





































Berkeley
Pharma Tech
Journal of Medicine

Correspondence: 
wojtaram@umich.edu 

Keywords:
Brain-skin connection 
Hypothalamic-Pituitary-Adrenal 
Axis (HPA)                                 
Skin diseases                    
Melanoma                            
Psoriasis

Submitted: August 28, 2022 

Accepted: September 26, 2022

Published:  December 28, 2022

Full Open Access

Creative Commons Attribution 
License 4.0

Abstract
The brain-skin connection has been a topic of growing interest in the neuroscience and 
dermatology communities. Research has suggested a bi-directional relationship between the 
brain and skin. They share a common embryologic origin as both are derived from ectoblast 
differentiation and the skin has a fully functional peripheral equivalent of the Hypothalamic-
Pituitary-Adrenal Axis (HPA) which allows it to maintain homeostasis and interact with the 
brain. Additionally, serotonin (5-HT), which is a well-known neurotransmitter, has been 
shown to act as a mediator between the skin and the neuroendocrine system. In the skin 
itself, 5-HT, which can be produced or metabolized by several skin cells, is involved in 
vasodilation, inflammation, and immunomodulation. The skin serves a neuroendocrine 
function through its role in maintaining homeostasis and its communication with the central 
neuroendocrine system. This connection also establishes that psychological stress can have 
effects on skin including the development or exacerbation of skin diseases such as melanoma 
and psoriasis. As our knowledge of the brain and neuroendocrine system grows, so does our 
understanding of this brain-skin connection. Therefore, exploring the role of the brain-skin 
connection can help establish efficacious long-term therapeutic avenues for the treatment of 
skin diseases.

Brain-Skin Connection: Considerations for Novel 
Therapies for Skin Diseases
By: Magda Wojtara



 

Berkeley Pharma Tech Journal of Medicine | 105 

1. Introduction 

Recent research has focused on the ‘brain-skin’ axis as a complex interplay 
between the nervous, endocrine, and immune systems, emphasizing the 
underlying pathophysiological mechanisms by which psychological stress 
influences skin homeostasis and clinical applications of this relationship1. 
Perceived psychological stress has become widely known as a force that 
disrupts the dynamic equilibrium between the nervous, endocrine, and 
immune systems, thereby triggering and aggravating disease manifestation2. 
It has also been established in the past decade that the skin has a fully 
functional equivalent to the Hypothalamus-Pituitary-Adrenal Axis (HPA). 
This finding is crucial because it parallels how other parts of the body utilize 
the HPA axis to maintain homeostasis. It also shows a potential bidirectional 
relationship between the neuroendocrine system and the skin. The interplay 
between this HPA and the other systems can be explained by the schematic 
in Figure 1, which shows how stress impacts the three axes and what 
downstream effects result from stress. Suggested routes of the skin-brain axis 
include the immune system, HPA axis, and the peripheral and central 
nervous system3. The skin can be said to be a “diagnostic window into the 
brain.” The ‘brain-skin’ connection is complex because of the skin’s ability 
to produce its own serotonin (5-HT) and neurotrophins due to its common 
embryonic origin with the brain4. 



 

Berkeley Pharma Tech Journal of Medicine | 106 

Figure 1: Schematic Representation of the Three-Stress Axis. This includes the 
Sympathetic Nervous System, HPA Axis, and Neurotrophin-Neuropeptide Axis.  

