Yi-Hsuan Chang’s research while affiliated with Taipei Medical University and other places

Introduction This study aims to investigate the locus coeruleus-norepinephrine system (LC-NE) function in late-life depression (LLD) patients by examining task-evoked pupil dilation in the emotional face-word Stroop task, given the recently established coupling between task-evoked pupil dilation and LC-NE activation. Materials and Methods Using video-based eye-tracking and principal component analysis, we explored task-evoked pupil responses and eye blinks in LLD patients (N = 25) and older healthy controls (CTRL) (N = 29) to determine whether there were alterations in pupil responses and eye blinks in LLD compared to CTRL. Results LLD patients exhibited significantly different pupil and eye-blink behavior compared to CTRL, with dampened task-evoked pupil dilation associated with emotional congruency and valence processing mediated by the sympathetic system compared to CTRL. Eye-blink rates associated with emotional valence were also altered in LLD compared to CTRL Moreover, Geriatric Depression Scale-15 scores in LLD correlated with emotional congruency effects revealed by task-evoked pupil dilation. Conclusion The findings demonstrate that LLD patients display altered pupil behavior compared to CTRL. These altered responses correlated with the severity of depressive symptoms, indicating their potential as objective biomarkers for use in large at-risk populations for LLD.

Late-life depression (LLD) is a psychiatric disorder in older adults, characterized by high prevalence and significant mortality rates. Thus, it is imperative to develop objective and cost-effective methods for detecting LLD. Individuals with depression often exhibit disrupted levels of arousal, and microsaccades, as a type of fixational eye movement that can be measured non-invasively, are known to be modulated by arousal. This makes microsaccades a promising candidate as biomarkers for LLD. In this study, we used a high-resolution, video-based eye-tracker to examine microsaccade behavior in a visual fixation task between LLD patients and age-matched healthy controls (CTRL). Our goal was to determine whether microsaccade responses are disrupted in LLD compared to CTRL. LLD patients exhibited significantly higher microsaccade peak velocities and larger amplitudes compared to CTRL. Although microsaccade rates were lower in LLD than in CTRL, these differences were not statistically significant. Additionally, while both groups displayed microsaccadic inhibition and rebound in response to changes in background luminance, this modulation was significantly blunted in LLD patients, suggesting dysfunction in the neural circuits responsible for microsaccade generation. Together, these findings, for the first time, demonstrate significant alterations in microsaccade behavior in LLD patients compared to CTRL, highlighting the potential of these disrupted responses as behavioral biomarkers for identifying individuals at risk for LLD.

Pupil size is a non‐invasive index for autonomic arousal mediated by the locus coeruleus–norepinephrine (LC‐NE) system. While pupil size and its derivative (velocity) are increasingly used as indicators of arousal, limited research has investigated the relationships between pupil size and other well‐known autonomic responses. Here, we simultaneously recorded pupillometry, heart rate, skin conductance, pulse wave amplitude, and respiration signals during an emotional face–word Stroop task, in which task‐evoked (phasic) pupil dilation correlates with LC‐NE responsivity. We hypothesized that emotional conflict and valence would affect pupil and other autonomic responses, and trial‐by‐trial correlations between pupil and other autonomic responses would be observed during both tonic and phasic epochs. Larger pupil dilations, higher pupil size derivative, and lower heart rates were observed in the incongruent condition compared to the congruent condition. Additionally, following incongruent trials, the congruency effect was reduced, and arousal levels indexed by previous‐trial pupil dilation were correlated with subsequent reaction times. Furthermore, linear mixed models revealed that larger pupil dilations correlated with higher heart rates, higher skin conductance responses, higher respiration amplitudes, and lower pulse wave amplitudes on a trial‐by‐trial basis. Similar effects were seen between positive and negative valence conditions. Moreover, tonic pupil size before stimulus presentation significantly correlated with all other tonic autonomic responses, whereas tonic pupil size derivative correlated with heart rates and skin conductance responses. These results demonstrate a trial‐by‐trial relationship between pupil dynamics and other autonomic responses, highlighting pupil size as an effective real‐time index for autonomic arousal during emotional conflict and valence processing.

