The ‘Itch-to-Brain’ Circuit, Neural Change and Depression

People who suffer from chronic itching in the form of atopic dermatitis (AD) are seven times more likely to develop a major depressive disorder. This link is well-established, but the “why” remains elusive. Are the depressive symptoms simply due to inflammation, sleep disruption and the psychological distress of living with chronic illness? Or is it possible that AD could be somehow changing the brain itself?

In a new opinion piece, Santosh Mishra, associate professor of molecular biomedical sciences at NC State, proposes the latter: that AD-associated chronic itch signaling from lesional skin not only causes inflammation, stress, and distress; it drives neuroplastic changes in the brain’s sensory, emotional, and cognitive control circuits, which can lead to depression.

The Abstract sat down with Mishra to talk about the piece, which appears in JAMA Psychiatry.

The Abstract (TA): How long have we known that there was a connection between AD and depression?

Mishra: The connection between AD and depression has been recognized for some time. Specifically, the first landmark paper highlighting that patients with AD experience higher rates of depression was published nearly three decades ago by Hashiro and Okumura (J Dermatol Sci. 1997). In recent years, however, research has evolved significantly, suggesting that depressive disorder may actually share underlying immune abnormalities with inflammatory skin diseases.

TA: I know that you’re just beginning to explore this connection, but is the basic idea that the constant, repetitive signaling involved in AD causes the brain to be more susceptible to depression?

Mishra: That is exactly the direction we would like to pursue. While depression in AD has traditionally been viewed as a secondary outcome of chronic stress and sleep deprivation, we are exploring a more direct biological link. We are investigating whether the constant signaling from the skin – either through the peripheral nervous system or via systemic cytokine invasion – actually alters brain structure and function. Our goal is to determine if these cutaneous signals are not just a nuisance, but a primary driver of neurobiological changes in the brain.

TA: How do you theorize that works? Is it due to overstimulation? Do portions of the pre-frontal cortex essentially get “rewired?”

Mishra: That is a compelling hypothesis. We theorize that this process involves more than just simple overstimulation. Chronic, repetitive signaling from the skin may induce maladaptive neuroplasticity – essentially ‘rewiring’ circuits in the brain. Specifically, we would be interested in two things. First, how persistent peripheral inflammation or itch might trigger structural changes (such as altering synaptic density) in the brain. And second, how those triggers may cause functional changes in the brain by creating imbalance in excitatory or inhibitory inputs in regions like the prefrontal cortex and the amygdala, which are central to mood regulation. This might lower the threshold for depression, making the brain more vulnerable to emotional distress even after the physical itch is treated.

TA: How do you propose that the scientific community approach this question?

Mishra: We should adopt a multidisciplinary approach to this question. Being open to various mechanisms is essential because, ultimately, a deeper understanding of these diverse pathways provides more opportunities to treat these comorbid conditions. Since AD and depression often act as ‘fuel on the fire’ for one another, a holistic strategy – integrating immunology, neuroscience and psychology – will be key to developing more effective, personalized treatments for our patients.

TA: What are your next steps?

Mishra: Our primary next step is to establish a robust preclinical mouse model that accurately recapitulates the co-occurrence of atopic dermatitis and depressive-like behavior. Given our expertise in the neurobiology of itch, this approach allows us to examine how chronic sensory signaling from the skin to the peripheral nervous system may act as a driver for these central behavioral changes. By utilizing these validated models, we can systematically investigate the neuro-immune axis and the specific molecular pathways bridging skin inflammation and mood disorders. Ultimately, the goal would be to identify novel therapeutic targets that would allow for topical interventions with less side effects as well as reducing the reliance on psychotropic drugs or invasive procedures like deep-brain stimulation.