Our current knowledge of the ‘brain-skin’ axis has been derived from 
technological advances. Graph Theory is used to assess coordinated brain 
activity and estimate the efficiency of information flow5. It has been 
mathematically applied to psychosocial stress5. Salivary cortisol, heart rate, 
and skin conductance are indices of stress, and psychosocial stress was 
associated with a decrease in the efficiency of the flow of information within 
the brain5. Functional neuroimaging, especially functional magnetic 
resonance imaging (fMRI), has enabled indirect visualization of brain 
function, which has been crucial for understanding more about this 
bidirectional relationship. A recent study has concluded that sensory testing, 
skin biopsy, and brain imaging show additional promise as pain biomarkers 
and should be considered for possible inclusion in the design of clinical trials 
of pain treatments6. Another study utilized fMRI to demonstrate cerebellar 
activity and connectivity in skin-picking disorder, which is now known to be 
a potentially maladaptive emotion regulation strategy7. Prior to fMRI 
research, electroencephalography (EEG) was widely utilized, dating back to 
studies in the 1950s investigating brain activity in syphilis patients. On the 
other hand, positron emission tomography (PET) allowed scientists to 
indirectly measure hemodynamic changes. Notably, fMRI has helped 



 

Berkeley Pharma Tech Journal of Medicine | 107 

scientists make strides in establishing their knowledge of crosstalk between 
the skin and the brain’s HPA axis. 

Many common skin diseases are worsened by stress, and itch (pruritus) is the 
most well-known symptom associated with inflammatory skin diseases. 
Several candidate molecules of this stress response, including corticotropin-
releasing hormone (CRH) and mast cells, have been shown to have strong 
pruritogenic potential1. Mast cells, white blood cells that are abundant in the 
skin, occupy a switchboard position and play critical roles in regulating 
neurogenic inflammation during stress responses1. Furthermore, there has 
been research showcasing close interactions between the nervous and 
immune systems in the regulation of peripheral inflammation which links 
stress with chronic somatic disease and aging8. Emerging data suggests that 
chronic inflammations lead to the pro-inflammatory status, known as 
inflammaging, which underlies premature aging8,9. It is important to note 
that dynamic equilibrium disruptions among these systems can also be 
referred to as maladaptive plasticity. Maladaptive plasticity induced by 
neuroendocrine mediators promotes inflammaging and it is believed that 
neurotrophins, neurotransmitters, and neuropeptides play a potential role in 
this process9. 

2. Mechanism of the Brain-Skin Connection 

The skin is perhaps most well-known for its role as a physical barrier from the 
environment which requires it to have precise calibration and a high degree 
of local autonomy to perform daily functions. Highly localized responses are 
coordinated partly by a skin neuroendocrine system that can reset adaptation 
mechanisms through either rapid (neural) or slow (humoral) pathways10. 
These pathways can act on local or systemic levels10. Cutaneous responses 
have a primary goal of protecting, restoring, or maintaining homeostasis and 
dynamic equilibrium with other systems11. Its fundamental functions are 
believed to have originated from its embryonic origin. However, under 
evolutionary pressure, it has been suggested that autoregulatory circuitry may 
have undergone specialization and separation resulting in new functions10. A 
variety of different neuromodulators involve in this connection, resulting in 
many proposed canonical and noncanonical pathways10. 



 

Berkeley Pharma Tech Journal of Medicine | 108 

One way the skin modifies homeostasis is through direct and indirect 
stimulation of the adrenal cortex (Figure 2). Psychological stress induces 
many downstream effects. For example, stress results in an increase in 
glucocorticoids which decreases differentiation and proliferation, thereby 
decreasing lipid synthesis, lamellar body production in the skin and 
ultimately resulting in abnormal permeability and abnormal stratum 
corneum integrity and cohesion. Skin disorders are sometimes adversely 
affected by psychological stress and are frequently characterized by this 
defective cutaneous permeability barrier function10. This is due to the 
reduced density of lamellar bodies. The barrier to pathogenic microbes is also 
impacted because psychological stress reduces epidermal AMP levels, which 
are needed to decrease the growth of microbes10. This ultimately results in 
increased severity of infections due to abnormalities brought on by 
psychological stress.  

Figure 2: Flowchart Demonstrating How Skin Modifies Body Homeostasis Through 
Direct and Indirect Stimulation of the Adrenal Cortex. Red lines indicate inhibition 
and green lines indicate activation. IL represents interleukins, which aid T cells. TNF is a 
tumor necrosis factor. URC stands for urotropins and CRF for corticotropin releasing factor. 
ACTH stands for acetylcholine. POMC is pro-opiomelanocortin, which is a precursor to 
ACTH. 

