Occlusal effects on text reading: an eye-tracker study.

Introduction: Asymmetric electromyographic (EMG) activity during teeth clenching has been linked to cognitive impairment, as evaluated by the Spinnler-Tognoni matrices test, and to asymmetric pupil size (anisocoria). Anisocoria indicates an asymmetric Locus Coeruleus activity, leading to an asymmetric hemispheric excitability worsening cognitive performance. Bite splint wearing corrects EMG asymmetry, reduces anisocoria and improves cognitive performance. This study explores the possible effect of EMG asymmetry on oculomotor behavior during text reading. Methods: In subjects showing different degrees of EMG asymmetry during clenching, the number and duration of fixation periods during a reading task, performed under two different occlusal conditions were analyzed. The first lecture was executed with a dental impression (imprint) interposed between the dental arches (corrected condition) and the second one with the arches in direct contact (habitual condition), without clenching effort. The imprint reduced the EMG asymmetries during clenching. Results: In both occlusal conditions, total reading time correlated with duration of fixations, but not with their number. An inverse relation was observed between the number of fixations and their duration across individuals. Fixation frequency and duration were positively and negatively correlated with the amplitude of EMG asymmetry, respectively. Differently, total reading time was not related to the EMG asymmetry. When switching from the corrected to the habitual condition, an increase in the number of fixations and a reduction in their duration was observed, while total reading time could be either increased or decreased. An increased fixation frequency was observed in most of the subjects, while a reduced duration only among individuals with shorter reading times in habitual condition. Discussion: In the habitual condition, EMG asymmetry influences reading patterns (more saccades/shorter fixations, less saccades/longer fixations) in our sample. The changes in text reading behavior elicited by occlusal correction can be explained by assuming that occlusal disharmony negatively interferes with the reading task by increasing the number of saccades necessary for text scanning. This finding may also indicate an increased difficulty in processing of visual information. The potential involvement of trigeminal pathways in the relation between occlusal factors and oculomotor control is discussed.

Trigeminal Stimulation and Visuospatial Performance: The Struggle between Chewing and Trigeminal Asymmetries.

Chewing improves visuospatial performance through locus coeruleus (LC) activation. The effects of bilateral and unilateral mastication were investigated in subjects showing different degrees of asymmetry in masseter electromyographic (EMG) activity during clenching and in pupil size at rest (anisocoria), which is a proxy of LC imbalance. Correlations between performance changes and asymmetry values were found in males, but not in females. Among males, subjects with low asymmetry values (balanced-BAL) were more sensitive than those with high asymmetry values (imbalanced-IMB) to bilateral and unilateral chewing on the side with higher EMG activity (hypertonic). The opposite was true for hypotonic side chewing. BAL subjects were sensitive to unilateral chewing on both sides, while in IMB subjects, hypertonic side chewing did not influence performance in either males or females. Bilateral chewing elicited larger effects in BAL subjects than in IMB subjects, exceeding the values predicted from unilateral chewing in both groups. Finally, pupil size and anisocoria changes elicited by chewing were correlated with asymmetry values, independent of sex. Data confirmed the facilitation of visuospatial performance exerted by chewing. Trigeminal asymmetries modulate the chewing effects, making occlusal rebalancing an appropriate strategy to improve performance.

Thalamocortical Spectral Transmission Relies on Balanced Input Strengths.

The thalamus is a key element of sensory transmission in the brain, as it gates and selects sensory streams through a modulation of its internal activity. A preponderant role in these functions is played by its internal activity in the alpha range ([8-14] Hz), but the mechanism underlying this process is not completely understood. In particular, how do thalamocortical connections convey stimulus driven information selectively over the back-ground of thalamic internally generated activity? Here we investigate this issue with a spiking network model of feedforward connectivity between thalamus and primary sensory cortex reproducing the local field potential of both areas. We found that in a feedforward network, thalamic oscillations in the alpha range do not entrain cortical activity for two reasons: (i) alpha range oscillations are weaker in neurons projecting to the cortex, (ii) the gamma resonance dynamics of cortical networks hampers oscillations over the 10-20 Hz range thus weakening alpha range oscillations. This latter mechanism depends on the balance of the strength of thalamocortical connections toward excitatory and inhibitory neurons in the cortex. Our results highlight the relevance of corticothalamic feedback to sustain alpha range oscillations and pave the way toward an integrated understanding of the sensory streams traveling between the periphery and the cortex.

The path from trigeminal asymmetry to cognitive impairment: a behavioral and molecular study.

