Neural Basis of Oral and Facial Function

Neural Basis of Oral and Facial Function BJ Sessle, University of Toronto, Toronto, ON, Canada Ó 2014 Elsevier Inc. All rights reserved.

Glossary Allodynia This refers to pain that is produced by a stimulus that is normally not noxious. Examples are the pain that may be produced when sunburned skin is lightly touched or when a sore jaw muscle is lightly pressed. Dental pulp Soft tissues inside each tooth; sometimes referred to as the ‘nerve’ of the tooth because it contains a profuse nerve supply; some of these nerve fibers provide the peripheral basis for pain from the tooth, and some control the blood vessels and blood supply of the pulp. Hyperalgesia This refers to an augmented pain that is produced by a noxious stimulus that normally produces only mild or moderate pain. Examples include the severe pain that may be produced when sunburned skin is slapped (i.e., normally a mildly painful stimulus) or when a sore jaw muscle is heavily pressed. Periodontal tissues (or periodontium) Supporting tissues of the teeth, which surround the root of each tooth and serve to attach the root of the tooth to its socket in the

Introduction

studies in animals have been indispensable and crucial to most of the current knowledge of their mechanisms.

Before reviewing the neural mechanisms underlying the sensory and motor functions of the face and mouth, it first should be noted that the orofacial region is remarkable in its high level of sensory discriminability and sensitivity. This is probably a reflection of its great innervation density and the large amount of brain tissue devoted to the representation of the oral cavity and surrounding areas. In addition, specialized receptor systems are associated with the periodontal supporting tissues of the teeth and, in many subprimates, with the facial whiskers (vibrissae). These receptors provide an added dimension of sensory experience, and together with the tongue and lips, are most important for exploration of the environment and controlling movement and behavior. In addition, some of the most common pains occur in this region (e.g., toothache, headache), and some sensory functions are unique to the region (e.g., taste). Likewise, the orofacial region is remarkable in the vast array of simple and complex sensorimotor activities that are manifested within it. These activities range from relatively simple reflexes, such as the jaw-opening reflex, to the very complex motor activities associated with speech, mastication, and swallowing, and utilizing sensory inputs into the brain from the receptors in the face and mouth to initiate or guide them. These activities involve the coordinated neuronal activity of many parts of the brain and provide for social communication and the intake of food and fluid vital for life. It is also important to note that while this article focuses on human orofacial somatosensory and motor functions,

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enveloping alveolar bone; they also contain nerve fibers that control the periodontal blood vessels and, thus, the blood supply of the periodontal tissues, as well as sense organs (receptors) and their associated nerve fibers, which provide the peripheral basis for pain and touch from these tissues. Temporomandibular joint The ‘jaw joint’ immediately in front of the ear; it also has a nerve supply, particularly on the posterolateral aspect of its capsule, that supplies receptors involved in pain, jaw position sense, etc. Trigeminal nerve Fifth cranial nerve that has three major branches: the ophthalmic, maxillary, and mandibular; these three branches provide most of the sensory innervation of the face and oral cavity, and the mandibular branch also contains motor axons that supply several muscles of the orofacial region, principally those moving the jaw (mandible).

Sensory Functions Touch (for Review, see Dubner et al., 1978; Miles et al., 2004) The ability to sense touch (i.e., tactile sensibility) is extremely well developed in the orofacial region. Tests to measure touch include tactile threshold, stereognosis (a term referring to the ability to recognize the form of objects), and two-point discrimination, and they have shown that some orofacial tissues such as the tongue tip and lips have a greater tactile sensitivity than any other part of the body. These peripheral tissues are densely innervated by primary afferent nerve fibers, each of which terminates peripherally as sensory organs called receptors. These receptors ‘sense’ stimuli and changes in the environment and transduce this information into electrochemical energy, which is then carried along the afferent fibers, into the brain, as action potentials. We also have analogous receptor mechanisms for our ability to detect and discriminate the size of small objects placed between the teeth, their hardness and texture, and bite force; these functions have largely been attributed to receptors that are located in the periodontal tissues around the root of each tooth. It is also becoming increasingly apparent that other receptors, such as those in the jaw joint and even in jaw muscles, make an important contribution. Receptors in this joint (the temporomandibular joint (TMJ)) as well as those in the jaw muscles

