Can Botox make us happier?

Posted by Susan Lubejko on February 10, 2022 in depression, Neuroscience, Neuroscience in pop culture | Leave a comment

I’ll admit it – I absolutely love Netflix reality shows depicting beautiful people, their lifestyles, and their interpersonal issues (looking at you Selling Sunset…). At least once per season on my favorite shows, a cosmetic surgeon shows up to give Botox injections to any willing participant to help keep their skin wrinkle-free. As a Netflix watcher, I am fascinated by these events. As a neuroscientist, I am more fascinated by the science behind Botox. Botox injections are made up of botulinum toxin (BoNT), a neurotoxin found in certain bacteria that blocks the release of the neurochemical acetylcholine, which usually transfers information from nerves to muscles to cause muscle contraction. By blocking acetylcholine where the nerve connects to the muscle, BoNT causes muscle paralysis. In addition to using BoNT for the cosmetic paralysis of facial muscles to decrease the appearance of wrinkles, you might be surprised to hear that it is also commonly used to treat disorders that involve overly excited and contracted muscles such as neck and muscle spasms, overactive bladder, drooling, eye twitching, excessive sweating and migraines. 

The benefits for BoNT use in these conditions is clear. If a patient presents with an extremely rigid neck that causes contortion and pain, relaxing the neck muscles and preventing their contraction with BoNT will relieve these symptoms. I was surprised, then, to come across a recent study done in part by researchers at the UCSD Skaggs School of Pharmacy that suggested that Botox injections given for a myriad of the indications above also relieve symptoms of anxiety. How might BoNT injection interact with our mental health to improve outcomes? 

Botulinum toxin interactions with anxiety and depression

The recent study that caught my attention aimed to determine whether botulinum toxin injection can relieve anxiety symptoms through a survey approach. The researchers combed through the FDA Adverse Event Reporting System (FAERS) for self reports by patients that had received BoNT injections for cosmetic and medical indications. After eliminating reports given by legal representatives and by patients already on anti-anxiety medication, the researchers had over 12 million reports to include in their analysis. They found that BoNT administration had a protective effect against anxiety incidence reports for patients that had received the toxin for cosmetic purposes, migraine, and muscle and neck spasms. On the other hand, BoNT for eye twitching had a small anxiety-producing effect [1]. 

Taking a deeper dive into the rationale behind this study, it became clear that BoNT for relief of mental health disorders has been of interest to researchers and doctors for more than a decade. The same group of researchers recently used FAERS to determine that BoNT injection protected against depression, regardless of the site injected or for which medical condition [2]. While using patient self-reports of adverse events can lead to bias in survey data by missing or withheld information, these results actually build upon a years-long effort to study BoNT injection in the lab for the treatment of depression. Multiple laboratory studies have shown that patients’ ratings on scales of depression decrease with BoNT injections in and around the glabellar region (that area between your eyebrows, right above your nose) as compared to patients that had injections of saline in the same place [3, 4], and that this effect persists for up to 16 weeks [3]. A major caveat of these studies, however, is that obvious facial muscle relaxation clues both the patients and the researchers in as to who received the BoNT injections and might skew ratings. These results together with the FAERS results, however, combine unbiased reports with careful laboratory testing. 

How do botulinum toxin injections affect mental health?

As I read these studies, I kept coming back to the same question: how does BoNT injection affect the seemingly unrelated concept of mental health? The short answer to this question is, we don’t exactly know, but there are a few interesting theories to explore.

Facial Feedback Hypothesis. The first compelling theory relies on the fact that facial expressions are more important for mood than we might think. While the unidirectional effect of mood on facial expression is well understood by everyone (I am sad so therefore I frown), there is evidence that the relationship is actually bidirectional and the two reinforce each other  (I am sad so therefore I frown, but my frown also might be making me more sad). These hypotheses have been studied in the lab by asking subjects to rate the funniness of cartoons while holding a pen in their mouth to prevent smiling or between their teeth to cause smiling. In this way, subjects weren’t explicitly told to experience a certain feeling, but were made to form facial expressions that at least partially mimicked them. The forced smiling subjects found the cartoons funnier [5]. Another study found that subjects’ automatic bodily processes, such as heart rate and sweating, were greatly modified when the subjects were told to hold their faces in a certain way to mimic an emotional facial expression without being instructed as to what that emotion actually was [6]. 

This theory fits nicely with the groups of patients who were observed to have decreased depression and anxiety after BoNT in the glabellar area for cosmetic reasons or migraine. Interruption of the muscles in this area disrupts the ability to make facial expressions associated with negative feelings, which may in turn alleviate some of these negative feelings. Interestingly, paralysis of the muscles around the eyes using injections for eye twitching could theoretically also disrupt the ability to form a true smile, possibly giving a reason for why the eye twitch patients had slightly more anxiety than other BoNT-injected patients [1]. Additionally, an extension of this theory could explain the anxiety relief provided by bodily BoNT injections for muscle spasticity and excessive sweating. Increased muscle tone and excessive sweating commonly occur in patients with anxiety disorders. A loss of feedback from the body after these traits have been alleviated by muscle relaxation could decrease the intensity of the perceived anxiety and depression [1]. For a very recent review of a similar theory involving our holistic understanding of our automatic bodily processes and their interaction with emotion, see this Neuwrite article. 

