#286 ‒ Journal club with Andrew Huberman: the impact of light exposure on mental health and an immunotherapy breakthrough for cancer treatment

Andrew Huberman, professor of neurobiology at Stanford University and host of the Huberman Lab podcast, returns for another special journal club episode. Andrew introduces an observational study investigating the influence of light exposure on circadian clock regulation and its link to mental health, while Peter covers a phase III clinical trial employing immune checkpoint inhibitors for the treatment of metastatic cancer. They delve into the essential findings of their respective papers, elucidate the reasons for their enthusiasm, and tackle potential limitations and unanswered questions. Additionally, they provide valuable insights into their approaches for comprehending research studies, aiding listeners in independently navigating this process.

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We discuss:

• The intricate relationship between light exposure, circadian rhythms, and mental health [3:30];
• The importance of low solar angle sunlight, and other types of light needed for optimal mental and physical health [12:00];
• Promising new lightbulb technology that simulates low solar angle sunlight [17:45];
• The significance of both darkness and the need for direct light exposure to the eyes, specifically [20:00];
• Some tips and advice regarding optimizing light exposure, dark exposure, blue blockers, and the effect on the circadian rhythm [22:15];
• Andrew presents a paper which suggests avoiding light at night and seeking light during the day is associated with better mental health [25:45];
• Examining the data: the negative impact of increasing nighttime light exposure and the positive effects of daytime light exposure [34:30];
• Statistical analysis: the importance of focusing not only on statistical significance but also clinical relevance, power analysis, error bar range, and more [45:45];
• Takeaways from the study of daytime and nighttime light exposure [49:45];
• The practicalities of minimizing light exposure and screen time at night, the use of sleep trackers, and overall challenge of modern, indoor lifestyles [55:15];
• Potential limitations of the light exposure study, reverse causality, and the complex interplay of variables in epidemiological studies [1:06:00];
• A tangent on diet soda and sugar substitutes as an example of reverse causality [1:13:15];
• Andrew and Peter’s take on the causality vs. correlation of light exposure to mental health, the damage of circadian disruption, and the interpretation of observational data [1:17:30];
• A primer on the immune system as background for the paper Peter chose [1:25:00];
• Background on cancer: causes, how it evades the immune system, and the logic behind immune checkpoint inhibitor therapy [1:35:45];
• Peter presents a paper on immune checkpoint inhibitor therapy in cancer patients [1:50:15];
• Unpacking the results of the checkpoint inhibitor trial [1:59:45];
• Other noteworthy observations including the differing results between males and females [2:15:30];
• Adverse effects resulting from treatment with an immune checkpoint inhibitor targeting CTLA-4 [2:20:00];
• Why melanoma is especially responsive to immunotherapy, and the remarkable success story of immunotherapy for pancreatic cancer [2:25:15];
• Why immunotherapy may be the most important hope we have for treating cancer [2:35:30];
• Avoiding melanoma: the sunscreen debate, sunburn as the biggest risk factor, and more [2:38:45]; and
• More.

The intricate relationship between light exposure, circadian rhythms, and mental health [3:30]

• Andrew is excited about this journal club because he gets to pick papers he’s really excited about, and he gets to hear about papers Peter is really excited about
  • They get to sharpen their skills at reading and sharing data, and people listening can do that as well
• Andrew is excited about this paper for a number of reasons
  • It’s powerful in the sense that it examined light exposure behavior as well as dark exposure behavior
  • This was a study of >85,000 people as part of a cohort in the UK Biobank

There’s a longstanding interest in the relationship between light and mental health and physical health, and we can throw up some very well agreed upon bullet points 

• 1 – There is such a thing as seasonal affective disorder 
  • It doesn’t just impact people living at really northern locations, but basically there’s a correlation between day length and mood and mental health such that for many people (not all) when days are longer in the spring and summer, they feel better, and they report fewer depressive symptoms
  • Conversely, when days are shorter, significantly more people report feeling lower mood and affect
  • There’s a longstanding treatment for seasonal affective disorder, which is to give people exposure to very bright light, especially in the morning
    • That’s normally accomplished with SAD lamps (seasonal affective disorder lamps), and those lamps are basically bright (more than 10,000 lux lights)
    • They place on their kitchen counter or at their table in the morning or in their office so they’re getting a lot of bright light
    • That has proven to be fairly effective for the treatment of seasonal affective disorder
• What’s less understood is how light exposure in the middle of the night can negatively impact mood and health

Where we are headed with this is that there seems to be (based on the conclusions of this new study) a powerful and independent role of both daytime light exposure and nighttime dark exposure for mental health 

