronto Rehabilitation Institute - University Health Network, Toronto, ON, M5G 2A2, Canada. venkat.bhat@utoronto.ca.
¹⁷ CRANIA, University Health Network, Toronto, ON, M5G 2C4, Canada. venkat.bhat@utoronto.ca.
¹⁸ Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5T 1R8, Canada. venkat.bhat@utoronto.ca.

PMID: 37193985
PMCID: PMC10190013
DOI: 10.1186/s12984-023-01187-8

Abstract

Background: Major Depressive Disorder (MDD) is associated with interoceptive deficits expressed throughout the body, particularly the facial musculature. According to the facial feedback hypothesis, afferent feedback from the facial muscles suffices to alter the emotional experience. Thus, manipulating the facial muscles could provide a new "mind-body" intervention for MDD. This article provides a conceptual overview of functional electrical stimulation (FES), a novel neuromodulation-based treatment modality that can be potentially used in the treatment of disorders of disrupted brain connectivity, such as MDD.

Methods: A focused literature search was performed for clinical studies of FES as a modulatory treatment for mood symptoms. The literature is reviewed in a narrative format, integrating theories of emotion, facial expression, and MDD.

Results: A rich body of literature on FES supports the notion that peripheral muscle manipulation in patients with stroke or spinal cord injury may enhance central neuroplasticity, restoring lost sensorimotor function. These neuroplastic effects suggest that FES may be a promising innovative intervention for psychiatric disorders of disrupted brain connectivity, such as MDD. Recent pilot data on repetitive FES applied to the facial muscles in healthy participants and patients with MDD show early promise, suggesting that FES may attenuate the negative interoceptive bias associated with MDD by enhancing positive facial feedback. Neurobiologically, the amygdala and nodes of the emotion-to-motor transformation loop may serve as potential neural targets for facial FES in MDD, as they integrate proprioceptive and interoceptive inputs from muscles of facial expression and fine-tune their motor output in line with socio-emotional context.

Conclusions: Manipulating facial muscles may represent a mechanistically novel treatment strategy for MDD and other disorders of disrupted brain connectivity that is worthy of investigation in phase II/III trials.

Keywords: Amygdala; Depressive disorder; Facial expression; Facial muscles; Functional electrical stimulation; Interoception; Myofunctional therapy; Neurological rehabilitation; Neuromodulation; Neuroplasticity.

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Conflict of interest statement

Ilya Demchenko, Naaz Desai, Stephanie N. Iwasa, Fatemeh Gholamali Nezhad, and Nicholas O. Rule declare no conflict of interest. José Zariffa is the patent inventor for functional electrical stimulation to modulate affect (US-9259576-B2; approved on February 16, 2016); the patent belongs to University Health Network; he has received research support from the Natural Sciences and Engineering Research Council of Canada, Craig H. Neilsen Foundation, Heart and Stroke Foundation of Canada, Wings for Life Spinal Cord Research Foundation, Ontario Ministry of Colleges and Universities, and Praxis Spinal Cord Institute. Sidney H. Kennedy has received honoraria or research funds from Abbott, Alkermes, Allergan, Boehringer Ingelheim, Brain Canada, Canadian Institutes of Health Research, Janssen, Lundbeck, Lundbeck Institute, Merck, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion, Sun Pharmaceuticals, Xian-Janssen, and holds stock in Field Trip Health. Jeffrey F. Cohn reports grants or contracts from National Institutes of Health and National Science Foundation, and royalties/licenses from the University of Pittsburgh. He receives consulting fees from RealEyes, Xtrodes, Skylyte, has a patent approved on image normalization for facial analysis (US11244206), holds a leadership or fiduciary role at IEEE International Conference on Automatic Face and Gesture Recognition and Association for Affective Computing Society, and holds stock in Deliberate AI and Embodied. Milos R. Popovic is the inventor of the patent for facial electrical stimulation to modulate affect belonging to University Health Network, is the Chief Technology Officer and the Director of Myndtec, Inc., a company that manufactures transcutaneous functional electrical stimulators. He is the Director of KITE, Toronto Rehabilitation Institute – University Health Network (Toronto, ON, Canada) and reports grants or contracts from Connaught Innovation Award, Brain Canada, Mitacs, Webster Foundation, Dean Strategic Funding at the University of Toronto, Natural Sciences and Engineering Research Council of Canada, and Canadian Fund for Innovation. He has a patent approved on February 16, 2016 (USA US-9259576-B2) with Dr. S. Hitzig and Dr. J. Zariffa “Functional electrical stimulation method, use and apparatus for mood alteration”; the patent belongs to University Health Network. He is consulting for a company Fourier Intelligence, which designs rehabilitation robotics technologies, and holds stock in MyndTec. Benoit H. Mulsant holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives or has received for the past three years research support from Brain Canada, Canadian Institutes of Health Research, Center for Addiction and Mental Health Foundation, Patient-Centered Outcomes Research Institute, National Institute of Health, Capital Solution Design LLC (software used in a study funded by Center for Addiction and Mental Health Foundation), and HAPPYneuron (software used in a study funded by Brain Canada). He has also been an unpaid consultant to Myriad Neuroscience for the past three years. Venkat Bhat is supported by an Academic Scholar Award from the Department of Psychiatry at the University of Toronto; he has received research support from the Canadian Institutes of Health Research, Brain & Behavior Foundation, Ministry of Health/Ontario Medical Association Innovation Funds, New Frontiers in Research Fund, Department of National Defense (Government of Canada), and an investigator-initiated trial from Roche Canada.

