Chin-An Wang

A circuit for pupil orienting responses: implications for cognitive modulation of pupil size

Pupil size, as a component of orienting, changes rapidly in response to local salient events in the environment, in addition to its well-known illumination-dependent modulation. Recent research has shown that visual, auditory, or audiovisual stimuli can elicit transient pupil dilation, and the timing and size of the evoked responses are systematically modulated by stimulus salience. Moreover, weak microstimulation of the superior colliculus (SC), a midbrain structure involved in eye movements and attention, evokes similar transient pupil dilation, suggesting that the SC coordinates the orienting response which includes transient pupil dilation. Projections from the SC to the pupil control circuitry provide a novel neural substrate underlying pupil modulation by various cognitive processes.

Microstimulation of the Monkey Superior Colliculus Induces Pupil Dilation Without Evoking Saccades

The orienting reflex is initiated by a salient stimulus and facilitates quick, appropriate action. It involves a rapid shift of the eyes, head, and attention and other physiological responses such as changes in heart rate and transient pupil dilation. The SC is a critical structure in the midbrain that selects incoming stimuli based on saliency and relevance to coordinate orienting behaviors, particularly gaze shifts, but its causal role in pupil dilation remains poorly understood in mammals. Here, we examined the role of the primate SC in the control of pupil dynamics. While requiring monkeys to keep their gaze fixed, we delivered weak electrical microstimulation to the SC, so that saccadic eye movements were not evoked. Pupil size increased transiently after microstimulation of the intermediate SC layers (SCi) and the size of evoked pupil dilation was larger on a dim versus bright background. In contrast, microstimulation of the superficial SC layers did not cause pupil dilation. Thus, the SCi is directly involved not only in shifts of gaze and attention, but also in pupil dilation as part of the orienting reflex, and the function of pupil dilation may be related to increasing visual sensitivity. The shared neural mechanisms suggest that pupil dilation may be associated with covert attention.

Transient Pupil Response Is Modulated by Contrast-Based Saliency

The sudden appearance of a novel stimulus in the environment initiates a series of orienting responses that include coordinated shifts of gaze and attention, and also transient changes in pupil size. Although numerous studies have identified a significant effect of stimulus saliency on shifts of gaze and attention, saliency effects on pupil size are less understood. To examine salience-evoked pupil responses, we presented visual, auditory, or audiovisual stimuli while monkeys fixated a central visual spot. Transient pupil dilation was elicited after visual stimulus presentation regardless of target luminance relative to background, and auditory stimuli also evoked similar pupil responses. Importantly, the evoked pupil response was modulated by contrast-based saliency, with faster and larger pupil responses following the presentation of more salient stimuli. The initial transient component of pupil dilation was qualitatively similar to that evoked by weak microstimulation of the midbrain superior colliculus. The pupil responses elicited by audiovisual stimuli were well predicted by a linear summation of each modality response. Together, the results suggest that the transient pupil response, as one component of orienting, is modulated by contrast-based saliency, and the superior colliculus is likely involved in its coordination.

Pupil size reveals preparatory processes in the generation of pro-saccades and anti-saccades

The ability to generate flexible behaviors to accommodate changing goals in response to identical sensory stimuli is a signature that is inherited in humans and higher‐level animals. In the oculomotor system, this function has often been examined with the anti‐saccade task, in which subjects are instructed, prior to stimulus appearance, to either automatically look at the peripheral stimulus (pro‐saccade) or to suppress the automatic response and voluntarily look in the opposite direction from the stimulus (anti‐saccade). Distinct neural preparatory activity between the pro‐saccade and anti‐saccade conditions has been well documented, particularly in the superior colliculus (SC) and the frontal eye field (FEF), and this has shown higher inhibition‐related fixation activity in preparation for anti‐saccades than in preparation for pro‐saccades. Moreover, the level of preparatory activity related to motor preparation is negatively correlated with reaction times. We hypothesised that preparatory signals may be reflected in pupil size through a link between the SC and the pupil control circuitry. Here, we examined human pupil dynamics during saccade preparation prior to the execution of pro‐saccades and anti‐saccades. Pupil size was larger in preparation for correct anti‐saccades than in preparation for correct pro‐saccades and erroneous pro‐saccades made in the anti‐saccade condition. Furthermore, larger pupil dilation prior to stimulus appearance accompanied saccades with faster reaction times, with a trial‐by‐trial correlation between dilation size and anti‐saccade reaction times. Overall, our results demonstrate that pupil size is modulated by saccade preparation, and neural activity in the SC, together with the FEF, supports these findings, providing unique insights into the neural substrate coordinating cognitive processing and pupil diameter.

