**Trigeminal input, pupil size and cognitive performance: from oral to brain matter.** Maria Paola Tramonti Fantozzi1,#, Vincenzo De Cicco1,#, Serena Argento1, Davide De Cicco2, Massimo Barresi1, Enrico Cataldo3, Luca Bruschini4, Paola d’Ascanio 1, Ugo Faraguna1,5*, Diego Manzoni1,* 1 Department of Translational Research on New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy 2Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples “Federico II”, Naples, Italy 3Department of Physics, University of Pisa, Pisa, Italy 4Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy 5Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Pisa, Italy #The authors contributed equally to the work *The authors shared senior coauthorship Correspondence: mail to: Diego Manzoni, email: diego.manzoni@unipi.it Abstract It has been observed that, in patients affected by temporomandibular disorders (TMDs) and edentulism, a left-right asymmetry in electromyographic (EMG) activity of masseter muscles during clenching and in pupil size at rest (anisocoria) is present. Both are greatly reduced by an orthotic-prosthetic correction. In parallel, the correction significantly improves cognitive performance. These effects are possibly due to the recovery of a cortical balance, via Locus Coeruleus (LC) modulation, whose activity is powerfully affected by the sensorimotor trigeminal input. The role of this functional axis was further investigated in subjects without overt occlusal or dental problems. In these individuals, the EMG asymmetry was significantly correlated to anisocoria at rest, with the dental arches open or in contact. Also in normal subjects, both the EMG and the pupil asymmetry during clenching could be significantly reduced by an orthotic (bite) correction. Closing the arches without bite increased anisocoria and reduced performance in the Spinnler-Tognoni matrices test, as well as the mydriasis induced by a haptic task. When the bite was interposed, anisocoria was reduced, while both performance and task-related mydriasis were enhanced. Since pupil size is considered a proxy of the LC activity, these results suggest that asymmetric occlusion biases the LC discharge and the hemispheric excitability, possibly via a sensorimotor trigeminal imbalance. Removing the anisocoria through bite correction re-establishes a symmetric LC discharge, improving performance and enhancing task-related mydriasis. Therefore, occlusal balancing may represent a tool for improving subjective performance and may be exploited for training and rehabilitative purposes. Keywords: trigeminal imbalance, pupil size, Locus Coeruleus, hemispheric imbalance, performance