From sequences of discrete events, humans build mental models of their world. Referred to as graph learning, the process produces a model encoding the graph of event-to-event transition probabilities. Recent evidence suggests that some networks are easier to learn than others, but the neural underpinnings of this effect remain unknown. Here we use fMRI to show that even over short timescales the network structure of a temporal sequence of stimuli determines the fidelity of event representations as well as the dimensionality of the space in which those representations are encoded: when the graph was modular as opposed to lattice-like, BOLD representations in visual areas better predicted trial identity and displayed higher intrinsic dimensionality. Broadly, our study shows that network context influences the strength of learned neural representations, motivating future work in the design, optimization, and adaptation of network contexts for distinct types of learning.

The primary goal of this study was to develop a parametric model that relates variation in stimulation of the trigeminal nerve to properties of the blink response. We measured blink responses in 17 healthy, adult participants to air puffs directed at the lateral canthus of the eye at five different, log-spaced intensities (3.5-60 PSI). Lid position over time was decomposed into amplitude and velocity components. We found that blink amplitude was systematically related to log stimulus intensity, with the relationship well described by a sigmoidal function. The parameters of the model fit correspond to the slope of the function and the stimulus intensity required to produce half of a maximal blink response (the half-response threshold). There was a reliable increase in the half-response threshold for the contralateral as compared to the ipsilateral blink response. This increase was consistent across participants despite substantial individual differences in the half-response threshold and slope parameters of the overall sensitivity function, suggesting that the laterality effect arises in the neural circuit subsequent to individual differences in sensitivity. Overall, we find that graded mechanical stimulation of the somatosensory trigeminal afferents elicits a graded response that is well described by a simple parametric model. We discuss the application of parametric measurements of the blink response to the detection of group differences in trigeminal sensitivity.

Human experience is built upon sequences of discrete events. From those sequences, humans build impressively accurate models of their world. This process has been referred to as graph learning, a form of structure learning in which the mental model encodes the graph of event-to-event transition probabilities [1], [2], typically in medial temporal cortex [3]–[6]. Recent evidence suggests that some network structures are easier to learn than others [7]–[9], but the neural properties of this effect remain unknown. Here we use fMRI to show that the network structure of a temporal sequence of stimuli influences the fidelity with which those stimuli are represented in the brain. Healthy adult human participants learned a set of stimulus-motor associations following one of two graph structures. The design of our experiment allowed us to separate regional sensitivity to the structural, stimulus, and motor response components of the task. As expected, whereas the motor response could be decoded from neural representations in postcentral gyrus, the shape of the stimulus could be decoded from lateral occipital cortex. The structure of the graph impacted the nature of neural representations: when the graph was modular as opposed to lattice-like, BOLD representations in visual areas better predicted trial identity in a held-out run and displayed higher intrinsic dimensionality. Our results demonstrate that even over relatively short timescales, graph structure determines the fidelity of event representations as well as the dimensionality of the space in which those representations are encoded. More broadly, our study shows that network context influences the strength of learned neural representations, motivating future work in the design, optimization, and adaptation of network contexts for distinct types of learning over different timescales.

The pupil constricts to illusory brightness, presumably mediated by a cortical mechanism. People with migraine with aura (MwA) have greater discomfort and cortical response to visual stimuli. We tested if people with MwA have an enhanced pupil response to illusory brightness as compared to migraineurs without aura (MwoA) and headache-free controls (HaF). Our pre-registered study is of 15 subjects from each of the 3 headache diagnostic categories. Pupil responses are recorded while subjects view many, 1s presentations of three different stimuli, equated in integrated spatial luminance. Each radially symmetric, annular stimulus has an identical, lighter center, and a varying, darker surround. The surround is either Uniform, or has a linear slope that increases towards the periphery (Halo), or the center (Glow). Enhancement of the perceived brightness of the stimulus center has been reported for the Glow and Halo stimuli (Tamura 2016 JoV). The mean % change in pupil size is computed for each stimulus type for each subject. We report here interim results from the 40 subjects studied to date. Across all subjects, as compared to the response to Uniform (6.4% constriction), there was a greater constriction to both Glow (9.1%, p=0.06) and Halo (8.2%, p=0.026); Glow and Halo responses were not significantly different (p=0.23). In a pre-registered test, MwA subjects had a greater difference between the Glow and Uniform stimuli (4.0%) than did the HaF subjects (1.9%), but this difference is not significant (p=0.24); similar to HaF, MwoA subjects had a small difference between the Glow and Uniform stimuli (2.3%). The pattern of responses across subject groups for Halo vs. Uniform stimuli is quite similar. Our interim conclusions are that illusory brightness enhances pupil constriction, and that we have not yet rejected the possibility that this effect may be greater in people with migraine with aura.

