Insights

The Chemistry Experiment in Your Brain

A variety of forces gang up on us during cancer that cause chemical changes in the brain. These changes contribute to emotional volatility and variability. The disease itself, surgery and the anesthesia from surgery affect brain chemistry. So do the increased cortisol from stress and constant pain as well as the synthetic cortisol—prednisone or dexamethasone—we may be taking as part of treatment. Then there are the hormonal changes as a result of surgery and treatment. And the chemo/immunotherapy drugs themselves that also contribute to our emotional response.

One of the key drivers of this increased emotional volatility is a class of proteins called cytokines that our bodies produce to help cells in our immune systems coordinate in the fight against threats. We have pro-inflammation cytokines and anti-inflammation cytokines that work together to initiate an immune response when a threat is perceived, and resolve it when the threat has passed. Get a paper cut and pro-inflammation cytokines are released to tell your body to bring white blood cells and platelets to the site to heal the wound. A virus, too much exercise, pollen—there are lots of ways to trigger an immune response and they all involve pro-inflammatory cytokines.

The anti-inflammatory cytokines kick in when the cut is healed, the virus eradicated, the muscles repaired. It’s the balance of the two classes of cytokines that keeps an immune system healthy, and it’s the imbalance that lead to autoimmune diseases like allergies and rheumatoid arthritis. Somehow, the signal to shut down the inflammation doesn’t get through, and we stay inflamed.

Swimming in Cytokines

There is always some cytokine activity going on in the body and, the bigger the threat, the more the activity. Not surprisingly, our bodies perceive cancer as a threat. And that causes the release of pro-inflammatory cytokines. So does the stress we feel as a result of having cancer. Double whammy. And if a paper cut can release cytokines, just imagine what surgery can do. Radiation? Check. Chemotherapy? Check. Even the successful outcome of treatment—the death of cancer cells—increases cytokines. We are swimming in pro-inflammatory cytokines as we start cancer treatment.

But, cytokines are not all bad. In fact, cytokines also are used to help fight cancer. Some immunotherapy treatments harness the natural power of specific cytokines to regulate immune response: Interleukin 2, which is produced by the body to help fight infection, and Interferon-alpha, which helps fight off viruses and bacteria. These cytokines are infused like chemo to stimulate antibodies and attack unhealthy cells. But they do come with nasty side effects…

Sickness Behavior

While doing their thing in our bodies, cytokines also affect the brain. One way they do this is by interfering with normal function in the pre-frontal cortex. That’s the rational, analytical part of the brain. This interference allows the limbic system, the emotional part of the brain, to rule the day. When cytokine activity is high, the brain signals the body to behave as if it’s sick, leading to fatigue and flu-like symptoms that drive us back to bed. The rational part of the brain might otherwise encourage us to get up and go for a walk, but it isn’t functioning appropriately, so we don’t.

It’s not just that we are tired and mopey because we have cancer. We’re tired and mopey because our cytokines are on overdrive. They keep telling us to shut down. We feel less motivated to do anything and more tearful and dependent. In fact, depression is one of the major side effects of pro-inflammatory cytokine Interferon therapy.[1]

Some of that is good—after all, our bodies are working hard at recovery—and it can help ensure we get the rest and care from others we need. But it can be too much of a good thing when we don’t bounce back as we should after surgery and treatment. And sickness behavior is less productive when we’re dealing with emotional stress rather than physical stress. Hiding under the covers doesn’t decrease our natural anxiety about recurrence or having to go through another unpleasant treatment. So what is causing us to be so depressed?

No Rewards

As if messing around with normal function in the pre-frontal cortex weren’t enough,  inflammation also suppresses dopamine, the natural reward hormone. Without dopamine we don’t experience normal levels of motivation and arousal, and are increasingly sensitive to negative input from the environment. We become hypervigilant and protective against attack,[2]which feeds into anxiety about the disease and prognosis. Every little twinge becomes another warning sign that cancer is back or getting worse. This increased anxiety leads to increased cytokines and makes us less motivated to take a walk when exercise might actually help reduce inflammation and put those cytokines back in balance. It’s a downward spiral of inflammation and angst. No wonder it can be hard to get on with life while fighting cancer!

Our perceived control over stress is a key variability in this cytokine response cycle.[3]When we think the stress is predictable and we can control it, we learn to manage it. Our brains come to expect that particular stress and it no longer signals an automatic inflammatory response. But when we perceive stress as uncontrollable, such as cancer, look out. That’s when our bodies and brains become awash with cytokines. It’s like the difference between the adrenalin rush of a sports event vs. being stuck in traffic when we are late for an important meeting.

Individual Variability

As with most things having to do with emotions and the brain, each of us responds to inflammatory cytokines differently. Genetic predisposition and prior stress exposure, as well as BMI, age and gender (women are more likely than men to be sensitive to the behavioral effects of inflammation) play a role in how our systems respond to inflammation and the behavioral symptoms we experience. This creates tremendous variation in our susceptibility to depression, irritable anger, poor appetite and fatigue. And because cytokines also influence other neurotransmitters and hormones, it can be hard to predict exactly how any of us is going to feel. Suffice it to say, there is a chemistry experiment going on in there making emotions run high.

