In an article published in the Journal of Psychiatric Research in of June, 2016, authors Eric Finzi, MD, PhD and Norman E. Rosenthal, MD, devised the concept of emotional proprioception, through which the muscles of facial expression play a pivotal role in encoding and transmitting information to the brain’s emotional circuitry, and define its fundamental neuroanatomy. They investigated the role of facial expression in both mirroring and affecting depressed mood. The circuitry involved in this latter effect is a logical target for treatment with botulinum toxin A, also known as BOTOX®, and they assessed the evidence in support of this approach. Clinical trial data suggests that botulinum toxin A is effective in treating Depression. We discuss the clinical and theoretical implications of this data. This unique treatment method is just one example of the potential importance of the cranial nerves in the treatment of Depression.
We and others have recently discovered that botulinum toxin A injected into the brow muscles has significant antidepressant effects as compared to placebo in randomized controlled studies.
While these findings may seem surprising at first blush, they may have been predicted by a hypothesis dating back over a century. Although it is obvious that our emotions affect our facial expressions, the reverse is less obvious. Yet Charles Darwin proposed this to be the case over a century ago, and William James concurred.
Both of these scientists made special reference to this facial feedback effect, which we are calling emotional proprioception, in relation to Depression. Darwin, for example, first observed the omega sign between the eyebrows, shaped like the last letter of the Greek alphabet (Ω), a result of the corrugator muscles contracting and producing two vertical slits between the eyebrows, joined at the top by a horizontal crease. He recognized the omega sign as an indicator of melancholy and noted its disappearance when patients recovered. James famously stated that he did not cry because he was sad; instead, he was sad because he cried. In both cases the theory was that the external embodiments of sorrow or grief were actually signaling back to the emotional centers of the brain, causing or intensifying feelings of distress.
Over the subsequent decades experimental psychologists pursued what became better known as the facial feedback hypothesis, and produced numerous results suggesting that Darwin and James were indeed correct. Signaling between the emotional centers of the brain and the facial muscles is bidirectional.
Facial Feedback Theory
It took approximately a century following Darwin’s groundbreaking observations for researchers to methodically research what happens to emotional states in the brain when, either consciously, or unconsciously, the musculature of facial expression is activated.
Preliminary research revealed that people rated cartoons more amusing when smiling versus when frowning. Similarly, people also rated negative imagery as more aggressive\when frowning, than when smiling. Opponents of these early experiments remarked that participants were cognizant that their facial expressions were happy or sad, which may have skewed the results. To try and eliminate this predisposition, ensuing researchers provided a good cover story for the experiment so that subjects were not aware of its true intention. Instead of asking subjects to adopt a specific expression, they asked them to perform discrete facial actions, apparently unrelated to emotional expressions. For instance, researchers asked subjects to hold a pen between their lips, (to hinder smiling) or between their teeth (to enable it). Subjects then rated the humor of cartoons. Smiling subjects found the cartoons more amusing than those prevented from smiling. Consequently, the simple contraction of the zygomaticus muscle, such as occurs when we smile, gives a positive spin to decision-making.
Similarly, experiments have demonstrated that attaching golf tees to both sides of the forehead, and asking people to use their facial muscles to bring the tees closer together, causes people to rate unpleasant photographs more negatively Frowning, regardless of why, results in a more negative perception of an emotional image and impacts decision-making.
Numerous researchers have reached similar conclusions using different methods to manipulate facial expressions. For example, one group utilized the fact that pronouncing certain vowels causes contraction of different sets of facial muscles. For instance, the inclusion of the German vowel u in a word will prevent its speaker from smiling, while, at the same time, help create a frown. In one study, native German speakers were asked to read two stories aloud. Each story was equivalent in emotional tone and semantic content, but one story contained numerous words containing the u vowel, while the other contained no u words. The subjects were then asked to rate the stories on several criteria, including which one they preferred. Their participants liked the no-u stories better, implying that frowning negatively impacts emotion based decision-making.
To investigate how facial expressions, affect the Autonomic Nervous System (ANS), Ekman and associates asked their subjects to contract precise sets of facial muscles, creating expressions of surprise, fear, disgust, anger, happiness and disgust, or to remember an experience that provoked these emotions. Objective measures of the ANS — heart rate, blood pressure, skin conductance, sweating — were altered more by contracting facial muscles than by the recall of an emotional memory.
In short, converging lines of evidence indicate a significant effect of the facial muscles on mood: explicitly, the zygomaticus muscles involved in smiling promote happy mood, and the corrugator muscles involved in frowning promote gloomy mood.