There is substantial variation between healthy individuals in the number of retinal ganglion cells (RGC) in the eye, with commensurate variation in the number of axons in the optic tracts. Fixel-based analysis of diffusion MR produces estimates of fiber density (FD) and cross section (FC). Using these fixel measurements along with retinal imaging, we asked if individual differences in RGC tissue volume are correlated with individual differences in FD and FC measurements obtained from the optic tracts, and subsequent structures along the cortical visual pathway. We find that RGC endowment is correlated with optic tract FC, but not with FD. RGC volume had a decreasing relationship with measurements from subsequent regions of the visual system (LGN volume, optic radiation FC/FD, and V1 surface area). However, we also found that the variations in each visual area were correlated with the variations in its immediately adjacent visual structure. We only observed these serial correlations when FC is used as the measure of interest for the optic tract and radiations, but no significant relationship was found when FD represented these white matter structures. From these results, we conclude that the variations in RGC endowment, LGN volume, and V1 surface area are better predicted by the overall cross section of the optic tract and optic radiations as compared to the intra-axonal restricted signal component of these white matter pathways. Additionally, the presence of significant correlations between adjacent, but not distant, anatomical structures suggests that there are multiple, local sources of anatomical variation along the visual pathway.

In addition to the rod and cone photoreceptors the retina contains intrinsically photosensitive retinal ganglion cells (ipRGCs). These cells express the photopigment melanopsin and are known to be involved in reflexive visual functions such as pupil response and photo-entrainment of the circadian rhythm. It is possible that the ipRGCs contribute to conscious visual perception, either by providing an independent signal to the geniculo-striate pathway, or by interacting with and thus modifying signals arising from “classical” retinal ganglion cells that combine and contrast cone input. Here, we tested for the existence of an interaction by asking if a 350% change in melanopsin stimulation alters psychophysical sensitivity for the detection of luminance flicker. In Experiment 1, we tested for a change in the threshold for detecting luminance flicker in three participants after they adapted to backgrounds with different degrees of tonic melanopsin stimulation. In Experiments 2 and 3, this test was repeated, but now for luminance flicker presented on a transient pedestal of melanopsin stimulation. Across the three experiments, no effect of melanopsin stimulation upon threshold flicker sensitivity was found. Our results suggest that even large changes in melanopsin stimulation do not affect near-threshold, cone-mediated visual perception.