http://dx.doi.org/10.1016/B978-0-12-801238-3.00035-0

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also largely account for our conscious perception of jaw position (see Temporomandibular Disorders). The receptors in the facial skin, oral mucosa, periodontal tissues, and TMJ that are responsible for the sensibility to mechanical stimuli such as touch or pressure stimuli can be broadly categorized into two types: free nerve endings and corpuscular receptors, of which several anatomically distinct examples exist (e.g., Figure 1). Functionally, these so-called mechanoreceptors are primarily associated with largediameter, fast-conducting afferent nerve fibers, and they can respond either transiently (so-called velocity detectors) or throughout (static-position detectors) an innocuous mechanical stimulus applied to an orofacial site. This is reflected, respectively, in a brief or sustained burst of action potentials in their associated nerve fiber, which conducts these action potentials into the brain stem. By these neural signals, the mechanoreceptors collectively can provide the brain with detailed information of, for example, the location, quality, intensity, duration, and rate of movement of an orofacial tactile stimulus. Many types of mechanoreceptors are exclusively activated by tactile stimuli. This physiological specificity, coupled with the existence of an anatomically recognized receptor structure for some of these mechanoreceptors, and of many neurons in the central relay stations (see below) that respond exclusively to tactile stimulation, strongly supports the

concept of a specificity theory. According to this theory, a specific set of receptors and afferent nerve fibers, and nerve cells and relay stations in the brain, respond exclusively to tactile stimuli and provide the cerebral cortex only with neural information related to touch and not, for example, pain or temperature. The major primary afferent pathway carrying the neural signals from the orofacial mechanoreceptors is the trigeminal nerve (the fifth cranial nerve). The afferent nerve fibers in this nerve pass via the trigeminal ganglion, where their primary afferent cell bodies are located, and the trigeminal sensory nerve root to the trigeminal brain stem sensory nuclear complex (Figure 2). The neural signals are transferred to nerve cells (i.e., neurons) at all levels of the brain stem complex. This complex can be subdivided into a main sensory nucleus and a spinal tract nucleus; the latter is subdivided further into the subnuclei oralis, interpolaris, and caudalis. These second-order neurons then project to higher sensorimotor centers as well as to local brain stem regions, including those responsible for activating muscles. Thereby, they serve as so-called interneurons involved in reflexes or more complex sensorimotor behaviors. A major projection from these trigeminal brain stem neurons, however, is concerned with touch perception and passes primarily to the ventroposterior thalamus of the opposite (i.e., contralateral) side (Figure 2). After synaptic

Figure 1 The nerves supplying the tooth innervate the periodontal ligament tissues, which are the supporting tissues of the tooth, as well as the dental pulp. After entering the pulp at the root apex of the tooth, the pulpal nerves arborize extensively, especially in the crown of the tooth (a, b), much less so at the gingival (c) and root (d) levels of the tooth. They form a nerve plexus (n) in the periphery of the pulp beneath the layer of odontoblast cells (o), which have processes extending into the tubules in the overlying dentin (d), which are involved in dentin formation. Some individual nerve fibers leave the subodontoblastic plexus; especially in the crown of the tooth (see e), a number enter the dentinal tubules, although many terminate in the odontoblastic layer. Perivascular dendritic cells (dc), fibroblasts (f), and vascular innervation (VI) are shown in the diagram of the root. Reproduced, with permission, from Byers, Narhi, 1999. Dental injury models: experimental tools for understanding neuroinflammatory interactions and poly modal neciceptor functions. Crit. Rev. Oral Biol. Med. 10 (1), 4–39.

