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Cite as: J. Neurosci 2020; 10.1523/JNEUROSCI.2484-19.2020
Received: 14 October 2019Revised: 12 May 2020Accepted: 14 May 2020
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Cholinergic modulation of binocular vision
Yasha Sheynina, Pedro Rosa-Netoc, Robert F. Hessa,1,2,∗, Elvire Vaucherb,2,∗
aMcGill Vision Research, McGill University, Montréal, QC, Canada, H3G 1A4bLaboratoire de Neurobiologie de la Cognition Visuelle, École d’Optométrie, Université de
Montréal, QC, Canada, H3T 1P1cDouglas Mental Health University Institute, McGill University, Montréal, QC, Canada,
H4H 1R3
# pages: 14# figures: 3# words abstract: 185# words introduction: 237# words discussion: 129
Conflict of interest
The authors declare no competing financial interests.
Acknowledgments
This research was funded by Canadian Institutes of Health Research (CIHR);Grant number: 148579 (RFH), MOP-111003 (EV); the Natural Sciences and En-gineering Research Council of Canada; Grant number: 228103 (RFH), 238835-2011 (EV); Foundation Nazareth and Louis Braille Institute (INLB, Longueuil,Canada) to EV. We would also like to thank the Centre for InterdisciplinaryResearch in Rehabilitation of Greater Montreal and the FRQS Vision HealthResearch Network for their resource support, and to Jacqueline Higgins for herassistance with data collection.
∗Corresponding authorsEmail addresses: [email protected] (Robert F. Hess),
[email protected] (Elvire Vaucher)1Lead contact2The senior authors contributed equally to this work
Preprint submitted to Journal of Neuroscience May 20, 2020
Abstract
The endogenous neurotransmitter acetylcholine (ACh) is known to affect theexcitatory/inhibitory (E/I) balance of primate visual cortex, enhancing feedfor-ward thalamocortical gain while suppressing cortico-cortical synapses. Recentadvances in the study of the human visual system suggest that ACh is a likelycomponent underlying interocular interactions. However, our understanding ofits precise role in binocular processes is currently lacking. Here we use binocu-lar rivalry as a probe of interocular dynamics to determine ACh’s effects – viathe acetylcholinesterase inhibitor (AChEI) donepezil – on the binocular visualsystem. 23 Subjects (13 male) completed two cross-over experimental sessionswhere binocular rivalry measurements were obtained before and after takingeither donepezil (5 mg) or a placebo (lactose) pill. We report that enhancedcholinergic potentiation attenuates perceptual suppression during binocular ri-valry, reducing the overall rate of interocular competition while enhancing thevisibility of superimposition mixed percepts. Considering recent evidence thatperceptual suppression during binocular rivalry is causally modulated by theinhibitory neurotransmitter GABA, our results suggest that cholinergic activitycounteracts the effect of GABA with regards to interocular dynamics and maymodulate the inhibitory drive within the visual cortex.
Significance Statement1
Our research demonstrates that the cholinergic system is implicated in mod-2
ulating binocular interactions in the human visual cortex. Increasing the poten-3
tiation of acetylcholine via the cholinergic drug donepezil reduces the extent to4
which the eyes compete for perceptual dominance when presented two separate,5
incongruent images.6
2
Introduction7
Binocularity, a defining feature of human vision that enables stereopsis, is8
predicated on the ability to combine inputs from the two eyes to create a singular9
representation of the visual world in depth. Binocular integration occurs in layer10
2/3 in the primary visual cortex (V1), where inhibitory lateral connections con-11
trol monocular inputs from the thalamorecipient layer 4 (Basgoze et al., 2018).12
Previous work has implicated the endogenous neurotransmitter acetylcholine13
(ACh) in the excitatory/inhibitory (E/I) balance of V1, modulating the gain14
of thalamocortical synapses in layer 4c while also inhibiting intracortical in-15
teractions (Disney et al., 2012; Obermayer et al., 2017). Here we use binocular16
rivalry - a sensitive probe of interocular dynamics (Tong et al., 2006) – to charac-17
terize ACh’s role in binocular integration. Importantly, mixed visibility during18
rivalry highlights periods when complete interocular suppression fails. On the19
contrary, exclusive visibility indicates instances of complete perceptual suppres-20
sion - recently causally linked to enhanced GABAergic inhibition (Mentch et al.,21
2019). Consequently, the diverse phenomenology of binocular rivalry percepts22
constitutes an indirect assay of cortical E/I balance (Robertson et al., 2013,23
2016; Van Loon et al., 2013; Mentch et al., 2019).24
Utilizing a double-blind placebo controlled crossover design, we demon-25
strate that a single administration of the acetlycholinesterase inhibitor (AChEI)26
donepezil (5mg, oral) strongly affects binocular rivalry dynamics, with impor-27