Modulation of stimulus contrast on the human pupil orienting response

The sudden appearance of a novel stimulus initiates a series of responses to orient the body for appropriate actions, including not only shifts of gaze and attention, but also transient pupil dilation. Modulation of pupil dynamics by stimulus properties is less understood, although its effects on other components of orienting have been extensively explored. Microstimulation of the superior colliculus evoked transient pupil dilation, and the initial component of pupil dilation evoked by microstimulation was similar to that elicited by the presentation of salient sensory stimuli, suggesting a coordinated role of the superior colliculus on this behavior, although evidence in humans is yet to be established. To examine pupil orienting responses in humans, we presented visual stimuli while participants fixated on a central visual spot. Transient pupil dilation in humans was elicited after presentation of a visual stimulus in the periphery. The evoked pupil responses were modulated systematically by stimulus contrast, with faster and larger pupil responses triggered by higher contrast stimuli. The pupil response onset latencies for high contrast stimuli were similar to those produced by the light reflex and significantly faster than the darkness reflex, suggesting that the initial component of pupil dilation is probably mediated by inhibition of the parasympathetic pathway. The contrast modulation was pronounced under different levels of baseline pupil size. Together, our results demonstrate visual contrast modulation on the orienting pupil response in humans.

Disruption of pupil size modulation correlates with voluntary motor preparation deficits in Parkinson's disease.

Pupil size is an easy-to-measure, non-invasive method to index various cognitive processes. Although a growing number of studies have incorporated measures of pupil size into clinical investigation, there have only been limited studies in Parkinsons disease (PD). Convergent evidence has suggested PD patients exhibit cognitive impairment at or soon after diagnosis. Here, we used an interleaved pro- and anti-saccade paradigm while monitoring pupil size with saccadic eye movements to examine the relationship between executive function deficits and pupil size in PD patients. Subjects initially fixated a central cue, the color of which instructed them to either look at a peripheral stimulus automatically (pro-saccade) or suppress the automatic response and voluntarily look in the opposite direction of the stimulus (anti-saccade). We hypothesized that deficits of voluntary control should be revealed not only on saccadic but also on pupil responses because of the recently suggested link between the saccade and pupil control circuits. In elderly controls, pupil size was modulated by task preparation, showing larger dilation prior to stimulus appearance in preparation for correct anti-saccades, compared to correct pro-saccades, or erroneous pro-saccades made in the anti-saccade condition. Moreover, the size of pupil dilation correlated negatively with anti-saccade reaction times. However, this profile of pupil size modulation was significantly blunted in PD patients, reflecting dysfunctional circuits for anti-saccade preparation. Our results demonstrate disruptions of modulated pupil responses by voluntary movement preparation in PD patients, highlighting the potential of using low-cost pupil size measurement to examine executive function deficits in early PD.

Multisensory integration in orienting behavior: Pupil size, microsaccades, and saccades

Signals from different sensory modalities are integrated in the brain to optimize behavior. Although multisensory integration has been demonstrated in saccadic eye movements, its influence on other orienting responses, including pupil size and microsaccades, is still poorly understood. We examined human gaze orienting responses following presentation of visual, auditory, or combined audiovisual stimuli. Transient pupil dilation and microsaccade inhibition were evoked shortly after the appearance of a salient stimulus. Audiovisual stimuli evoked larger pupil dilation, greater microsaccade inhibition, and faster saccade reaction times compared to unimodal conditions. Trials with faster saccadic reaction times were accompanied with greater pupil dilation responses. Similar modulation of pre-stimulus pupil-size-change rate was observed between stimulus-evoked saccadic and pupillary responses. Thus, multisensory integration impacts multiple components of orienting, with coordination between saccade and pupil responses, implicating the superior colliculus in coordinating these responses because of its central role in both orienting behavior and multisensory integration.

