This blog post has probably been the most difficult to draft. It runs the risk of being misinterpreted as a personal cry for help. (It is not, and I love you for caring.) It risks sounding judgmental. (It is not, and I am here to help whether we are now friends or soon to be friends.) It is a taboo subject for many. (It should not be, and that discomfort says more about them than the topic.) It risks the perception that I am weak and therefore unhireable as an advisor/consultant/etc.. (Discussing the hard things requires strength, not weakness, in business and life. Oh, and I am happy to compare IQ tests, go for a looooong run together, or do a pullup contest. :))
Medicine has given people with multiple sclerosis an extraordinary gift: time. Where once an MS diagnosis meant a dramatically shortened lifespan, today’s disease-modifying therapies have extended both life expectancy and qualify of life expectancy. Yet this triumph of medical science brings with it an unexpected psychological burden. As people with MS live longer, they also live longer with something the human brain finds uniquely difficult to tolerate: profound, inescapable uncertainty.
The Depression Reality in Multiple Sclerosis
Before examining the relationship between uncertainty and mental health in MS, we must acknowledge the current scope of the problem. The statistics are sobering. Depression affects approximately 25 to 30 percent of people with MS at any given time, and the lifetime prevalence reaches an alarming 50 percent. To place these numbers in context, a large study of nearly 14,000 MS patients found that 18.2 percent experienced moderate to severe depressive symptoms, compared to just 8.5 percent in the general population.
These are not merely numbers on a page. Depression in MS patients correlates strongly with disability level, fatigue, and reduced quality of life. It affects treatment adherence, employment outcomes, and relationships. At the extreme end of this spectrum, people with MS face twice the suicide risk of the general population. Depression worsens with disease progression: while 19.2 percent of those with lower disability levels (EDSS 0 to 4) experience depression, that number climbs to 31.9 percent for those with EDSS scores of 4.5 and above.
What makes these statistics particularly troubling is the treatment gap. Of those MS patients with depression, nearly 30 percent receive no treatment whatsoever. Among those who do receive treatment, 26 percent continue to experience symptoms severe enough to meet the threshold for probable depression. The mental health needs of the MS population are vast, and our current systems are not meeting them.
Why Uncertainty Is Neurologically Stressful
To understand why living with MS (or any lifelong debilitating disease) creates such profound psychological challenges, we must look to the neuroscience of uncertainty itself. A landmark study published in Nature Communications provides crucial insights into how the human brain responds to unpredictability. (Thanks to John Jennings who brought this study to my attention in his book, The Uncertainty Solution.)
Researchers at University College London subjected healthy volunteers to a learning task in which they had to predict whether painful electric shocks would follow certain visual cues. The probabilities changed throughout the experiment, creating varying levels of uncertainty. Using computational modeling, the researchers tracked three distinct forms of uncertainty: irreducible uncertainty (the inherent randomness of outcomes), estimation uncertainty (lack of knowledge about probabilities), and volatility uncertainty (instability in the environment).
The findings were striking. Both subjective stress ratings and physiological stress markers (pupil dilation, skin conductance, and cortisol levels) tracked most closely with irreducible uncertainty. Stress peaked when participants believed the probability of receiving a shock was around 50 percent, the point of maximum unpredictability. This is not merely a psychological preference for certainty; it represents a fundamental way the brain processes threat. When outcomes are completely unpredictable, the stress response system activates more intensely than when outcomes are certain, even if the certain outcome is negative.
Perhaps most relevant to MS, the study found that people with higher baseline stress levels demonstrated what the researchers called higher “metavolatility.” These individuals behaved as though they believed the world was fundamentally less stable. Their internal models of the environment assumed more frequent, unpredictable changes. In other words, chronic exposure to uncertainty appears to recalibrate how the brain expects the world to behave.
Multiple Sclerosis: A Disease Defined by Irreducible Uncertainty
The relevance to MS becomes immediately apparent. MS is a disease fundamentally characterized by unpredictability across multiple dimensions:
Relapse unpredictability: Even with effective treatment, patients cannot know when or if the next relapse will occur. The disease can remain quiet for months or years, then flare without warning.