Social Feedback. As a social species, we heavily use our facial expressions to communicate with others. It is possible that the removal of the ability to make expressions associated with negative emotions that occurs during glabellar BoNT injection improves our perceived emotional state by others, and in turn improves the positivity of their feedback to us. This positive and persistent loop may possibly improve mental health outcomes [7]. 

Relief from the primary disorder. Patients that receive BoNT injections for muscle spasms, overactive bladder, migraines, and the like are experiencing a chronic condition that can disrupt their daily lives with pain and discomfort. Chronic illnesses are often associated with secondary comorbidities like depression and anxiety. Possibly, depression and anxiety in these patients is alleviated simply by alleviating the symptoms of the primary disorder that led to getting the injections in the first place, especially if these conditions had been difficult to treat using other conventional methods and medications. For patients that used BoNT for cosmetic purposes, the patients and control group exhibited less depression at baseline than those with a chronic illness, which made it difficult for the researchers to make any strong claims about cosmetic BoNT in relation to this theory [2]. 

Effects on the central nervous system. Finally, although the injection is restricted to the neural connections with the muscles, BoNT injections exert effects on activity in the central nervous system, including the brain. Human neuroimaging studies suggest that the injections to treat random muscle contractions in the body lead to reorganization of activity in cerebral cortex and cerebellum, areas known for their initiation and organization of movement [8]. In the realm of emotional response, facial BoNT injection affects the activation of the amygdala, an area of the brain that has a role in emotional processing, in response to emotional stimuli [1]. To find a potential mechanism by which these injections affect brain activity, BoNT injections have even preliminarily been shown to elicit decreased depression-like behaviors when injected into the whiskers of mice (An aside: are mice subject to the facial feedback hypothesis, too? Read this previous NeuWrite article to get some insight on rodent facial expressions and how they may use them). These experiments in mice suggest that BoNT may somehow indirectly increase levels of serotonin, an important neurochemical for mood regulation, in multiple regions of the brain and decrease neuroinflammation that can contribute to depression [9]. 

    So, exactly how would BoNT in the muscles affect brain signaling and activity? It is possible, but very unlikely, that the toxin somehow travels back through the nerves from the injection site to the emotional centers of the brain. More likely, BoNT changes the signaling of neurons adjacent to the muscles that send information back to the brain on the status of the muscles. It is hypothesized that this change in input to the brain causes reorganization of neural patterns, activity, and communication [8].

A future for the study of botulinum toxin and mental health?

While there are a ton of interesting theories on how BoNT affects mental wellbeing, you may leave this article feeling like none of them quite fit for all of the various BoNT uses. Although BoNT and depression have been studied for over a decade, we are still in the midst of examining the phenomenon in humans, as well as the underlying mechanisms by which it happens. Admittedly, some researchers are not as convinced by the existing data in the field and urge other scientists to study further before recommending the treatment specifically for mental health disorders in the absence of other indications.

Although certain theories of how our body, facial expressions, and emotions are related date back to Charles Darwin, recent studies on using BoNT injections for psychiatric benefit serve to show that our emotions are not sequestered on an island away from our physical well being. The abovementioned studies point to a fascinating future for the investigation of using botulinum toxin injections for the alleviation of more psychiatric disorders and a better understanding of how exactly it does the job. 

References

1. Wollmer MA, Makunts T, Kruger TH, Abagya R (2021) Postmarketing safety surveillance data reveals protective effects of botulinum toxin injections against incident anxiety. Scientific Reports, 11:24173
2. Makunts T, Wollmer MA, Abagyan R (2020) Postmarketing safety surveillance data reveals antidepressant effects of botulinum toxin across various indications and injection sites. Scientific Reports, 10:12851
3. Wollmer MA, de Boer C, Kalak N, et al. (2012) Facing depression with botulinum toxin: A randomized controlled trial. Journal of Psychiatric Research, 46:574-581
4. Finzi E, Rosenthal NE (2014) Treatment of depression with onabotulinumtoxin A: A randomized, double-blind, placebo controlled trial. Journal of Psychiatric Research, 52:1-6
5. Strack F, Martin LL, Stepper S (1988) Inhibiting and facilitating conditions of the human smile: A nonobtrusive test of the facial feedback hypothesis. Journal of Personality and Social Psychology, 54(5):768-777
6. Finzi E, Rosenthal NE (2016) Emotional proprioception: Treatment of depression with afferent facial feedback. Journal of Psychiatric Research, 80:93-96
7. Li Y, Liu T, Luo W (2021) Botulinum neurotoxin therapy for depression: Therapeutic mechanisms and future perspective. Frontiers in Psychiatry, 12:584416
8. Weise D, Weise CM, Naumann M (2019) Central effects of botulinum neurotoxin – evidence from human studies. Toxins, 11:21
9. Li Y, Liu J, Liu X, et al. (2019) Antidepressant-like action of single facial injection of botulinum neurotoxin A is associated with augmented 5-HT levels and BDNF/ERK/CREB pathways in mouse brain. Neuroscience Bulletins, 35(4):661-672

Featured Image: flickr.com/Marco Verch Professional Photographer