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

It has been shown that, in subjects with high hypnotizability (Highs), imagined somatosensory stimulation can involuntarily activate the neural circuits involved in the modulation of reflex action. In this vein, aim of the study was to investigate whether the imagery of nociceptive stimulation in one leg may produce both subjective experience of pain and congruent postural adjustments during normal upright stance. The displacement of the centre of pressure (CoP) was studied during imagery of leg pain (LP) and during the control conditions of imagery of tactile stimulation of the same leg and of throat pain (TP) in 12 Highs and 12 low hypnotizable subjects (Lows). The results showed that the vividness of imagery was higher in Highs than in Lows for all tasks and that only Highs reported actually feeling pain during LP and TP. Congruently, during LP only Highs displaced their CoP towards the leg opposite to the one that was the object of painful imagery and increased their CoP mean velocity and area of excursion. Since the Highs' postural changes were not accounted for only by vividness of imagery and perceived pain intensity, high hypnotizability is apparently responsible for part of the postural effects of pain imagery.

Postural effects of imagined leg pain as a function of hypnotizability.

Previous studies on the role of hypnotizability in postural control indicate that the body sway of subjects with high or low hypnotizability to hypnosis is differentially modulated by eye closure. The aim of this study was to investigate whether hypnotizability also modulates the postural response to electrical vestibular stimulation and to head rotation in nonhypnotized individuals. The center of pressure (CoP) displacements were monitored in highs and lows standing on a stabilometric platform with closed eyes during basal conditions and electrical vestibular stimulation in 3 different positions of the head. Results showed that the CoP stimulus-locked displacements as well as the CoP mean position, area, and mean velocity were similar in highs and lows, but only in lows did the head position modulate the mean velocity. This finding might reflect a difference in sensory-motor integration between the 2 groups.

Effects of vestibular and neck proprioceptive stimulation on posture as a function of hypnotizability.

Subjects with high (Highs) and low (Lows) susceptibility to hypnosis show differences in the sensory-motor integration for postural control and in the cardiovascular response to stress and experimental pain. Aim of the experiment was to assess whether the cardiac response to gravity-related stimulation depending on changes in the body position were different in the two groups. Thus, heart rate (HR) and heart rate variability (HRV) were evaluated in sitting and upright position in Highs and Lows. Position-related HRV changes were studied in the time (statistical indexes, Poincaré Plot) and frequency (spectral analysis) domain. Results indicated that upright stance was associated with similar changes in heart rate and different modulation of HRV in the two groups. The association of time and frequency domain analyses allowed hypothesizing different control mechanisms as responsible for the cardiac response to upright stance in Highs and Lows, likely due to a different role of the Very Low Frequency (VLF) spectral component of HRV in the two groups. The results are in line with previous findings indicating a natural protection of Highs against cardiovascular events and suggest that the Highs' cardiac function might be less impaired by microgravity than the Lows' one.

Hypnotizability-dependent modulation of the changes in heart rate control induced by upright stance.

Abstract In the general population, suppression of vision modulates body sway by increasing the center of pressure (CoP) velocity, while a light fingertip touch reduces the area of the CoP displacement in blindfolded subjects. This study assessed whether imagined fixation and fingertip touch differentially stabilize posture in subjects with high (highs) and low (lows) hypnotizability. Visual and tactile imageries were ineffective in lows. In highs, the effects of visual imagery could not be evaluated because the real information was ineffective; real tactile stimulation was effective only on velocity, but the imagery effects could not be definitely assessed owing to low effect size. The highs' larger variability could account for this and represents the most important finding. 

Stabilizing posture through imagery.

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 aim of this exploratory study was to assess the EEG correlates of head positions (which have never been studied in humans) in participants with different psychophysiological characteristics, as encoded by their hypnotizability scores. This choice is motivated by earlier studies suggesting different processing of vestibular/neck proprioceptive information in subjects with high (highs) and low (lows) hypnotizability scores maintaining their head rotated toward one side (RH).

Spectral and topological analyses of the cortical representation of the head position: Does hypnotizability matter?

In order to assess possible influences of occlusion on motor performance, we studied by functional magnetic resonance imaging (fMRI) the changes in the blood oxygenation level dependent (BOLD) signal induced at brain level by a finger to thumb motor task in a population of subjects characterized by an asymmetric activation of jaw muscles during clenching (malocclusion). In these subjects, appropriate occlusal correction by an oral orthotic (bite) reduced the masticatory asymmetry. The finger to thumb task was performed while the subject's dental arches were touching, in two conditions: (a) with the teeth in direct contact (Bite OFF) and (b) with the bite interposed between the arches (Bite ON). Both conditions required only a very slight activation of masticatory muscles. Maps of the BOLD signal recorded during the movement were contrasted with the resting condition (activation maps). Between conditions comparison of the activation maps (Bite OFF/Bite ON) showed that, in Bite OFF, the BOLD signal was significantly higher in the trigeminal sensorimotor region, the premotor cortex, the cerebellum, the inferior temporal and occipital cortex, the calcarine cortex, the precuneus on both sides, as well as in the right posterior cingulate cortex. These data are consistent with the hypothesis that malocclusion makes movement performance more difficult, leading to a stronger activation of (a) sensorimotor areas not dealing with the control of the involved body part, (b) regions planning the motor sequence, and (c) the cerebellum, which is essential in motor coordination. Moreover, the findings of a higher activation of temporo-occipital cortex and precuneus/cingulus, respectively, suggest that, during malocclusion, the movement occurs with an increased visual imagery activity, and requires a stronger attentive effort.

Diego Manzoni

Department of Translational Research and of New Surgical and Medical Technologies

University of Pisa

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

Diego Manzoni

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Translational Research and of New Surgical and Medical Technologies

University of Pisa

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

Department of Translational Research and of New Surgical and Medical Technologies