Speaking of hormones, testosterone and estrogen, which we all have in varying amounts regardless of age or gender, often take a beating with cancer. Surgery that removes any organs that produce or are receptive to hormones has an obvious impact. So does stress and any treatment that alters our baseline hormone levels and their natural fluctuations, such as estrogen or androgen suppression. Estrogen helps us manage fear and stress. Higher levels of estrogen increase physical and emotional resiliency. Sudden withdrawal of estrogen (think PMS, post-partum depression or surgical removal of ovaries) increases anxiety. Meanwhile, stress shuts down testosterone production, reducing our energy and stamina. And cortisol, either natural or in the synthetic form of prednisone or dexamethasone, messes around with both.

To Sleep, Perchance to Dream

Many of these factors also affect sleep patterns, which in turn affect emotions. Disrupted sleep is frequently associated with depression, anxiety and PTSD in a chicken-and-egg relationship that is difficult to sort out but often builds[4]. We are anxious because we are dealing with stress, the anxiety makes it difficult to sleep. Sleep disruptions throw off our natural cortisol cycles, making it harder for the pre-frontal cortex to do its job, and we become more susceptible to our emotions, feeling more anxious, which makes it difficult to sleep, etc., etc.

In addition to this chemically-induced emotional volatility, with cancer we often begin to struggle with cognitive changes. Stress itself can inhibit normal thinking patterns, making us hyper-focused on the threat but unable to concentrate on just about everything else. And, by interfering with normal function of the pre-frontal cortex, cytokines also affect memory, learning and attention. Meanwhile treatment itself, particularly chemotherapy, interferes with thinking ability in direct and indirect ways. While not universal, many patients—as many as 75% of those with breast cancer[5]— experience cognitive changes while undergoing treatment.

Chemo Brain

Whether called Cancer-Related Cognitive Impairment or Chemo Related Cognitive Dysfunction, or just plain “chemo brain,” there is something going on we don’t fully understand. Scientists think that cytokines are a contributing factor. So are hormonal changes. But they also are investigating whether chemo and other treatments increase cellular damage, which may change memory formation and learning. Higher levels of oxidative stress, a normal side effect of metabolism usually kept in check by a healthy lifestyle, is another possible cause, as is the potential that chemo reprograms the way we produce new cells and synapses in the brain, and alters the natural life span of brain cells.

A variety of factors influence who among us will experience chemo brain and how noticeable it will be. The type of treatment received. The degree to which we are already taxing our brains. Genetics, age at time of treatment, and general health all contribute.[6]There is a lot of research on the effect, but few clear answers, particularly as it is such a difficult thing to measure and test. In the meantime, it is one more insult many patients must endure and contributes to the emotional response we have to the disease. The good news is, most chemo brain dissipates in one to two years. Although, that can be a frustratingly long time.

Help and Hope

It is common to experience emotional and cognitive changes during treatment. It’s not a sign of weakness or a character flaw, it’s just chemistry. While it’s unsettling on many levels, just knowing that there are chemical divers of those changes can lessen the sting. It’s also helpful to know that there are things you and your medical team can do about it. Diet, exercise and meditation can help rebalance brain chemistry. Acupuncture and acupressure help reduce fatigue and battle depression. Cognitive behavioral therapy helps reduce emotional volatility, as can prescription antianxiety and antidepressant drugs. If the chemistry experiment in your brain seems like it is out of control, talk to your care team. Get the help you need to quiet the storm.

Read more about how meditation helps break the cycle of stress and inflammation.

Learn how exercise can reduce side effects and boost immunity.

And if you would like more information about the benefits of acupuncture, acupressure and other mind-body therapies, check out Memorial Sloan Kettering Cancer Center’s website on Integrative Medicine.

 

[1]Greenblatt, JM, The Brain on Fire: Inflammation and Depression, Psychology Today, November 23, 2011, https://www.psychologytoday.com/us/blog/the-breakthrough-depression-solution/201111/the-brain-fire-inflammation-and-depression.

[2]Miller, AH and Raison, CL, The role of inflammation in depression: from evolutionary imperative to modern treatment target, National Review of Immunology, January 16(1). Doi: 10.1028/nri.2015.5

[3]Donner, NC, et al, Two models of inescapable stress increase tph2 mRNA expression in the anxiety-related dorsomedial part of the dorsal raphe nucleus, Neurobiology of Stress, January 2018. Doi.org/10.1016/j.ynstr.2018.01.003

[4]Thompson, RS, et al, Effects of stressor controllability on diurnal physiological rhythms, Physiological Behavior, 2013 March 15; 0: 32–39. Doi:10.1016/j.physbeh.2013.02.009.

[5]Ahles, TA, Root, JC and Ryan, EL, Cancer- and Cancer Treatment-Associated Cognitive Change: An Update on the State of the Science, Journal of Clinical Oncology, 2012 Oct 20; 30(30): 3675–3686. Doi: 10.1200/JCO.2012.43.0116

[6]Wang, XM et al, Chemobrain: A critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy, Cytokine,2015 Mar; 72(1) 86-96, Doi: 10.1016/j.cyto.2014.12.006

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