Pupil size reveals preparatory processes in the generation of pro- and anti-saccades

The ability to generate flexible behaviors to accommodate changing goals in response to identical sensory stimuli is a signature inherited in humans and higher-level animals. In the oculomotor system, this function has often been examined using the anti-saccade task in which subjects are instructed, prior to stimulus appearance, to either look at the peripheral stimulus automatically (pro-saccade) or to suppress the automatic response and voluntarily look in the opposite direction of the stimulus (anti-saccade). Distinct neural preparatory activity has been well-documented between the pro-saccade and anti-saccade conditions, particularly in the superior colliculus (SC) and the frontal eye field (FEF), showing higher inhibition-related fixation activity in preparation for anti- compared to pro-saccades. Moreover, the level of preparatory activity related to motor preparation negatively correlated with reaction times. Pupil size is widely used to index cognitive and neural processing, a link between the SC and the pupil control circuitry has been suggested recently, showing pupil dilation evoked transiently by weak microstimulation of the SC. We hypothesize that preparatory signals in the SC should be reflected on pupil size through this pathway. Here, we examined pupil dynamics in humans during saccade preparation prior to the execution of pro- and anti-saccades. Pupil size was larger in preparation for correct anti-saccades, compared to either correct pro-saccades or erroneous pro-saccades made in the anti-saccade condition. Furthermore, larger pupil size prior to stimulus appearance accompanied saccades with faster reaction times. Overall, our results demonstrated that pupil size was modulated by saccade preparation, providing unique insight into the neural substrate coordinating cognitive processing, saccade preparation, and pupil diameter. Meeting abstract presented at VSS 2015.

Spatio-temporal response properties of local field potentials in the primate superior colliculus

Local field potentials (LFPs) are becoming increasingly popular in neurophysiological studies. However, to date, most of the knowledge about LFPs has been obtained from cortical recordings. Here, we recorded single unit activity (SUA) and LFPs simultaneously from the superior colliculus (SC) of behaving rhesus monkeys. The SC is a midbrain structure that plays a central role in the visual orienting response. Previous studies have characterised the visual and visuomotor response properties of SUA in the superficial layers of the SC and the intermediate layers of the SC, respectively. We found that the signal properties of SUA were well preserved in the LFPs recorded from the SC. The SUA and LFPs had similar spatial and temporal properties, and the response properties of LFPs differed across layers, i.e. purely visual in the superficial layers of the SC but showing significant motor responses in the intermediate layers of the SC. There were also differences between SUA and LFPs. LFPs showed a significant reversal of activity following the phasic visual response, suggesting that the neighboring neurons were suppressed. The results indicate that the LFP can be used as a reliable measure of the SC activity in lieu of SUA, and open up a new way to assess sensorimotor processing within the SC.

Neural basis of location-specific pupil luminance modulation

Significance The pupil regulates the amount of light entering the eyes to optimize visual sensitivity and sharpness. The visual system selects objects of interest for future fixation, and pupil size can be adjusted for object luminance before fixation. This study demonstrates that the intermediate layers of the superior colliculus (SC), a phylogenetically conserved structure for controlling eye movements and spatial attention, coordinates this predictive pupil response. By manipulating intermediate SC (SCi) excitability via microstimulation and lidocaine microinjection, we show that, although global luminance remained unchanged, pupil size was modulated by local luminance at the next fixated location. These results highlight a causal role of the SCi to prepare the pupil for local luminance conditions at the saccadic goal. Spatial attention enables us to focus visual processing toward specific locations or stimuli before the next fixation. Recent evidence has suggested that local luminance at the spatial locus of attention or saccade preparation influences pupil size independent of global luminance levels. However, it remains to be determined which neural pathways produce this location-specific modulation of pupil size. The intermediate layers of the midbrain superior colliculus (SC) form part of the network of brain areas involved in spatial attention and modulation of pupil size. Here, we demonstrated that pupil size was altered according to local luminance level at the spatial location corresponding to a microstimulated location in the intermediate SC (SCi) map of monkeys. Moreover, local SCi inactivation through injection of lidocaine reversed this local luminance modulation. Our findings reveal a causal role of the SCi in preparing pupil size for local luminance conditions at the next saccadic goal.