• 2 – The biological mechanisms for all this are really well established
  • There’s a set of cells in the neural retina which lines the back of your eye
    • They’re sometimes called intrinsically photosensitive
    • Retinal ganglion cells are sometimes called melanopsin retinal ganglion cells
  • It’s well known that those cells are the ones that respond to two different types of light input (not one, but two different types of light input) and send information to the hypothalamus where your master circadian clock resides
  • Then your master circadian clock sends out secretory signals (so peptides, hormones, but also neural signals) to the brain and body and say, “Hey, now it’s daytime, now it’s nighttime, be awake, be asleep.” 
  • But it goes way beyond that
  • These melanopsin intrinsically photosensitive retinal ganglion cells also project to areas of the brain like the habenula, which can trigger negative affect, negative mood
    • They can trigger the release of dopamine or the suppression of dopamine, the release of serotonin, the suppression of serotonin, and so they’re not just cells for setting your circadian clock
    • They also have a direct line (literally one synapse away) into the structures of the brain that we know powerfully control mood
    • The mechanistic basis for all this is there
• There’s just a couple of other key points to understand for people to really be able to digest the data in this paper fully
• 3 – There are basically two types of stimuli that these cells respond to 
  • #1 is very bright light, as we just talked about
    • That’s why getting a lot of daytime sunlight is correlated with elevated mood
    • That’s why looking at a 10,000 lux artificial lamp can offset seasonal affective disorder

Peter asks, “How many lux does the sun provide on a sunny day at noon?” 

• On a really bright day with minimal cloud cover, it could be 300,000 lux
• Most indoor environments [are dim], even though they might seem very bright, a department store with the bright lights, is probably only closer to 6,000 lux maximum and probably more like 4,000 lux

Most brightly lit indoor environments are not that bright when it comes down to total photon energy 

• On a cloudy day when you’re outside, it can be as bright as an average of 100,000 lux, but it won’t seem bright because you don’t see the sun
  • Also, when there’s cloud cover, a lot of those long wavelengths of light (such as orange and red light) aren’t coming through
• 4 – The circadian clock (the suprachiasmatic nucleus), it sums photons 
  • “It’s a photon summing system”
  • If you’re outside in 8,000 lux, a very overcast UK winter day, and you’re walking around (hopefully without sunglasses because sunglasses are going to filter a lot of those photons out), your circadian clock is summing the photons
  • It’s an integration mechanism; it’s not triggered in a moment
• The experiments of recording from these cells (first done by David Berson at Brown) were historic in the field of visual neuroscience
  • When shown bright light on these intrinsically photosensitive cells, you could crank up the intensity of the light and the neurons would ramp up their membrane potential and then start spiking firing action potentials
  • Long trains of action potentials that have been shown to go on for hours
    • “That’s the signal that’s propagating into the whole brain and body” 

The important thing to understand is this is not a quick switch, and that’s why Andrew suggests on non-cloudy days, that people get 10 minutes or so of sunlight in their eyes in the early part of the day, another 10 minimum in the later part of the day 

• He recommends people get as much sunlight in their eyes as they safely can throughout the day
• The key time for people to get sunlight in their eyes is when the sun is low in the sky (low solar angle sunlight), and Andrew will explain more about this later
  • Since Peter is a physician, he had a guest on talking about this recently
  • When the sun is low in the sky, you run very, very little risk of inducing cataract by looking in the general direction of the sun, you should still blink as needed to protect the eyes 
  • It’s when the sun is overhead, there’s all those photons coming in quickly in a short period of time that you do have to be concerned about cataract and macular degeneration if you’re getting too much daytime sunlight
  • The idea is sunglasses in the middle of the day are fine, but you really should avoid using them in the early and later part of the day 
    • Unless you’re driving into the sun for safety reasons

Peter asks, “If a person is indoors, but they have large windows, they’re getting tons of sunlight into their space, and they don’t even need ambient indoor light. How much of the photons are making it through the glass and how does that compare to this effect?” 

In general, unless the light is coming directly through the window, most of the relevant wavelengths are filtered out 

• In other words, if you can’t see the sun through the window, even if sufficient light is being provided, that’s insufficient to trigger this phenomenon
• However, if you have windows on your roof (skylights), that makes the situation much better
• The neurons in the eye that signal to the circadian clock and these mood centers in the brain reside mainly in the bottom two thirds of the neural retina and are responsible for looking up
  • Basically, they’re gathering light from above
  • These cells are also very low resolution
    • Think of them as big pixels
    • They’re not interested in patterns and edges and movement
    • They’re interested in how much ambient light there happens to be
• Keep in mind that this mechanism is perhaps the most well conserved mechanism in cellular organisms

The importance of low solar angle sunlight, and other types of light needed for optimal mental and physical health [12:00]

• Types of light that one needs to see every 24 hours for optimal health
  • By optimal health, he really means mental health and physical health, but we’re going to talk about mental health mainly today in this paper

Why exposure to low solar angle sunlight (at sunrise and in the evening) is important

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Andrew Huberman, Ph.D.

Andrew Huberman earned his Bachelor’s degree from the University of California, Santa Barbara. He went on to earn a Master’s degree in Neurobiology and Behavior from the University of California, Berkeley, and a PhD in Neuroscience from the University of California, Davis. He completed his postdoctoral training at Stanford University. 

Dr. Huberman is currently an Associate Professor of Neurobiology and an Associate Professor (by courtesy) of Psychiatry and Behavioral Sciences at Stanford University. His laboratory studies neural regeneration with the goal of developing treatments to prevent and reverse vision loss. They also study neuroplasticity and circuits for anxiety and visually-driven autonomic arousal. 

In 2021 Andrew started the Huberman Lab podcast where he discusses neuroscience and the connections between the brain, our organs, our perceptions, our behaviors, and our health. This has become one of the top-10 podcasts on Apple Podcasts and Spotify. [Stanford]

Twitter: @hubermanlab

Instagram: hubermanlab