BACKGROUND AND OBJECTIVES:To quantify interictal photophobia in migraine with and without aura using reflexive eye closure as an implicit measure of light sensitivity and to assess the contribution of melanopsin and cone signals to these responses.METHODS:Participants were screened to meet criteria for 1 of 3 groups: headache-free (HF) controls, migraine without aura (MO), and migraine with visual aura (MA). MO and MA participants were included if they endorsed ictal and interictal photophobia. Exclusion criteria included impaired vision, inability to collect usable pupillometry, and history of either head trauma or seizure. Participants viewed light pulses that selectively targeted melanopsin, the cones, or their combination during recording of orbicularis oculi EMG (OO-EMG) and blinking activity.RESULTS:We studied 20 participants in each group. MA and MO groups reported increased visual discomfort to light stimuli (discomfort rating, 400% contrast, MA: 4.84 [95% confidence interval 0.33, 9.35]; MO: 5.23 [0.96, 9.50]) as compared to HF controls (2.71 [0, 6.47]). Time course analysis of OO-EMG and blinking activity demonstrated that reflexive eye closure was tightly coupled to the light pulses. The MA group had greater OO-EMG and blinking activity in response to these stimuli (EMG activity, 400% contrast: 42.9%Δ [28.4, 57.4]; blink activity, 400% contrast: 11.2% [8.8, 13.6]) as compared to the MO (EMG activity, 400% contrast: 9.9%Δ [5.8, 14.0]; blink activity, 400% contrast: 4.7% [3.5, 5.9]) and HF control (EMG activity, 400% contrast: 13.2%Δ [7.1, 19.3]; blink activity, 400% contrast: 4.5% [3.1, 5.9]) groups.DISCUSSION:Our findings suggest that the intrinsically photosensitive retinal ganglion cells (ipRGCs), which integrate melanopsin and cone signals, provide the afferent input for light-induced reflexive eye closure in a photophobic state. Moreover, we find a dissociation between implicit and explicit measures of interictal photophobia depending on a history of visual aura in migraine. This implies distinct pathophysiology in forms of migraine, interacting with separate neural pathways by which the amplification of ipRGC signals elicits implicit and explicit signs of visual discomfort.

Objective To assess the contribution of the melanopsin-containing, intrinsically photosensitive retinal ganglion cells (ipRGCs) and the cones to reflexive eye closure as an implicit measure of interictal photophobia in migraine. Methods We studied twenty participants in each of three groups: headache-free (HAf) controls, migraine without aura (MwoA), and migraine with visual aura (MwA). Participants viewed spectral pulses that selectively targeted melanopsin, the cones, or their combination while we recorded orbicularis oculi electromyography (OO-EMG) and blinking rate. Results Time course analysis of OO-EMG demonstrated that reflexive eye closure was tightly coupled to the spectral pulses. Compared to both the MwoA and HAf control groups, the MwA group had enhanced OO-EMG and blinking activity in response to melanopsin and cone stimulation in combination and in isolation. This response scaled with the contrast of the stimulus. Conclusions Our findings suggest that ipRGC signals, whether elicited by melanopsin stimulation or from presumed extrinsic cone input, provide the afferent input for light-induced reflexive eye closure in a photophobic state. Participants with migraine and visual aura had a distinctly different response to visual stimulation as compared to the other two groups. This is in contrast to prior findings in this same cohort in whom higher explicit ratings of visual discomfort were found for both MwA and MwoA as compared to controls. Such a dissociation suggests distinct pathophysiology in forms of migraine, interacting with separate neural pathways by which ipRGC signals elicit implicit and explicit signs of visual discomfort. ### Competing Interest Statement The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EAK has received royalties from a patent shared with Alder Biopharmaceuticals. The remaining authors declare that they have no relevant financial interests that relate to the research described in this paper.

Second only to headache, photophobia is the most debilitating symptom reported by people with migraine. While the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to play a role, how cone and melanopsin signals are integrated in this pathway to produce visual discomfort is poorly understood. We studied 60 people: 20 without headache and 20 each with interictal photophobia from migraine with or without visual aura. Participants viewed pulses of spectral change that selectively targeted melanopsin, the cones, or both and rated the degree of visual discomfort produced by these stimuli while we recorded pupil responses. We examined the data within a model that describes how cone and melanopsin signals are weighted and combined at the level of the retina and how this combined signal is transformed into a rating of discomfort or pupil response. Our results indicate that people with migraine do not differ from headache-free controls in the manner in which melanopsin and cone signals are combined. Instead, people with migraine demonstrate an enhanced response to integrated ipRGC signals for discomfort. This effect of migraine is selective for ratings of visual discomfort, in that an enhancement of pupil responses was not seen in the migraine group, nor were group differences found in surveys of other behaviors putatively linked to ipRGC function (chronotype, seasonal sensitivity, presence of a photic sneeze reflex). By revealing a dissociation in the amplification of discomfort vs. pupil response, our findings suggest a postretinal alteration in processing of ipRGC signals for photophobia in migraine.