assessing-pupil-linked-changes-locus-coeruleus-mediated-arousal

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

Current scientific literature provides evidence that trigeminal sensorimotor activity associated with chewing may affect arousal, attention, and cognitive ...

University of Pisa

Increasing evidence indicates that modulation of Na(+)/K(+) ATPase activity is involved in forms of neuronal and synaptic plasticity. In tactile (T) neurons of the leech Hirudo medicinalis, Na(+)/K(+) ATPase is the main determinant of the afterhyperpolarization (AHP), which characterizes the firing of these mechanosensory neurons. Previously, it has been reported that cAMP (3',5'-cyclic adenosine monophosphate), which mediates the effects of serotonin (5HT) in some forms of learning in the leech, negatively modulates Na(+)/K(+) ATPase activity, thereby reducing the AHP amplitude in T neurons. Here, we show that a transient inhibition of Na(+)/K(+) ATPase can affect the synaptic connection between two ipsilateral T neurons. Bath application of 10 nm dihydroouabain (DHO), an ouabain analogue, causes an increase in the amplitude of the synaptic potential (SP) recorded in the postsynaptic element when a test stimulus is applied in the presynaptic neuron. Iontophoretic injection of cAMP into the presynaptic T neuron also produces an increase of SP. Simulations carried out by using a computational model of the T neuron suggest that a reduction of the pump rate and a consequent depression of the AHP might facilitate the conduction of action potentials to the synaptic terminals. Moreover, nearly intact leeches injected with 10 nm DHO respond with a swimming episode more quickly to an electrical stimulation, which selectively activates T neurons exhibiting sensitization of swimming induction. Collectively, our results show that inhibition of Na(+)/K(+) ATPase is critical for short-term plasticity.

Inhibition of Na+/K+ ATPase potentiates synaptic transmission in tactile sensory neurons of the leech.

We studied whether patients affected by Temporo-Mandibular Disorder (TMD), showing asymmetric electromyographic (EMG) activity of masticatory muscles also display asymmetries in pupil size. In 30 pain free TMD patients a highly significant, positive correlation was found between left-right differences in EMG and pupil size. The asymmetry in pupil size was induced by the asymmetric sensorimotor signals arising from the orofacial region, since pupils became of about the same size following orthotic correction, which greatly reduced the EMG asymmetry. Moreover, bite wearing bilaterally increased the mydriasis induced by performing haptic tasks. Finally, unbalancing the occlusion by a precontact increased the diameter of the ipsilateral pupil and abolished the mydriasis induced by haptic tasks. In conclusion, trigeminal sensorimotor signals may exert a tonic control on autonomic structures regulating pupil size at rest and during sensorimotor tasks. Since task-associated mydriasis is correlated with task performance and is strictly proportional to the phasic release of noradrenaline at cerebral cortical level, the present findings may suggest an impact of unbalanced trigeminal activity on brain processing not directly related to the orofacial region.

Sensorimotor trigeminal unbalance modulates pupil size.

Several studies have demonstrated that chewing can be regarded as a preventive measure for cognitive impairment, whereas masticatory deficiency, associated with soft-diet feeding, is a risk factor for the development of dementia. At present the link between orofacial sensorimotor activity and cognitive functions is unknown. In subjects with unilateral molar loss we have shown asymmetries in both pupil size and masticatory muscles electromyographic (EMG) activity during clenching: the molar less side was characterized by a lower EMG activity and a smaller pupil. Since implant-prostheses, greatly reduced both the asymmetry in EMG activity and in pupil's size, trigeminal unbalance, leading to unbalance in the activity of the Locus Coeruleus (LC), may be responsible for the pupil's asymmetry. According to the findings obtained in animal models, we propose that the different activity of the right and left LC may induce an asymmetry in brain activity, thus leading to cognitive impairment. According to this hypothesis, prostheses improved the performance in a complex sensorimotor task and increased the mydriasis associated with haptic tasks. In conclusion, the present study indicates that the implant-prosthesis therapy, which reduces the unbalance of trigeminal proprioceptive afferents and the asymmetry in pupil's size, may improve arousal, boosting performance in a complex sensorimotor task. 

