The Global fMRI Signal Tracks Changes in Arousal

Post by Natalia Ladyka-Wojcik

The takeaway

A global brain signal closely correlates with changes in arousal across the brain and body, suggesting this signal may be shaped by the autonomic nervous system that modulates arousal. 

What's the science?

In functional magnetic resonance imaging (fMRI), the global signal is the average signal intensity across the whole brain. The global signal is one of the strongest and most consistent signals that neuroscientists detect, but it is often regressed out of neuroimaging analyses of functional connectivity because it is believed to represent physiological noise (such as heart rate or breathing) that could confound experimental results. Recently, however, some scientists have started to consider whether the global fMRI signal might reflect valuable information — it could also be tied to changes in arousal, like how awake or restful a person is. These slow brain signals (within a low-frequency, 0.01–0.1 Hz range) seem to line up with changes in both brain electrical activity captured with electroencephalography (EEG) and bodily responses related to arousal, such as pupil size. This week in Nature Neuroscience, Bolt and colleagues explored how closely the global fMRI signal is linked to activity in the autonomic nervous system, a part of the peripheral nervous system that regulates arousal-related processes in the body, including blood pressure and breathing. 

How did they do it?

The authors used several datasets, including fMRI, EEG, and recordings of physiological signals, to study what happens during rest and sleep with the global signal. They focused on things like heart rate changes, breathing patterns, sweating (measured through skin conductance), blood vessel pulsation, and changes in pupil size (with pupillometry) to see if these body signals fluctuated with the global fMRI signal. Importantly, they also examined whether moments when arousal levels spontaneously changed, like during brief events in sleep called “K-complexes” in EEG, were linked with coordinated changes in both the brain and body. Furthermore, their analysis included a dataset that measured how much carbon dioxide (CO₂) people exhaled (using a method called PETCO₂), which changes with arousal. By looking at how PETCO₂ was related to the global fMRI signal specifically, they could test whether breathing itself might simply be driving some of these global fluctuations between fMRI signal and physiological signals during rest, something that neuroimaging analyses typically aim to remove. 

What did they find?

The authors found that a single, global pattern could explain a lot of the shared activity between the brain’s global signal and various arousal systems. They observed this same brain–body pattern not only during spontaneous arousal changes in sleep (like K-complexes), but also when arousal was intentionally changed, for example, during deep breathing or sensory stimulation. Critically, they found that CO₂ levels alone could not explain the global brain fluctuations during rest. Instead, the authors suggest that their results demonstrate that the autonomic nervous system and brain signals that regulate arousal are likely driving these widespread patterns seen in fMRI. 

What's the impact?

This study is the first to show comprehensive evidence across many datasets to challenge the prevailing idea that global signals should be removed from fMRI simply because they are dominated by physiological noise. This research also highlights the potential importance of the global signal in understanding how the brain and body coordinate during rest and sleep.  

Access the original scientific publication here.

Striving for a Happier Brain

Post by Rebecca Glisson 

The takeaway

Recent studies have examined how happiness originates in the brain. The more we understand how we feel happy, the better we can work toward improving happiness at a societal level.

Searching for happiness in a stressful time

If you’ve been feeling stressed lately by recent events – climate change, political events, economic hardships – and you’re wondering how to find happiness and stay resilient, rest assured that scientists are wondering alongside you. Recent studies are exploring the link between stress and how our brains create the feeling of happiness. The World Health Organization, for example, reports that mental health issues are on the rise globally and that mental health impacts our ability to function in our daily lives. Another study has found that the more income inequality a nation experiences, the greater the inequality in national happiness. By understanding the neurobiology of happiness and how stress interferes, we can work to shape our society to increase overall happiness levels.

Dopamine and social media

Dopamine is a neurotransmitter that is widely associated with rewarding behavior. For example, when you eat something enjoyable, dopamine is released in the brain, you feel pleasure, and are more likely to repeat that behavior. However, stress can negatively impact how dopamine functions in response to pleasurable behaviors. Studies in rats have found that chronic stress is associated with less dopamine production in response to rewarding stimuli. In people, chronic stress could lead to a smaller and smaller dopamine response over time, which can result in more and more reward-seeking behavior to achieve the same dopamine response. You may have experienced this if you’ve ever gotten caught in a loop of endlessly browsing social media: looking at a new video or seeing a notification only releases a small amount of dopamine that disappears quickly, which starts a loop of further scrolling that releases even more dopamine. Limiting this kind of social media use is recommended, as it prevents you from developing a higher and higher tolerance to the dopamine response.

Oxytocin and social bonding

Another molecule associated with happiness in the brain is oxytocin, a hormone released in response to social bonding. One study found that if given an extra dose of oxytocin, a person will be more friendly to a stranger who gives them help. Another study showed that oxytocin given to depressed patients helps to maintain attention to a happy face. It is no wonder, then, that forced separation from regular social interaction due to pandemic shutdowns would lead to less oxytocin in our systems and less happiness from social lives.

What can we do to increase our happiness?

One science-backed way to increase happiness is by developing and maintaining strong social bonds, which are crucial for our well-being. We can work towards creating spaces for social bonding by designing our cities and living areas to foster meaningful social connections. Libraries and parks are great examples of places such as these where local events can lead to positive social interactions that can decrease our stress levels and increase our happiness over time.