tant perceptual consequences. Cholinergic stimulation via donepezil enhances28
both the fraction and median duration of mixed visibility during rivalry, thereby29
reducing the amount of time one eye suppresses the other. Simultaneously, ACh30
also reduces the rate of rivalry – another sensitive probe of cortical E/I balance31
(Robertson et al., 2013; Van Loon et al., 2013). Our findings indicate that ACh32
plays a fundamental role in modulating binocular vision, providing new insights33
into the neurophysiological basis of human binocularity and on ACh’s role in34
visual perception.35
Materials and Methods36
23 individuals completed two experimental sessions where binocular rivalry37
measurements were obtained before and after taking either donepezil or a placebo38
(lactose) pill. The binocular rivalry task consisted of a dichoptic stimulus where39
participants viewed a left-tilted grating in one eye and a right-tilted grating40
in the other for 90 seconds, continuously indicating via key-press whether they41
were seeing (i) the left eye’s image, (ii) the right eye’s image, (iii) a piecemeal42
mixture of the two images, or (iv) a superimposed mixture of the two images43
(see Figure 1). We used this task to better characterize the mixed percepts44
while also encouraging participants not to miscategorize a mixed percept as45
exclusive.46
3
Subjects47
A total of 24 individuals enrolled in the study. One participant was excluded48
from the study due to a failure to complete the full experiment, therefore in sum,49
23 individuals participated the study (13 male; age: 25 ± 3 range: 20 - 32).50
All subjects met the inclusion criteria (non-smoker, normal or corrected-to-51
normal visual acuity, normal stereo vision, no history of any neurological or52
ocular diseases, no prescription medications). The body-mass-index range was53
specified as 17–26 kg/m2 to ensure a similar distribution of the drug across54
subjects. All subjects were naive to the purpose of the experiment. A standard55
clinical and neurological examination was performed Dr. Pedro Rosa Neto,56
Wilson, H. R., 2003. Computational evidence for a rivalry hierarchy in vision.427
Proceedings of the National Academy of Sciences 100 (24), 14499–14503.428
12
+
superimposition
piecemeal
exclusive exclusive
rivalry
rivalryreplay
Left eyeRight eye
replay time
A
B
Figure 1: Experimental Design. (A) Each block consisted of two rivalry runs (whereparticipants viewed left- and right-tilted gratings presented individually to the two eyes) andtwo replay runs (where participants watched computer-generated videos of simulated binocularrivalry, presented identically to both eyes), each lasting 90 s. (B) Participants were instructedto continuously indicate via key-press whether they were seeing (l) the left eye’s image, (r)the right eye’s image, (l + r) a piecemeal mixture of the two images, or (m) a superimposedmixture of the two images.
13
Figure 2: Effect of donepezil on binocular rivalry dynamics. Each row illustrates (1)scatter plots of the raw data observed by taking the mean of each dependent variable acrossthree binocular rivalry runs at baseline (x-axis) and after treatment (y-axis) for both theplacebo and donepezil sessions, (2) a bar plot where each bar represents the average of threebinocular rivalry blocks conducted three hours after ingesting a donepezil/placebo pill, di-vided by the average of three identical rivalry blocks at baseline, averaged across participants,and (3) a scatter plot of donepezil’s effect on each dependent variable obtained by subtractingthe post/pre values of the placebo session from those of the donepezil session. Left columnillustrates data for the median durations of the four percept types, while the right columnillustrates data for the fraction durations of each percept type. Black asterisks between barsindicate significant differences observed with Tukey’s HSD tests in the post/pre values be-tween treatment conditions. Error bars are 95% confidence intervals (from 1000 bootstrappedsamples) of the mean. ** = Bonferroni-corrected p < 0.01, * = p < 0.05.
14
Figure 3: Effect of donepezil on replay rivalry criterion and response latency. Toensure any treatment effects were the result of changes in visual neural activity as opposedto changes in motor or executive function, we implemented a rivalry replay control experi-ment where participants watched computer-generated videos of simulated binocular rivalry,presented identically to both eyes. This control experiment allowed us to measure (A) thecriterion for categorizing a phyiscal stimulus as "mixed" and (B) the response latency for dis-criminating changes in the physical stimulus. There were no observable differences betweendonepezil and placebo sessions in the response latency or mixed criterion, suggesting thatchanges in non-simulated binocular rivalry dynamics are attributed to acetylcholine-inducedchanges in the network dynamics of visual cortex. See Figure 1 for additional details regard-ing the plots.