Figures

**Fig. 1**
**Bilateral functional electrical stimulation of facial muscles**. Cutaneous electrode placement for the functional electrical stimulation of bilateral zygomaticus major and orbicularis oculi muscles for the treatment of major depressive disorder. Created with BioRender.com, RRID:SCR_018361.

**Fig. 2**
**Functional electrical stimulation improves symptoms of major depressive disorder.** Distributions of depression scores measured in participants with major depressive disorder (n = 10) at baseline and after 10 sessions of bilateral functional electrical stimulation (FES) of the zygomaticus major and orbicularis oculi muscles. Both the (A) Hamilton Depression Rating Scale (HAM-D, p = .005); and (B) Inventory of Depressive Symptomatology (IDS, p = .008) scores were significantly reduced post-FES. Created with RAWGraphs 2.0 beta, using the data from Kapadia et al. (2019) [11].

**Fig. 3**
**Emotion-to-motor transformation loop**. Contraction of facial muscles relays proprioceptive (magenta) and interoceptive (purple) afferent signals to the amygdala (AMYG) via the trigeminal, glossopharyngeal, and vagus nerves and corresponding brainstem nuclei. AMYG forms a feedback loop with the anterior face area of the midcingulate cortex (M3). The AMYG-M3 connectivity establishes the processing center responsible for decision-making to select and produce a facial expression in response to a particular emotional context. These limbic inputs further calibrate the final motor output of the corticobulbar motor system, where the contraction of the upper (green) and lower (orange) face muscles is modulated via two separate anatomical pathways and the facial nerve. Dashed arrows represent afferent inputs, dotted arrows represent the processing center, and solid arrows represent efferent outputs. Abbreviations: AMYG, amygdala; CN V, cranial nerve V (trigeminal); CN VII, cranial nerve VII (facial); CN IX, cranial nerve IX (glossopharyngeal); CN X, cranial nerve X (vagus); INS, insula; LC, locus coeruleus; LFN, lateral facial nucleus; M1, primary motor cortex; M3, anterior face area of the midcingulate cortex; M4, caudal face area of the midcingulate cortex; MFN, medial facial nucleus; MTN, mesencephalic trigeminal nucleus; NTS, nucleus tractus solitarius; PBN, parabrachial nuclei; PMCvl, ventrolateral regions of the premotor cortex; SMA, supplementary motor area. Created with BioRender.com, RRID:SCR_018361.

See this image and copyright information in PMC

References

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Manipulating facial musculature with functional electrical stimulation as an intervention for major depressive disorder: a focused search of literature for a proposal

Affiliations

Manipulating facial musculature with functional electrical stimulation as an intervention for major depressive disorder: a focused search of literature for a proposal

Authors

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Abstract

Conflict of interest statement

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