Pupil size primarily changes to regulate the amount of light entering the retina, optimizing the balance between visual acuity and sensitivity for effective visual processing. However, research directly examining the relationship between pupil size and visual processing has been limited. While a few studies have recorded pupil size and EEG signals to investigate the role of pupil size in visual processing, these studies have predominantly focused on the domain of visual sensitivity. Causal effects of pupil size on visual acuity, therefore, remain poorly understood. By manipulating peripheral background luminance levels and target stimulus contrast while simultaneously recording pupillometry and EEG signals, we examined how absolute pupil size affects visual discrimination and visually evoked potentials (VEP) in a task using optotype mimicking the Snellen eye chart, the most common assessment of visual acuity. Our findings indicate that both higher background luminance levels and higher target contrast were associated with improved target discrimination and faster correct reaction times. Moreover, while higher contrast visual stimuli evoked larger VEPs, the effects of pupil size on VEPs were not significant. Additionally, we did not observe inter-individual correlations between absolute pupil size and discrimination performance or VEP amplitude. Together, our results demonstrate that absolute pupil size, regulated by global luminance level, played a functional role in enhancing visual discrimination performance in an optotype discrimination task. The differential VEP effects of pupil size compared to those of stimulus contrast further suggested distinct neural mechanisms involved in facilitating visual acuity under small pupils.

Autistic individuals encounter challenges in recognizing emotional expressions of others. Pupillary response has been proposed as an indicator of arousal dysregulation or cognitive load. The pupillary response of autistic individuals during socio‐affective tasks remains unclear. This study investigated pupillary response in autistic adults when viewing emotional faces/eyes and recognizing emotions during the Reading the Mind in the Eyes Test (RMET) and watching interpersonal touch scenes in the social touch task. The study included 98 participants diagnosed with autism spectrum disorder and 37 typically developing controls (TD). Pupil size was measured using the Tobii X2‐30 Eye Tracker. The results showed that autistic adults had larger maximal pupil sizes, smaller minimal pupil sizes, and greater change rates of pupil size, particularly during the RMET Eyes task. Clinical correlations revealed that attention switching difficulty positively correlated with mean pupil size in TD participants, while social communication deficits positively correlated with mean pupil size in autistic participants. In conclusion, our findings suggest atypical pupillary responses in autistic adults during socio‐affective tasks, indicating heightened cognitive demand. Further investigation is necessary to understand the underlying mechanisms and their association with autistic traits.

Background Late-life depression (LLD) is a prevalent neuropsychiatric disorder in the older population. While LLD exhibits high mortality rates, depressive symptoms in older adults are often masked by physical health conditions. In younger adults, depression is associated with deficits in pupil light reflex and eye blink rate, suggesting the potential use of these responses as biomarkers for LLD. Methods We conducted a study using video-based eye-tracking to investigate pupil and blink responses in LLD patients (n = 25), older (OLD) healthy controls (n = 29), and younger (YOUNG) healthy controls (n = 25). The aim was to determine whether there were alterations in pupil and blink responses in LLD compared to both OLD and YOUNG groups. Results LLD patients displayed significantly higher blink rates and dampened pupil constriction responses compared to OLD and YOUNG controls. While tonic pupil size in YOUNG differed from that of OLD, LLD patients did not exhibit a significant difference compared to OLD and YOUNG controls. GDS-15 scores in older adults correlated with light and darkness reflex response variability and blink rates. PHQ-15 scores showed a correlation with blink rates, while MoCA scores correlated with tonic pupil sizes. Conclusions The findings demonstrate that LLD patients display altered pupil and blink behavior compared to OLD and YOUNG controls. These altered responses correlated differently with the severity of depressive, somatic, and cognitive symptoms, indicating their potential as objective biomarkers for LLD.

