Our eye’s pupil provides an indirect readout of the arousal state of our brain(1) if lighting conditions are controlled: it dilates when we are tense or stressed and constricts when we relax and calm down. This arousal state, which strongly influences mental well-being and cognition, is controlled by several key neuromodulatory systems in the brain(2,3,4). One of them is the Locus Coeruleus, in short LC, a small structure in the brainstem and the main source of the neurotransmitter noradrenaline(5).

Until today, regulating arousal relies mainly on drugs that can have pronounced side-effects. In our study, we took a non-invasive and drug-free pupil-based biofeedback approach to investigate whether receiving real-time feedback on pupil size allows us to self-regulate our pupil size and thereby the brain’s arousal state.

What did we do and what did we find?

We first tested whether healthy volunteers can learn to volitionally control their own pupil size when receiving three days of pupil-based biofeedback training. Therefore, participants were assigned to a pupil-based biofeedback group and received instructions on mental strategies for up- or downregulating pupil size. For example, upregulation can be achieved by imagining emotional (i.e., fearful, or joyful) situations, downregulation by imaging relaxing, safe situations together with focusing on their body or conscious breathing. Importantly, they received visual real-time feedback on pupil size which indicated whether the individual mental relaxation or activation techniques were effective. This was achieved by using an eye tracker recording pupil size and translating the measurement after fast online processing into an isoluminant visual feedback guiding the participants. Additionally, we recruited control participants that received the same instructions on mental strategies and the same amount of training, but they received uninformative feedback which was taken from randomly selected participants of the biofeedback group. These control participants were recruited to control for effects of visual input from the screen, learning effects due to mental rehearsal, or for effects related to motivation and perception of success. Participants who received real-time feedback about their own pupil size were significantly better in volitionally controlling their pupil size than control participants. Apparently, pupil-based feedback allowed participants to identify the mental strategies that worked best for them to up- and downregulate pupil size.

A look at the participants’ heart rate during volitional pupil regulation further revealed that up- and downregulating pupil size also resulted in a modulation of cardiac signals with higher heart rate during up- as compared to downregulation. And, interestingly, at the end of the training period, these differences in heart rate modulation were larger in the biofeedback than in the control group.

Next, we investigated whether such volitional changes in pupil size are indeed accompanied by activity changes in brainstem regions that regulate the arousal state of the brain, such as the noradrenergic LC. Therefore, we re-invited already trained participants of the biofeedback group and recorded their brain activity using functional magnetic resonance imaging while they were up- and downregulating their pupil size using their mental strategies. We found that up- and downregulation of pupil size were indeed accompanied by activity changes in the LC as well as other arousal regulating centers in the brainstem and basal forebrain.

Finally, we combined volitional up- and downregulation of pupil size with a simple auditory attention task, the “oddball task”. During the oddball task participants were listening to tones with a certain pitch which were occasionally replaced by a tone with a different pitch - the oddball - which required them to press a button. We used this task since task performance and physiological responses such as pupil dilation in response to the oddball tones have been shown to be closely linked to LC activity. We observed that when participants downregulated their pupil size, i.e., they lowered their state of arousal, they performed faster, and less variable on the task compared to when upregulating pupil size or performing a control task.

Why is it important?

Making the brain’s arousal system accessible to volitional control via pupil-based biofeedback has tremendous potential for basic neuroscience and behavioral research because it can be used to experimentally modulate the arousal state of the human brain, thereby enabling new discoveries into how arousal interacts with brain function and behavior. Even more important, our approach has a large potential for clinical translation both to diagnose and treat disorders that are characterized by abnormal arousal levels such as stress-related and anxiety disorders.

References

1. Bradshaw, J. Pupil Size ass a Measure of Arousal during Information Processing. Nature 216, 515-516 (1967).

2. Jones, B. E. Arousal systems. Front. Biosci. 8, s438–s451 (2003).

3. Zerbi, V. et al. Rapid reconfiguration of the functional connectome after chemogenetic locus coeruleus activation. Neuron 103, 702–718 (2019).

4. Reimer, J. et al. Pupil fluctuations track rapid changes in adrenergic and cholinergic activity in cortex. Nat. Commun. 7, 13289 (2016).

5. Samuels, E. R. & Szabadi, E. Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part I: principles of functional organisation. Curr. Neuropharmacol. 6, 235–253 (2008).