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Thermal Sensation (for Review, see Dubner et al., 1978; Miles et al., 2004) Our ability to sense the temperature of an object or substance is particularly well developed in the face and mouth, where thermal changes significantly <1  C can be readily detected and discriminated; however, temperature detection and discrimination can vary depending on the magnitude and rate of the thermal changes, the area of thermal stimulation, whether or not the area has undergone previous thermal changes, and the adapting temperature of the skin or oral mucosa. The receptors for temperature change (i.e., thermoreceptors) are associated with some of the smaller diameter, slowconducting afferent fibers. They are specifically activated by a small thermal change in either a cooling (cold afferent fibers) or warming (warm afferent fibers) direction, and they provide the brain with precise information on the location, magnitude, and rate of the temperature shift. The predominant relay site in the brain stem of the afferent signals carried in thermoreceptive primary afferent fibers appears to be the trigeminal subnucleus caudalis. Some neurons in this part of the trigeminal brain stem complex are exclusively activated by thermal stimulation of localized parts of the face and mouth, and this thermal information is relayed to the contralateral thalamus and then to the somatosensory cerebral cortex. The specificity theory thereby appears to be consistent with the properties of peripheral and central neural elements underlying our thermal sensibility. Figure 2 Major somatosensory pathway from the face and mouth. Trigeminal (V) primary afferents have their cell bodies in the trigeminal ganglion and project to second-order neurons in the V brainstem sensory nuclear complex. These neurons may project to neurons in higher levels of the brain (e.g., in the thalamus) or in brainstem regions such as cranial nerve motor nuclei or the reticular formation (RF). The sensory inputs also include orofacial afferents supplying the cornea and sinuses (e.g., maxillary). Also, not shown are the projections of some cervical nerve afferents and cranial nerve VII, IX, X, and XII afferents to the V brainstem complex and the projection of many V, VII, IX, and X afferents to the solitary tract nucleus. Reproduced, with permission, from Sessle, B.J., 2000. Acute and chronic craniofacial pain: brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit. Rev. Oral Biol. Med. 11, 57–91.

transmission through third-order neurons, the signals are relayed from here especially to a part of the overlying somatosensory cerebral cortex where the face and mouth are represented and where the cortical neural processing begins that eventually leads to the perception of a touch stimulus. The second-, third-, and fourth-order neurons in this pathway to the cortex show many functional properties comparable with those of mechanoreceptive primary afferent fibers. They also retain much of the ‘specificity’ of the tactile primary afferents, thus providing further support for the specificity theory of touch. However, by means of the complex ultrastructure and regulatory mechanisms existing at each of the relay sites, considerable modification of tactile transmission can occur, as a result of other incoming sensory signals and descending influences from higher brain centers. This may explain, for example, how distraction or focusing one’s attention on a particular task at hand can depress the awareness of a touch stimulus.

Taste As to the special sense of taste, three aspects are briefly mentioned here because they relate to some of the other functions discussed in this article. First, as with pain (see below), taste has affective, cognitive, and motivational dimensions as well as a sensory-discriminative dimension. For example, we find some tastes pleasurable and are motivated to seek them out, whereas other tastes have the opposite effect. Indeed, humans may have innate as well as acquired taste preferences, and the food industry is well aware of our ‘sweet tooth,’ an inborn preference for sweetness. Second, taste sensibility is now known not to be confined to specific areas of the tongue; extralingual (e.g., palatal) taste buds may also make an important contribution to taste. Finally, a number of factors have been reported to modify taste; these may include other sensory experiences (e.g., smell), decreased saliva, wearing of dentures, poor oral hygiene, local anesthetics, plant extracts, and perhaps genetic, metabolic, and endocrine factors and the age of the individual.

Pain (for Review, see Dubner et al., 1978; Miles et al., 2004; Sessle, 1987, 2000; Sessle et al., 2008) Pain deserves special emphasis because it can cause great human suffering and represents a major economic burden on society through health care costs, time lost from work, etc. Moreover, orofacial pains are particularly noteworthy because they are very common (e.g., toothache) and are often chronic and disabling. Pain is now conceptualized as a multifactorial experience. It not only includes a sensory-discriminative component, an aspect that allows us to discriminate the

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quality, location, duration, and intensity of a noxious stimulus (i.e., a tissue-damaging stimulus), but also encompasses cognitive, motivational, and affective variables, which can modify a person’s response to the stimulus. Thus, the reactions to a noxious stimulus can vary from individual to individual. It can depend not only on the magnitude of the noxious stimulus but also on factors such as the meaning of the situation in which the pain occurs, the person’s emotional state and motivation to get rid of the pain, and even racial and cultural background and gender. Of course, this multifactorial nature of pain can complicate diagnosis and treatment of pain for the clinician and also makes the experimental study of pain exceedingly difficult. Nonetheless, pain studies in humans and experimental animals have used a variety of approaches (e.g., behavioral, electrophysiological, anatomical) to give us some insights into the neural mechanisms underlying pain.