The locus coeruleus‐norepinephrine (LC‐NE) system, which regulates arousal levels, is important for cognitive control, including emotional conflict resolution. Additionally, the LC‐NE system is implicated in P300 generation. If the P300 is mediated by the LC‐NE system, and considering the established correlations between LC activity and pupil dilation, P300 amplitude should correlate with task‐evoked (phasic) pupil dilation on a trial‐by‐trial basis. However, prior studies, predominantly utilizing oddball‐type paradigms, have not demonstrated correlations between concurrently recorded task‐evoked pupil dilation and P300 responses. Using a recently developed emotional face‐word Stroop task that links pupil dilation to the LC‐NE system, here, we examined both intra‐ and inter‐individual correlations between task‐evoked pupil dilation and P300 amplitude. We found that lower accuracy, slower reaction times, and larger task‐evoked pupil dilation were obtained in the incongruent compared to the congruent condition. Furthermore, we observed intra‐individual correlations between task‐evoked pupil dilation and P300 amplitude, with larger pupil dilation correlating with a greater P300 amplitude. In contrast, pupil dilation did not exhibit consistent correlations with N450 and N170 amplitudes. Baseline (tonic) pupil size also showed correlations with P300 and N170 amplitudes, with smaller pupil size corresponding to larger amplitude. Moreover, inter‐individual differences in task‐evoked pupil dilation between the congruent and incongruent conditions correlated with differences in reaction time and P300 amplitude, though these effects only approached significance. To summarize, our study provides evidence for a connection between task‐evoked pupil dilation and P300 amplitude at the single‐trial level, suggesting the involvement of the LC‐NE system in P300 generation.

Pupil size undergoes constant changes primarily influenced by ambient luminance. These changes are referred to as the pupillary light reflex (PLR), where the pupil transiently constricts in response to light. PLR kinematics provides valuable insights into autonomic nervous system function and have significant clinical applications. Recent research indicates that attention plays a role in modulating the PLR, and the circuit involving the frontal eye field (FEF) and superior colliculus is causally involved in controlling this pupillary modulation. However, there is limited research exploring the role of the human FEF in these pupillary responses, and its impact on PLR metrics remains unexplored. Additionally, although the protocol of continuous theta-burst stimulation (cTBS) is well-established, the period of disruption after cTBS is yet to be examined in pupillary responses. Our study aimed to investigate the effects of FEF cTBS on pupillary and saccadic metrics in relation to time spent performing a task (referred to as time-on-task). We presented a bright stimulus to induce the PLR in visual- and memory-delay saccade tasks following cTBS over the right FEF or vertex. FEF cTBS, compared to vertex cTBS, resulted in decreased baseline pupil size, peak constriction velocities, and amplitude. Furthermore, the time-on-task effects on baseline pupil size, peak amplitude, and peak time differed between the two stimulation conditions. In contrast, the time-on-task effects on saccadic metrics were less pronounced between the two conditions. In summary, our study provides the first evidence that FEF cTBS affects human PLR metrics and that these effects are modulated by time-on-task.

Pupil size primarily changes to regulate the amount of light entering the retina, optimizing the balance between visual acuity and sensitivity for effective visual processing. However, research directly examining the relationship between pupil size and visual processing has been limited. While a few studies have recorded pupil size and EEG signals to investigate the role of pupil size in visual processing, these studies have predominantly focused on the domain of visual sensitivity. Causal effects of pupil size on visual acuity, therefore, remain poorly understood. By manipulating peripheral background luminance levels and target stimulus contrast while simultaneously recording pupillometry and EEG signals, we examined how absolute pupil size impacts visual discrimination and visually evoked potentials (VEP) in a task mimicking the Snellen eye chart, the most common assessment of visual acuity. Our findings indicate that both higher background luminance levels and higher target contrast were associated with improved target discrimination and faster correct reaction times. Moreover, while higher contrast visual stimuli evoked larger VEPs, the effects of pupil size on VEPs were not significant. Additionally, we did not observe inter-individual correlations between absolute pupil size and discrimination performance or VEP amplitude. Together, our results demonstrate that absolute pupil size, regulated by global luminance level, played a functional role in enhancing visual discrimination performance in a Snellen eye chart task. The differential VEP effects of pupil size compared to those of stimulus contrast further suggested distinct neural mechanisms involved in facilitating visual acuity under small pupils.