References +

Alexander, R., Aragón, O. R., Bookwala, J., Cherbuin, N., Gatt, J. M., Kahrilas, I. J., ... & Styliadis, C. (2021). The neuroscience of positive emotions and affect: Implications for cultivating happiness and wellbeing. Neuroscience & Biobehavioral Reviews, 121, 220-249.

Bates, C. R., Bohnert, A. M., & Gerstein, D. E. (2018). Green schoolyards in low-income urban neighborhoods: natural spaces for positive youth development outcomes. Frontiers in psychology, 9, 805.

Berridge, K. C., & Kringelbach, M. L. (2011). Building a neuroscience of pleasure and well-being. Psychology of Well-Being: Theory, Research and Practice, 1, 1-26.

Di Chiara, G., Loddo, P., & Tanda, G. (1999). Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stress: implications for the psychobiology of depression. Biological psychiatry, 46(12), 1624-1633.

Domes, G., Normann, C., & Heinrichs, M. (2016). The effect of oxytocin on attention to angry and happy faces in chronic depression. BMC psychiatry, 16, 1-8.

Human, L. J., Woolley, J. D., & Mendes, W. B. (2018). Effects of oxytocin administration on receiving help. Emotion, 18(7), 980.

Macit, H. B., Macit, G., & Güngör, O. (2018). A research on social media addiction and dopamine driven feedback. Journal of Mehmet Akif Ersoy University Economics and Administrative Sciences Faculty, 5(3), 882-897.

Pressman, S. D., Jenkins, B. N., & Moskowitz, J. T. (2019). Positive affect and health: What do we know and where next should we go?. Annual review of psychology, 70(1), 627-650.

The Body Responds to “Cold Memories”

Post by Anastasia Sares

The takeaway

This study shows that bodily responses to warm and cold environments can be changed through conditioning, just like other behaviors. It also identifies a network of neurons including the hippocampus (important for forming memories) and the hypothalamus (important for controlling basic bodily states) that, when stimulated in mice, can reactivate these “cold memories,” causing their body to act as if it is in a cold environment even when the temperature is normal.

What's the science?

In Pavlovian conditioning, an animal learns to associate a stimulus with a consequence, and soon, the animal reacts to the stimulus alone, even when the consequence is absent. Classically, Pavlovian conditioning was demonstrated by teaching a dog that it would get food after the sound of a bell. Soon, the bell alone is enough to make the dog begin to salivate, even in the absence of food. In modern days, we have methods that allow us to record and stimulate specific brain circuits to figure out what parts of the brain are responsible for this conditioning.

This week in Nature, Muñoz Zamora and colleagues combined Pavlovian conditioning and modern cell neuroscience techniques to first locate—and then stimulate—the brain network in mice that connects contextual memories to our temperature regulation system.

How did they do it?

The authors placed mice into two different contexts over several training days: context A was a unique environment that was always at room temperature (21°C), while context B was a different unique environment that was always around refrigerator temperature (4°C). Being in a cold environment changes the mouse’s metabolism, burning a special kind of fat and consuming more oxygen and energy. At test time, they exposed the mice to context B but at room temperature. This way, whatever brain and body responses the mice had would be from their memory of the cold, not any actual cold.

To tell which cells are active while learning this association, the authors euthanized some mice after each of three phases: baseline (normal temperature, context A), first cold exposure (cold temperature, context B), and cold memory test (normal temperature, context B). They tested the brains for a type of gene (FOS) that is turned on in response to recent neural activity.

Finally, the authors were able to activate or suppress the groups of cells that had been involved in the temperature response. The method used to activate specific cells is called optogenetics, and it involves inserting a gene that makes neurons fire when exposed to light. Implanted lights can then be used to turn certain cells on in a precise manner. To suppress the circuit, the authors used a different process that relies on chemicals that bind to specific cells and inhibit their activity.

What did they find?

Upon exposure to a cold environment, oxygen use, energy use, and movement increased as mice responded to the new temperature. The mice’s metabolism also accelerated, as indicated by an increased amount of RNA in their cells relating to temperature regulation. After being trained to experience cold temperatures in context B, the mice’s brains and bodies went into this same “cold mode” anytime they were exposed to context B, even when it was no longer cold. This confirmed that the Pavlovian conditioning had worked.

The authors observed that the brains of mice that had recently done the cold memory test (context B, but room temperature) had higher FOS expression in certain brain areas, including the hypothalamus, which is responsible for regulating bodily states, and parts of the hippocampus, a structure involved in forming memories. They concluded that these two structures worked together to create this learned cold response. Further experiments confirmed that this pattern of expression was not a general stress response, but specific to cold. Targeting these cells with optogenetics allowed them to activate this network. Activating the network re-created cold response behaviors in mice. Chemical inhibition also removed the cold response in mice that had already learned it.

What's the impact?

The ability to regulate body temperature efficiently is important to survival, especially in climates with harsh weather. If mammals are able to use context to anticipate temperature changes, this could have helped them immensely in their evolutionary path. This research shows that our experiences and memories can affect bodily processes that we usually think of as “purely physical.”

Access the original scientific publication here.