Afferent nerve fibers appear to relay emotional information to the brain on a moment to moment basis, signaling our emotional state. We propose that the brain utilizes facial muscle expression to provide such emotional proprioception. When we paralyze muscle fibers with botulinum toxin A this may signal to trigeminal nerve endings — possibly those involved in registering pain, position and muscle tension — a relief of physical stress, resulting in decreased emotional stress. A link between corrugator muscle activity and amygdala activation has been observed. Brain FMRI data and EMG recordings of the corrugator muscle were simultaneously obtained in subjects who viewed emotionally negative or neutral images. Negative-picture viewing induced increases in corrugator activity along with increases in amygdala activation. Increased corrugator activity was also associated with deactivation of the ventromedial PFC. Depressed patients who experience a remission induced either by paroxetine, or by cognitive behavioral therapy, demonstrate decreased amygdala overactivity.
Proof of Antidepressant Effects of botulinum toxin A
In an initial case series, botulinum toxin A was injected into the frown of ten depressed patients, 8 of whom experienced remission after 1 treatment. The study was limited by its small size, lack of controls, and lack of blinding. In three subsequent randomized, double blind and placebo controlled trials showed response rates of 50 – 60 percent in major Depression, with approximately one-third of patients experiencing remission. BOTOX® revealed antidepressant effects when used as an ancillary treatment as well as by itself.
How would injecting BOTOX® into the corrugator muscle impact the emotional brain?
FMRI imaging has shown that subjects who received BOTOX® injections into their frown muscles had amygdala that were less responsive to negative stimuli. Recent work has confirmed that amygdala activity in response to angry faces decreased when the frown muscles were paralyzed by BOTOX® injection. Moreover, amygdala activity returned to its original inducible state after the effects of the BOTOX® injection had worn off, verifying that BOTOX® reversibly severed afferent feedback from the corrugator muscle to the amygdala.
Hence, understanding the impact of EP on mood regulation has led to a potentially valuable new antidepressant methodology — BOTOX® as an antidepressant. This methodology is particularly interesting since facially injected BOTOX® has few side effects, virtually no described interactions with systemically administered drugs, and can be used as a stand-alone therapy or adjunctive to concomitant antidepressant medications.
Potential fundamental neuroanatomical circuitry associated with BOTOX® antidepressant effect
In order to understand the EP pathway that may be at work in this antidepressant effect it is worth noting that muscular activity in the region of the brow influences proprioceptive fibers of the optic branch of the trigeminal nerve. This in consecutively may activate the ventromedial PFC through the mesencephalic trigeminal nucleus and locus ceruleus, the latter of which has direct connections with both the amygdala and the PFC — structures essential for emotional regulation.
We speculate that by injecting BOTOX® into the brow, thus temporarily and reversibly paralyzing corrugator muscle, we affect the proprioceptive signal sent via the optic branch of the trigeminal nerve. Therefore, at a neuroanatomical level BOTOX® is essentially alleviating the pain and stress carried by the corrugator muscles of the brow, supporting a theory originally proposed by Darwin approximately 150 years ago.
The idea of EP as a target for therapeutic intervention leads to two lines of conjecture about how else we might be to help able patients suffering from emotional disorders. First, what other emotional conditions might benefit from intervention with BOTOX®? And second, might the effect of this one specific cranial nerve, the trigeminal, be just one example of therapeutic benefits of modifying cranial nerve functions?
First, expressions of distress such as frowns or grimaces are not exclusive to Depression. They are common to all situations that involve grief, panic, fear and anger — emotions that might be present for example in people with anxiety disorders and anger management problems. A logical extension of our work, consequently, would be to consider the use of BOTOX® for these and other conditions. Second, the cranial nerves might be valuable conduits for therapeutic exploration. Several interventions that affect cranial nerves have already been shown to have antidepressant effects. Therefore, light therapy (optic nerve) benefits both seasonal and non-seasonal Depression. Fragrances (olfactory nerve) might also boost mood. Vagal nerve stimulation has also been used in refractory Depression with beneficial effects. And music has long been valued for its calming, antidepressant effects. Further investigation of cranial nerve manipulation in psychiatry seems justified.
In conclusion, EP is a useful concept for understanding the impact that facial muscles have on the emotional centers of the brain. We propose that BOTOX® may be considered a potential treatment for Depression. As more data is collected, we will learn when and how best to implement this new tool. These studies of BOTOX® in Depression also provide new frontiers for other uses of this protein, and might stimulate us to give further consideration to the antidepressant uses of the cranial nerves.