Furthermore, there have been observations suggesting corticotropin-
releasing factor (CRF) driven responses are another important component 



 

Berkeley Pharma Tech Journal of Medicine | 109 

to the mechanism of the brain-skin connection10. These are properties 
displayed most clearly by neural crest-derived melanocytes and hair follicles 
which have activation sequences that closely reproduce basic features of the 
central HPA axis10. CRF1 and CRF2 are receptors of CRF and may have 
unique characteristics and effects. This is especially interesting to explore as 
there are differential expressions of isoforms of CRF1 resulting in coupling 
to different sets of signal transduction pathways. Many current research 
projects are investigating the effector functions of CRF1 and CRF2 agonists 
and antagonists, specifically in their regulation of keratinocytes, cells that 
produce keratin, and immunocytes, cells that produce antibodies, activities. 

Skin biomarkers for organ-specific diseases are another area of current 
research. It has recently been elucidated that alterations of the Wnt signaling 
pathway may predict the aging status of the cardiovascular system, the brain, 
and bones11. This signaling pathway is well known in the scientific 
community for its role in cell determination. Advanced glycosylation end-
products (AGE) and Wnt pathway proteins are considered laboratory 
biomarkers for systemic disorders and are believed to be gender-
independent11. Other intrinsic and extrinsic parameters may also influence 
aging, but this process is highly variable on an individual basis11. 

Another important contributor is UV energy. As UV light is absorbed by the 
skin, many downstream effects occur, resulting in mechanisms that defend 
skin integrity and induces skin pathology such as cancer. Exposure to UV 
radiation is the principal cause of nonmelanoma skin cancer, a process in 
which serotonin (5-HT) is intimately involved12. The skin is a target for 
neuroendocrine signals from circulation and via nerve endings. It is believed 
that the UV touches the brain and central neuroendocrine system to reset 
body homeostasis13. There are three biologically relevant spectra of UV, 
including UVC (200-280 nm), UVB (280-320 nm), and UVA (320 to 400 
nm). Among these, UVC is profoundly mutagenic and is absorbed by the 
stratum corneum13. 

UV is believed to stimulate both the intracutaneous and the cutaneous HPA 
(cHPA) axis through neural and humoral mechanisms which are wavelength 
dependent and rely on anatomical structures sensing UV energy14. Outside 
of this function, UVA and UVB light also stimulates the opioidergic system, 



 

Berkeley Pharma Tech Journal of Medicine | 110 

specifically stimulating β-endorphin levels in the skin and the brain14. UV-
induced immunosuppression is triggered via a cascade that begins with cis-
urocanic acid—an immune modulator produced in the stratum corneum 
that binds to the 5-HT receptor14. These connections provide another 
mechanism to explore and therapeutically target. 

3. Brain-Skin Connection and Melanoma 

The brain-skin connection is key in explaining how and why psychological 
stress can impact the skin15. Melanoma is a cancer of melanocytes—cells that 
give rise to skin tone, hair, and even eye color. It is also one of the most 
aggressive forms of skin cancer16,17. Many individuals with melanoma have 
brain metastases which are severe complications, and the prognosis for 
patients with metastasis has a median survival time of 6 months after 
diagnosis18. Melanoma cells can proliferate in the brain parenchyma or the 
meninges, and in cases where the blood-brain barrier is leaky, the lesions are 
also resistant to chemotherapeutic drugs18. A suggested mechanism involves 
very late antigen 4 (VLA-4), which regulates immune recruitment to 
inflamed endothelium. VLA-4 mediated adhesion of melanoma cells on the 
blood-brain barrier serves as a cue for melanoma cell intercalation and 
disruption of the barrier16. 92% of all human melanoma brain metastases 
stained VLA-4 positive16. This finding has further implications for multiple 
sclerosis as intercellular adhesion molecule 1 (ICAM-1) and vascular cell 
adhesion molecule-1 (VCAM-1), expressed at high levels during 
inflammation when VLA-4 is expressed, contribute to the development of 
autoimmune encephalomyelitis (EAE)16.  