Oral Implant-Prostheses: New Teeth for a Brighter Brain.

Trigeminal input to the ascending activating system is important for the maintenance of arousal and may affect the discharge of the noradrenergic neurons of the  (LC), whose activity influences both vigilance state and pupil size, inducing mydriasis. For this reason, pupil size evaluation is now considered an indicator of LC activity. Since mastication activates trigeminal afferent neurons, the aims of the present study, conducted on healthy adult participants, were to investigate whether chewing a bolus of different hardness may: (1) differentially affect the performance on a cognitive task (consisting in the retrieval of specific target numbers within numerical matrices) and (2) increase the dilatation of the pupil (mydriasis) induced by a haptic task, suggesting a change in LC activation. Results show that chewing significantly increased both the velocity of number retrieval (without affecting the number of errors) and the mydriasis associated with the haptic task, whereas simple task repetition did not modify either retrieval or mydriasis. Handgrip exercise, instead, significantly decreased both parameters. Effects were significantly stronger and longer lasting when subjects chewed hard pellets. Finally, chewing-induced improvements in performance and changes in mydriasis were positively correlated, which suggests that trigeminal signals enhanced by chewing may boost the cognitive performance by increasing LC activity.

Short-Term Effects of Chewing on Task Performance and Task-Induced Mydriasis: Trigeminal Influence on the Arousal Systems.

It is known that sensory signals sustain the background discharge of the ascending reticular activating system (ARAS) which includes the noradrenergic locus coeruleus (LC) neurons and controls the level of attention and alertness. Moreover, LC neurons influence brain metabolic activity, gene expression and brain inflammatory processes. As a consequence of the sensory control of ARAS/LC, stimulation of a sensory channel may potential influence neuronal activity and trophic state all over the brain, supporting cognitive functions and exerting a neuroprotective action. On the other hand, an imbalance of the same input on the two sides may lead to an asymmetric hemispheric excitability, leading to an impairment in cognitive functions. Among the inputs that may drive LC neurons and ARAS, those arising from the trigeminal region, from visceral organs and, possibly, from the vestibular system seem to be particularly relevant in regulating their activity. The trigeminal, visceral and vestibular control of ARAS/LC activity may explain why these input signals: (1) affect sensorimotor and cognitive functions which are not directly related to their specific informational content; and (2) are effective in relieving the symptoms of some brain pathologies, thus prompting peripheral activation of these input systems as a complementary approach for the treatment of cognitive impairments and neurodegenerative disorders.

Trigeminal, Visceral and Vestibular Inputs May Improve Cognitive Functions by Acting through the Locus Coeruleus and the Ascending Reticular Activating System: A New Hypothesis.

The thalamus plays a crucial role in modulating the cortical activity underlying sensory and cognitive processes. In particular, recent experimental findings highlighted that the thalamus does not merely act as a binary gate for sensory stimuli, but rather participates to the processing of sensory information. Clarifying such thalamic influence on cortical dynamics is also important as the thalamus is the target of therapies such as DBS for Tourette patients. In this perspective, various computational models have been proposed in the last decades. However, a detailed description of the propagation of thalamic activity to the cortex is missing. Here we present a simple computational model of thalamocortical connectivity accounting for the propagation of activity from the thalamus to the cortex. The model includes both the single-neuron scale and the mesoscopic level of Local Field Potential (LFP) signals. Numerical simulations at both levels reproduce typical thalamocortical dynamics which are consistent with experimental measurements and robust to parameters changes. In particular, our model correctly reproduces locally generated rhythms as spindle oscillations in the thalamus and gamma oscillations in the cortex. Our model paves the way to deeper investigations of the thalamic influence on cortical dynamics, with and without sensory inputs or therapeutic electrical stimulation.

Enrico Cataldo

Department of Physics

University of Pisa

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