Pain Transmission The neural basis for orofacial pain and, indeed, pain from anywhere in the body is still only partly understood, but considerable advances have been made in the last few years. These insights into pain and the mechanisms underlying its control have largely come from studies in animals. The classic concept for explaining pain and the other somatic sensations is the specificity theory; while apparently applicable in other sensations such as touch (see above), this theory has been shown to have a number of limitations in trying to explain pain on the basis of a specific peripheral and central system. As a consequence, other theories have been proposed to account for the complexity and multidimensionality of pain. The gate control theory of pain has attracted the most recent interest and research, and although it has its limitations, it does provide a good conceptual framework for considering the multifactorial nature of pain. First, this theory emphasizes the sensory interaction that occurs within the brain between the touch-related neural signals carried into the brain by the low-threshold, large-diameter primary afferent fibers, and those signals conveyed by the smalldiameter fibers; the peripheral terminals of many of the latter fibers respond to noxious stimuli. If, as a result of this interaction, the activity in the small so-called nociceptive fibers prevails, central transmission cells are excited (the ‘gate’ opens) and bring into action the central processes related to the perception of and reactions to noxious stimulation. Second, the theory also emphasizes descending central neural controls (i.e., coming from higher brain centers) related to cognitive, affective, and motivational processes that can modulate the gate. Recent experimental studies have revealed that some nociceptive primary afferent fibers are specifically sensitive to noxious stimuli, whereas others respond to innocuous stimuli as well. These nociceptive afferents are of small diameter and slowly conducting, and they terminate in the peripheral tissues as free nerve endings. Injury or inflammation of orofacial tissues will not only activate some of the numerous nociceptive afferents ending in the tissues, but also may induce an increased excitability of these nociceptive afferents. This peripheral sensitization is important in the increased pain sensitivity (e.g., hyperalgesia, allodynia) that can be detected clinically at a peripheral injury or inflammation site (e.g., as in myositis, arthritis, and pulpitis). Several chemicals, including

some that are normally associated with actions within the central nervous system (CNS) (e.g., excitatory amino acids, opioids), are involved in producing or modifying peripheral sensitization by interacting with ion channels or membrane receptors on the nociceptive afferent endings. Nonneural processes (e.g., satellite glial cells in the trigeminal ganglion, and immune cells in peripheral tissues such as the tooth pulp) may also modulate nociceptive afferent excitability in these tissues. Sex differences have also been documented in some of these peripheral processes and may account at least in part for the sex differences in the prevalence of a number of orofacial pain states. Furthermore, several drugs commonly used clinically to relieve orofacial pain (e.g., aspirin) may exert their analgesic action by interfering with some of these peripheral mechanisms. Those nociceptive primary afferent fibers supplying the face and mouth project via the trigeminal ganglion to part of the trigeminal brain stem sensory nuclear complex. The subnucleus caudalis (see Figure 2) is especially involved in pain (and temperature) transmission. Many subnucleus caudalis neurons receive the signals from orofacial nociceptive primary afferents and, thus, can respond to noxious stimulation of the face and mouth, TMJ, or jaw and tongue muscles. These neurons are either nociceptive specific or wide dynamic range (i.e., they respond to innocuous as well as noxious stimuli; a wide dynamic range neuron is shown in Figure 3). Also noteworthy, these neurons relay nociceptive information to the contralateral thalamus, from where information is relayed to the overlying cerebral cortex or other thalamic regions. While parts of the thalamus or cortex are involved in the various components of pain behavior (perception, motivation, etc.), the precise function of each region is still not fully understood. The ‘rostral’ parts of the trigeminal brain stem complex are especially concerned with the relay of tactile information (see above), but studies also indicate a role for them in orofacial pain mechanisms as well. For example, afferent fibers from the ‘nerve’ of the tooth (the dental pulp), generally assumed to represent a nociceptive input, synapse with neurons present not only in subnucleus caudalis but also at the more rostral levels of the complex.

Pain Control A variety of procedures are available for the control of pain, ranging from pharmacologic measures such as local and general anesthetics and analgesic drugs (e.g., aspirin, morphine) to therapeutic procedures such as acupuncture, transcutaneous electric stimulation, hypnosis, cognitive behavioral therapy, and psychiatric counseling. In extreme cases, neurosurgical methods may be employed. All these procedures are aimed at blocking pain signals either at the periphery (e.g., aspirin; see above), before nerve impulses enter the brain (e.g., local anesthesia), or within the brain (e.g., general anesthetics and many analgesic drugs). As described above, the trigeminal brain stem sensory nuclei have a complex structural organization by which they can interact in complex ways with many other parts of the nervous system. Interactions involving inhibitory processes that modulate pain transmission have been extensively documented; indeed, inhibitory modulatory processes are widespread in the brain and are involved, as noted above, in touch as well as in reflex activity

