Pupil Dilation during Reward Anticipation Is Correlated to Depressive Symptom Load in Patients with Major Depressive Disorder

Abstract

Depression is a debilitating disorder with high prevalence and socioeconomic cost, but the brain-physiological processes that are altered during depressive states are not well understood. Here, we build on recent findings in macaques that indicate a direct causal relationship between pupil dilation and anterior cingulate cortex mediated arousal during anticipation of reward. We translated these findings to human subjects with concomitant pupillometry/fMRI in a sample of unmedicated participants diagnosed with major depression and healthy controls. We could show that the upregulation and maintenance of arousal in anticipation of reward was disrupted in patients in a symptom-load dependent manner. We could further show that the failure to maintain reward anticipatory arousal showed state-marker properties, as it tracked the load and impact of depressive symptoms independent of prior diagnosis status. Further, group differences of anticipatory arousal and continuous correlations with symptom load were not traceable only at the level of pupillometric responses, but were mirrored also at the neural level within salience network hubs. The upregulation and maintenance of arousal during reward anticipation is a novel translational and well-traceable process that could prove a promising gateway to a physiologically informed patient stratification and targeted interventions.

Asymmetrical attention to gambling-related stimuli and pupillary dilation in response to wins and losses in problem gamblers

“…Previous studies have reported pupillary dilation during reward anticipation and violation of expectations. [12][13][14][15][16][17] In this study, a signi cant difference in the response to punishment was observed during the feedback and feedback phases, while a trend toward a difference in the responses to reward was observed during the xation phase. Therefore, punishments may surprise PGs, and rewards may enhance reward anticipation for the next trial.…”

“…Pupillary diameter is modulated by the noradrenergic locus coeruleus and re ects various cognitive processes and emotions, such as attraction, mental effort, surprise, attention, and exploration. [10,11] Previous studies using non-gambling tasks demonstrated that greater pupillary dilation occurs during anticipation of a reward [12,13], and that excessive pupillary diameter in response to reward predicts failure in a stopwatch task. [14] Pupillary diameter has been presumed to be modulated by uncertainty and violations of expectations during gambling.…”

Asymmetrical Attention to Gambling-related Stimuli and Pupillary Dilation in Response to Wins and Losses in Problem Gamblers

“…Previous studies reported pupillary dilation during reward anticipation and violation of expectation. [12][13][14][15][16][17] Signi cant differences in responses to punishment were observed mainly in the feedback phase, while differences in responses to reward were observed in the xation phase. Therefore, punishments may surprise PGs, and rewards may enhance reward anticipation for the next trial.…”

“…Pupillary diameter is modulated by the noradrenergic locus coeruleus and re ects various cognitive processes and emotions, such as attraction, mental effort, surprise, attention, and exploration. 10,11 Previous studies using non-gambling tasks have demonstrated that greater pupillary dilation occurs during reward anticipation, 12,13 and that excessive effects of reward magnitude on pupillary diameter were predictive of subsequent failure in a stopwatch task. 14 Pupillary diameter has been presumed to be modulated by uncertainty and violations of expectations during gambling.…”

PupilEXT: Flexible Open-Source Platform for High-Resolution Pupillometry in Vision Research

“…Today, the pupil behavior has become an interdisciplinary field of research (La Morgia et al, 2018;Schneider et al, 2020;Joshi, 2021;Pinheiro and da Costa, 2021) in which the number of involved scientists rises, as the trend of the number of publications with the keywords "pupil diameter" or "pupillometry" reveals (Figure 2). The renewed attention to the temporal pupil aperture (Binda and Gamlin, 2017), its application in clinical diagnostics (Granholm et al, 2017;Joyce et al, 2018;Chougule et al, 2019;Kercher et al, 2020;Tabashum et al, 2021) and increasing popularity of chromatic pupillometry (Rukmini et al, 2017;Crippa et al, 2018) topics requires additional efforts in terms of standardization and provision of consistent tools, contributing to comparability in measurement and pre-processing methodologies.…”