Trigeminal input exerts acute and chronic effects on the brain, modulating cognitive functions. Here, new data from humans and animals suggest that these effects are caused by trigeminal influences on the Locus Coeruleus (LC). In humans subjects clenching with masseter asymmetric activity, occlusal correction improved cognition, alongside with reductions in pupil size and anisocoria, proxies of LC activity and asymmetry, respectively. Notably, reductions in pupil size at rest on the hypertonic side predicted cognitive improvements. In adult rats, a distal unilateral section of the trigeminal mandibular branch reduced, on the contralateral side, the expression of c-Fos (brainstem) and BDNF (brainstem, hippocampus, frontal cortex). This counterintuitive finding can be explained by the following model: teeth contact perception loss on the lesioned side results in an increased occlusal effort, which enhances afferent inputs from muscle spindles and posterior periodontal receptors, spared by the distal lesion. Such effort leads to a reduced engagement of the intact side, with a corresponding reduction in the afferent inputs to the LC and in c-Fos and BDNF gene expression. In conclusion, acute effects of malocclusion on performance seem mediated by the LC, which could also contribute to the chronic trophic dysfunction induced by loss of trigeminal input.

Chewing and Cognitive Improvement: The Side Matters.

Chewing improves cognitive performance, which is impaired in subjects showing an asymmetry in electromyographic (EMG) masseter activity during clenching. In these subjects, the simultaneous presence of an asymmetry in pupil size (anisocoria) at rest indicates an imbalance in Ascending Reticular Activating System (ARAS) influencing arousal and pupil size. The aim of the present study was to verify whether a trigeminal EMG asymmetry may bias the stimulating effect of chewing on cognition. Cognitive performance and pupil size at rest were recorded before and after 1 min of unilateral chewing in 20 subjects with anisocoria, showing an EMG asymmetry during clenching. Unilateral chewing stimulated performance mainly when it occurred on the side of lower EMG activity (and smaller pupil size). Following chewing on the hypotonic side, changes in cognitive performance were negatively and positively correlated with those in anisocoria and pupil size, respectively. We propose that, following chewing on the hypotonic side, the arousing effects of trigeminal stimulation on performance are enhanced by a rebalancing of ARAS structures. At variance, following chewing on the hypertonic side, the arousing effect of trigeminal stimulation could be partially or completely prevented by the simultaneous increase in ARAS imbalance.

Trigeminal input, pupil size and cognitive performance: From oral to brain matter.

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.

Spherical-harmonics mode decomposition of neural field equations.

Large-scale neural networks can be described in the spatial continuous limit by neural field equations. For large-scale brain networks, the connectivity is typically translationally variant and imposes a large computational burden upon simulations. To reduce this burden, we take a semiquantitative approach and study the dynamics of neural fields described by a delayed integrodifferential equation. We decompose the connectivity into spatially variant and invariant contributions, which typically comprise the short- and long-range fiber systems, respectively. The neural fields are mapped on the two-dimensional spherical surface, which is choice consistent with routine mappings of cortical surfaces. Then, we perform mathematically a mode decomposition of the neural field equation into spherical harmonic basis functions. A spatial truncation of the leading orders at low wave number is consistent with the spatially coherent pattern formation of large-scale patterns observed in simulations and empirical brain imaging data and leads to a low-dimensional representation of the dynamics of the neural fields, bearing promise for an acceleration of the numerical simulations by orders of magnitude.

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 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.

Integrate-and-fire network model of activity propagation from thalamus to cortex.

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.

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

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 locus coeruleus (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.

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

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.

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

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.

Sensorimotor trigeminal unbalance modulates pupil size.

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.

In the rat brain acetyl-L-carnitine treatment modulates the expression of genes involved in neuronal ceroid lipofuscinosis.

Acetyl-L-carnitine (ALC) is a naturally occurring substance that, when administered at supraphysiological concentration, is neuroprotective. It is a molecule of considerable interest for its clinical application in various neural disorders, including Alzheimer's disease and painful neuropathies. Suppression subtractive hybridization methodology was used for the generation of subtracted cDNA libraries and the subsequent identification of differentially expressed transcripts in the rat brain after ALC treatment. The method generates an equalized representation of differentially expressed genes irrespective of their relative abundance and it is based on the construction of forward and reverse cDNA libraries that allow the identification of the genes which are regulated by ALC. We report that ALC treatment: (1) upregulates lysosomal H(+)/ATPase gene expression and (2) downregulates myelin basic protein gene expression. The expression of these genes is altered in some forms of neuronal ceroid lipofuscinosis (NCL) pathologies. In this case, ALC might rebalance the disorders underlying NCL disease represented by a disturbance in pH homeostasis affecting the acidification of vesicles transported to lysosomal compartment for degradation. This study provides evidence that ALC controls genes involved in these serious neurological pathologies and provides insights into the ways in which ALC might exert its therapeutic benefits.