Progression unpredictability: Some people with relapsing-remitting MS never convert to secondary progressive MS, while others do so within a decade. Current medicine cannot predict individual trajectories with precision.
Symptom unpredictability: Fatigue, cognitive symptoms, pain, and other manifestations fluctuate without clear patterns. A person may wake up feeling functional or impaired, with little ability to forecast their day.
Treatment unpredictability: While we have effective DMTs, individual responses vary. What works brilliantly for one patient may fail for another. What works brilliantly today may fail tomorrow. Side effects are also difficult to predict.
Disability unpredictability: The correlation between MRI lesion burden and clinical disability is notoriously imperfect. Two patients with similar MRI findings can have vastly different functional outcomes. I have an obscene number of lesions and run ultramarathons. Other MS warriors have a fraction and use mobility devices.
This is not uncertainty that resolves with more information or better decision-making. It is, to use the language of the Nature study, irreducible uncertainty. It is randomness inherent to the disease process itself. And if the research on stress and uncertainty is correct, this is precisely the type of uncertainty that the human stress response system finds most difficult to manage.
The Paradox of Progress: Living Decades with the Unknown
The history of MS treatment reads as a story of remarkable progress. Before the advent of disease-modifying therapies, life expectancy for people with MS was dramatically reduced. As recently as the 1980s and 1990s, MS was often portrayed as a rapidly disabling condition that would significantly shorten life.
The introduction of beta interferons in the 1990s marked a turning point. A long-term study from the University of British Columbia following nearly 6,000 people with relapsing MS found that those who took beta interferons for more than six months had a 32 percent lower mortality risk compared to those who did not. For those who took beta interferons for more than three years, the benefit was even more pronounced. This survival advantage persisted even for people who did not start treatment until five or more years after diagnosis.
The newer, more effective therapies introduced over the past decade have accelerated this trend. Current research indicates that life expectancy for people with MS who hit the 5-year marker without activity is now only 5 to 10 years shorter than the general population, down from gaps that were once much larger. Some recent studies suggest the gap may be as narrow as six to eight years. Many (but not all!) MS patients today can reasonably expect to live into their seventies, approaching the lifespan of their peers without MS.
This is, without question, a medical triumph. Yet it creates an unanticipated consequence: people with MS now face the prospect of living for decades with profound uncertainty about their future function, independence, and quality of life.
Consider the psychological position of a 30-year-old newly diagnosed with relapsing-remitting MS. Modern medicine can offer highly effective treatment that will likely slow disease progression and extend life expectancy. But it cannot tell this person whether they will be walking unassisted at age 50. It cannot predict whether cognitive changes will affect their career. It cannot guarantee that their current treatment will continue working or that side effects will remain tolerable. It cannot eliminate the possibility of a severe relapse that changes everything.
This individual may live another 45 years. That is 45 years of managing irreducible uncertainty. That is 45 years during which their brain’s stress response system must navigate a threat that cannot be predicted, controlled, or eliminated. If the Nature Communications research is correct, this chronic exposure to irreducible uncertainty may actually recalibrate their internal model of the world, making them increasingly likely to expect instability and unpredictability in all domains of life.
The Accumulation of Uncertainty Stress
The Nature study revealed another crucial finding: the relationship between uncertainty and stress was not momentary but cumulative. Subjects’ stress responses built over time as they encountered repeated unpredictable outcomes. This has profound implications for MS, where uncertainty is not a single event but a chronic condition.
Living with MS means living with multiple sources of ongoing uncertainty. Each MRI scan brings anxiety about new lesions. Each new symptom raises questions about progression. Each medication decision involves weighing imperfect probabilities of benefit and harm. The uncertainty does not resolve; it simply takes new forms as the disease and life circumstances evolve.
We might term this “cumulative uncertainty burden.” Unlike acute stressors that resolve, the uncertainty inherent to MS persists year after year, decade after decade. The person with MS cannot “solve” the problem of uncertainty or make it go away through better planning or decision-making. They can only learn to carry it.
