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Assessing Pupil-linked Changes in Locus Coeruleus-mediated Arousal Elicited by Trigeminal Stimulation

Published: November 26th, 2019



1Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, 2The BioRobotics Institute, Scuola Superiore Sant'Anna, 3Department of Excellence in Robotics & AI, Scuola Superiore Sant'Anna, 4Institut des Maladie Neurodegeneratives, University of Bordeaux, 5Department of Physics, University of Pisa, 6Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, 7Department of Developmental Neuroscience, IRCCS Foundation Stella Maris
* These authors contributed equally

To verify whether trigeminal effects on cognitive performance involve locus coeruleus activity, two protocols are presented that aim to evaluate possible correlations between the performance and task-related pupil size changes induced by chewing. These protocols may be applied to conditions in which locus coeruleus contribution is suspected.

Current scientific literature provides evidence that trigeminal sensorimotor activity associated with chewing may affect arousal, attention, and cognitive performance. These effects may be due to widespread connections of the trigeminal system to the ascending reticular activating system (ARAS), to which noradrenergic neurons of the locus coeruleus (LC) belongs. LC neurons contain projections to the whole brain, and it is known that their discharge co-varies with pupil size. LC activation is necessary for eliciting task-related mydriasis. If chewing effects on cognitive performance are mediated by the LC, it is reasonable to expect that changes in cognitive performance are correlated to changes in task-related mydriasis. Two novel protocols are presented here to verify this hypothesis and document that chewing effects are not attributable to aspecific motor activation. In both protocols, performance and pupil size changes observed during specific tasks are recorded before, soon after, and half an hour following a 2 min period of either: a) no activity, b) rhythmic, bilateral handgrip, c) bilateral chewing of soft pellet, and d) bilateral chewing of hard pellet. The first protocol measures level of performance in spotting target numbers displayed within numeric matrices. Since pupil size recordings are recorded by an appropriate pupillometer that impedes vision to ensure constant illumination levels, task-related mydriasis is evaluated during a haptic task. Results from this protocol reveal that 1) chewing-induced changes in performance and task-related mydriasis are correlated and 2) neither performance nor mydriasis are enhanced by handgrip. In the second protocol, use of a wearable pupillometer allows measurement of pupil size changes and performance during the same task, thus allowing even stronger evidence to be obtained regarding LC involvement in the trigeminal effects on cognitive activity. Both protocols have been run in the historical office of Prof. Giuseppe Moruzzi, the discoverer of ARAS, at the University of Pisa.

In humans, it is known that chewing quickens cognitive processing1,2 and improves arousal3,4, attention5, learning, and memory6,7. These effects are associated with shortening of the latencies of cortical event-related potentials8 and an increase in the perfusion of several cortical and subcortical structures2,9.

Within cranial nerves, the most relevant informat....

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All steps follow the guidelines of the Ethical Committee of the University of Pisa.

1. Participant Recruitment

  1. Recruit a subject population according to the specific goal of the study (i.e., normal subjects and/or patients, males and/or females, young people and/or elders).

2. Material Preparation

  1. Prepare a soft pellet; use commercially available chewing gum (Table of Materials; initial hardness = 20 Shore OO).
  2. <.......

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Figure 4 shows a representative example of the results obtained when protocol 1 was applied to a single subject (46 years old, female). PI was increased soon after having chewed (T7) both a hard (from 1.73 numb/s to 2.27 numb/s) and soft pellet (from 1.67 numb/s to 1.87 numb/s) (Figure 4A). However, 30 min later (T37), the increased performance persisted only for the hard pellet. On the other hand, both a lack of activity and the handgrip exerci.......

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The protocols presented in this study address the acute effects of sensorimotor trigeminal activity on cognitive performance and the role of the LC in this process. This topic has some relevance, considering that 1) during aging, the deterioration of masticatory activity correlates with cognitive decay32,33,34; people that preserve oral health are less prone to neurodegenerative phenomena; 2) malocclusion and teeth extraction in.......

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The research was supported by grants of the University of Pisa. We thank Mr. Paolo Orsini, Mr. Francesco Montanari, and Mrs. Cristina Pucci for valuable technical assistance, as well as the I.A.C.E.R. S.r.L. company for supporting Dr. Maria Paola Tramonti Fantozzi with a fellowship. Finally, we thank the OCM Projects company for preparing hard pellets and performing hardness and spring constant measurements.


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NameCompanyCatalog NumberComments
Anti-stress ballArtengo, Decathlon, FranceTB600
Chewing gumVigorsol, Perfetti, ItalyCommercially available product
Infrared Camera-Wearable pupillometerPupil Labs, Berlin, GermanyPupil Labs headset
PupillographerCSO, Florence, ItalyMOD i02, with chin support
Silicon rubberProchima, Italygls50
Software for pupil detection - wearable pupillometerPupil Labs, Berlin, GermanyPupil Labs headset
Tangram PuzzleCittà del Sole srl, Milano, ItalyTangram Puzzle
Wearable pupillometerPupil Labs, Berlin, GermanyPupil labs modelDimension of the frame: 13.5 x 15.5cm

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