Stochastic models for the in silico simulation of synaptic processes.

BACKGROUND: Research in life sciences is benefiting from a large availability of formal description techniques and analysis methodologies. These allow both the phenomena investigated to be precisely modeled and virtual experiments to be performed in silico. Such experiments may result in easier, faster, and satisfying approximations of their in vitro/vivo counterparts. A promising approach is represented by the study of biological phenomena as a collection of interactive entities through process calculi equipped with stochastic semantics. These exploit formal grounds developed in the theory of concurrency in computer science, account for the not continuous, nor discrete, nature of many phenomena, enjoy nice compositional properties and allow for simulations that have been demonstrated to be coherent with data in literature. RESULTS: Motivated by the need to address some aspects of the functioning of neural synapses, we have developed one such model for synaptic processes in the calyx of Held, which is a glutamatergic synapse in the auditory pathway of the mammalia. We have developed such a stochastic model starting from existing kinetic models based on ODEs of some sub-components of the synapse, integrating other data from literature and making some assumptions about non-fully understood processes. Experiments have confirmed the coherence of our model with known biological data, also validating the assumptions made. Our model overcomes some limitations of the kinetic ones and, to our knowledge, represents the first model of synaptic processes based on process calculi. The compositionality of the approach has permitted us to independently focus on tuning the models of the pre- and post- synaptic traits, and then to naturally connect them, by dealing with "interface" issues. Furthermore, we have improved the expressiveness of the model, e.g. by embedding easy control of element concentration time courses. Sensitivity analysis over several parameters of the model has provided results that may help clarify the dynamics of synaptic transmission, while experiments with the model of the complete synapse seem worth explaining short-term plasticity mechanisms. CONCLUSIONS: Specific presynaptic and postsynaptic mechanisms can be further analysed under various conditions, for instance by studying the presynaptic behaviour under repeated activations. The level of details of the description can be refined, for instance by further specifying the neurotransmitter generation and release steps. Taking advantage of the compositionality of the approach, an enhanced model could then be composed with other neural models, designed within the same framework, in order to obtain a more detailed and comprehensive model. In the long term, we are interested, in particular, in addressing models of synaptic plasticity, i.e. activity dependent mechanisms, which are the bases of memory and learning processes. More on the computer science side, we plan to follow some directions to improve the underlying computational model and the linguistic primitives it provides as suggested by the experiments carried out, e.g. by introducing a suitable notion of (spatial) locality.

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

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.

Computational model of touch sensory cells (T Cells) of the leech: role of the afterhyperpolarization (AHP) in activity-dependent conduction failure.

Bursts of spikes in T cells produce an AHP, which results from activation of a Na+/K+ pump and a Ca2+-dependent K+ current. Activity-dependent increases in the AHP are believed to induce conduction block of spikes in several regions of the neuron, which in turn, may decrease presynaptic invasion of spikes and thereby decrease transmitter release. To explore this possibility, we used the neurosimulator SNNAP to develop a multi-compartmental model of the T cell. The model incorporated empirical data that describe the geometry of the cell and activity-dependent changes of the AHP. Simulations indicated that at some branching points, activity-dependent increases of the AHP reduced the number of spikes transmitted from the minor receptive fields to the soma and beyond. More importantly, simulations also suggest that the AHP could modulate, under some circumstances, transmission from the soma to the synaptic terminals, suggesting that the AHP can regulate spike conduction within the presynaptic arborizations of the cell and could in principle contribute to the synaptic depression that is correlated with increases in the AHP.

Sensitization and dishabituation of swim induction in the leech Hirudo medicinalis: role of serotonin and cyclic AMP.

In this paper the role of serotonin (5HT) and cyclic AMP (cAMP) in sensitization and dishabituation of swim induction (SI) has been investigated in the leech Hirudo medicinalis. Electrical stimulation of the body wall evokes swimming activity with a constant latency. In animals with a disconnection between head ganglion and segmental ganglia, repetitive stimulation induces habituation of swimming whereas brushing on the dorsal skin provokes sensitization of a naïve response or dishabituation of a previously habituated response. Our findings indicate that 5HT is the neurotransmitter underlying both sensitization and dishabituation of SI. Injection of the 5HT receptor blocking agent methysergide impaires the onset of sensitization and dishabituation induced by brushing. Moreover, injection of 5HT mimics these forms of nonassociative learning, whereas injection of dopamine does not. Finally, the effects of 5HT are mediated by cAMP: (1) after injections of specific adenylate cyclase inhibitors such as MDL 12.330A or SQ22536, brushing becomes ineffective in facilitating the SI in either non-habituated or habituated animals. (2) 8Br-cAMP application mimics both sensitization and dishabituation of SI.