Recently, a reciprocal relationship has been demonstrated between 
Parkinson’s Disease (PD) and melanoma19. This is a relationship wherein PD 
patients are more susceptible to melanoma and vice versa. The current 
framework and hypothesis suggest that α- synuclein modulates the 
aggregation of Pmel17, a functional amyloid that serves as a scaffold for 
melanin biosynthesis 19. Research on α- synuclein can help the scientific 
community develop novel approaches to treating melanoma but also can 
reveal insights into its role in PD19. 



 

Berkeley Pharma Tech Journal of Medicine | 111 

4. Psoriasis Pathogenesis and Antipsoriatic Drug 
Development 

Psoriasis is a non-communicable chronic immune-mediated skin disease with 
pathogenesis derived from both genetic and environmental factors15. It has 
been previously established that 5-HT is a stress mediator that contributes to 
the effects of psychological stress on the disruption of skin homeostasis in a 
variety of skin diseases, including psoriasis15. Psoriasis is mediated by T 
lymphocytes with Th1 and Th17 profiles20.  Some of the main triggers of 
psoriasis include trauma, non-steroidal anti-inflammatories, infections, and 
of course, psychological stress15. To garner a better understanding of 
psoriasis, we should first begin by investigating the processes that underlie 
skin immunity and neuroendocrinology15. Psychological stress has been 
proposed to dysregulate the HPA axis, which thereby exacerbates psoriasis20. 
This is likely due to the release of proinflammatory cytokines and over-
activation of the HPA axis20. 

Sunlight deficiency strongly impacts the severity of psoriasis. NB-UVB, 
narrow-band UVB, is the only currently accepted form of treatment for 
psoriasis20. Vitamin D deficiency is an important factor in the development 
and progression of psoriasis, and high doses of vitamin D were found to be 
efficient in eradicating psoriatic plaques20. This is also a deficiency that is 
common in both psoriasis and depression, and there may even be a causal 
relationship whereby vitamin D deficiency may increase the risk of 
depression20. 

Mouse models provide the scientific community with a basis for studying 
psoriasis pathogenesis and antipsoriatic drug development20,21. It is not 
uncommon to utilize animal models to promote the discovery and 
development of drugs. The mouse model of psoriasis can be divided into 
spontaneous, genetically engineered (transgenic and knockout), 
xenotransplantation, and directly induced approaches21. Animal models and 
other research has helped scientists delineate that IL-23 mediates the Th17 
cells, which is a key part of the pathogenesis of psoriasis21.    

 



 

Berkeley Pharma Tech Journal of Medicine | 112 

5. Conclusion 

Overall, the scientific community has made significant strides, especially in 
the past decade, regarding our current knowledge on the ‘brain-skin’ axis. 
Psychosocial stress, brought about by multiple factors, is a force that disturbs 
the dynamic equilibrium established between the nervous, endocrine, and 
immune systems, thereby triggering and aggravating disease manifestation1. 
There are many complexities intrinsic to these connections. Currently, our 
understanding includes the sympathetic nervous system, HPA axis, and 
neutrophin-neuropeptide axis22. Animal models and advancements in fMRI 
technology have contributed to a growing body of knowledge and literature 
on these mechanisms and their relationships to potential therapeutic 
applications. 

This relationship has demonstrated impacts in research on melanoma and 
psoriasis as well as other diseases and conditions such as stroke and brain 
trauma23. Future therapeutic avenues include the development of drugs that 
restore homeostasis in terms of the brain-skin connection, such as current 
research into agonists and antagonists directed toward 5-HT receptors24. 

 



Berkeley Pharma Tech Journal of Medicine | 113 

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