This may explain why depression rates in MS remain so high despite improved medical outcomes. While DMTs have successfully extended lifespan and reduced disability progression, they have not eliminated the fundamental unpredictability of the disease. In some ways, they have extended the duration of exposure to that unpredictability.
What This Means for Care
When I was first diagnosed, Courtney and I came prepared. We had done our research and wanted to immediately discuss disease-modifying therapies. We were ready to make treatment decisions. My neurologist stopped us.
He looked at us and said something I will never forget: “If you cannot fight this, you need to find help to do so. The DMTs will be a reminder of the disease. The choice will not matter if you cannot fight because you will skip doses so you are not reminded.”
He understood something fundamental: the most sophisticated medical treatment in the world is meaningless if the patient cannot psychologically carry the burden of having the disease. The pills, the injections, the infusions, they all serve as daily reminders that you have MS. They force you to acknowledge the disease every single day. Without the mental fortitude to face that reality, even the best treatment plan will fail.
That conversation changed how I understood MS care. My neurologist recognized that mental health was not an afterthought or a secondary concern. It was the foundation upon which all other treatment would be built.
Understanding MS through the lens of uncertainty neuroscience suggests several important implications for how we approach mental health in this population:
Validation of the psychological burden: The mental health challenges of MS are not weakness or poor coping. They are predictable responses to a neurobiological stressor (uncertainty) that research shows is particularly difficult for the human brain to manage. This framing may help reduce stigma and encourage people to seek support.
Proactive mental health intervention: Given that 50 percent of MS patients will experience depression at some point, mental health screening and support should be standard components of MS care from diagnosis onward, not crisis interventions offered after psychological distress becomes severe.
Uncertainty-specific interventions: Psychological interventions that specifically address tolerance of uncertainty, such as certain forms of cognitive behavioral therapy, may be particularly valuable for this population. These approaches teach skills for living with unresolvable uncertainty rather than attempting to eliminate it.
Realistic expectations about treatment: While DMTs represent genuine progress, we must avoid creating false certainty about outcomes. Honest conversations about what treatment can and cannot predict may help patients develop more realistic mental models of their disease course.
Peer support and shared experience: The isolation of uncertainty may be particularly toxic. Connecting people with MS to others who understand the experience of living with profound unpredictability may provide crucial psychological support.
Looking Forward
The evolution of MS treatment over the past three decades represents one of neurology’s great success stories. We have transformed a disease that once reliably shortened life into one where many patients can expect near-normal lifespans. We have slowed disability progression, reduced relapse rates, and given millions of people more functional years than previous generations could have imagined.
Yet we must acknowledge what we have not yet achieved: we have not eliminated the fundamental uncertainty that makes MS so psychologically challenging. We have extended life without eliminating the unpredictability that makes that extended life, for many, profoundly stressful.
The neuroscience research on uncertainty helps us understand why mental health challenges persist even as medical outcomes improve. Living longer with MS means living longer with irreducible uncertainty, a neurological stressor that the brain is poorly equipped to handle indefinitely.
The next frontier in MS care must include serious attention to this psychological reality. We need mental health interventions as sophisticated as our disease-modifying therapies, approaches that acknowledge the unique challenge of living well amid inescapable uncertainty. We need health systems that treat depression in MS with the same urgency and resources we devote to preventing relapses. And we need a broader conversation about what quality of life means when the quantity of life has been extended but the uncertainty that pervades it remains.
Medical progress has given people with MS more years. Personally, I remind myself that I have a condition with a 100 percent mortality rate: being alive. I will do what everyone before me has done. I will die.
So, with that known, I get to choose how I will live. I do not want anything to steal today. Whatever takes my future will happen. I cannot control that. I will not give worry and fear the gift and blessing of today.
The question we now face is how to make those years not just longer, but livable with the psychological burden that extended uncertainty creates. The answer will require us to be as innovative about mental health as we have been about neurology, and as committed to understanding the mind as we are to protecting the brain.
Note: This post discusses research on depression and suicide in MS populations. If you are experiencing thoughts of self-harm, please contact the National Suicide Prevention Lifeline at 988 or the Crisis Text Line by texting HOME to 741741.