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Figure 3 (a) Diagram of major ascending trigeminal nociceptive pathway and a descending modulatory pathway that may suppress activity of neurons in the nociceptive pathway. Nociceptive neurons in the subnucleus caudalis receive and relay information from small-diameter primary afferent fibers (cross-hatched pathway) only, namely, nociceptive-specific neurons, or from small-diameter afferent fibers and from large-diameter primary afferent fibers (stippled pathway) as well, namely, wide dynamic range neurons; they predominate in layers I (marginalis, MAR) and V of the subnucleus caudalis. Substantia gelatinosa (SG) and magnocellularis (MAG) are other layers of the caudalis. Responses of both types of neurons to noxious orofacial stimuli can be suppressed by descending influences from the dorsal raphe nucleus in the periaqueductal gray and nucleus raphe magnus, as shown for the wide dynamic range neuron illustrated in (b). (Reproduced, with permission, from Dubner, R., Sessle, B.J., Storey, A.T., 1978. The Neural Basis of Oral and Facial Function. Plenum Press, New York.) (b) This caudalis nociceptive neuron fired with a brief burst of two action potentials when a light mechanical (tactile) stimulus was applied to a localized skin region of the cat’s face, and could also be activated when an electrical stimulus was applied to the canine dental pulp and when noxious radiant heat was applied to the same facial region; it was thus classified as a wide dynamic range neuron. These responses could be markedly suppressed when an electrical stimulus was also delivered to one of the raphe nuclei. Note in the records that with increasing intensity levels of electrical stimulation of the skin, late as well as early bursts of impulses could be evoked; the late discharge probably reflects inputs from nociceptive afferent fibers, and the early burst reflects inputs from faster conducting ‘tactile’ afferent fibers. Time duration of records: 100 msec.

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and more complex behavioral functions (see Section Neuromuscular Functions). There is evidence for inhibitory modulation of pain transmission through (1) sensory interaction and (2) descending central control mechanisms, as the gate theory postulates. The output of trigeminal nociceptive neurons, for example, can be markedly suppressed by large fiber afferent inputs activated by tactile stimulation of orofacial tissues (i.e., sensory interaction); however, in some situations, small-fiber nociceptive afferent stimulation may also suppress their activity. They can also be inhibited by stimulation of brain sites such as the midbrain periaqueductal gray matter and the nucleus raphe magnus in the lower brain stem (Figure 3); stimulation of such descending central controls produces marked analgesic effects in humans and experimental animals. Stimulation of other regions, such as the cerebral cortex, is less effective in suppressing the trigeminal nociceptive neurons, although cortical stimulation does have a profound influence on neurons excited by nonnoxious stimuli. These modulatory effects on nociceptive transmission are most exciting in terms of enhancing the understanding of pain mechanisms and developing better pain control procedures. The inhibitory effects have, for example, been linked in part to the release of endogenous (i.e., naturally occurring) chemicals that may activate the descending control systems or act relatively directly on the pain-transmission neurons. One of these endogenous substances is enkephalin, a peptide that is pharmacologically similar to the opiate drugs such as morphine; other neurochemicals such as 5-hydroxytryptamine (serotonin) also appear to be involved. When injected into certain parts of the brain, enkephalin produces analgesic effects; if applied locally in the vicinity of pain-transmission neurons in the trigeminal subnucleus caudalis or analogous neurons in the spinal cord, the responses of these neurons to noxious stimuli can be suppressed. Thus, pain-suppressing systems appear to occur naturally within the brain, and a number of important therapeutic procedures have been proposed that may exert their analgesic effects by utilizing such systems. The action of narcotic analgesics such as morphine has been linked to such systems, and therapeutic procedures involving skin, muscle, or nerve stimulation (transcutaneous electric stimulation and acupuncture) may exert their reported analgesic effect in part by exciting pathways to the brain that ultimately lead to activation of endogenous analgesic systems. Placebo analgesia also contributes to the effect of most pain-relieving procedures and involves some of these systems. Some segmental and descending pathways have the opposite effect, namely, facilitating nociceptive transmission. These facilitatory effects can thereby contribute to the enhancement of the pain experience, as might occur, for example, in the development and persistence of a chronic pain state and in enhanced pain levels associated with fear or anxiety. Facilitatory interactions between various convergent afferent inputs to trigeminal nociceptive neurons in the CNS appear to contribute to the so-called referral of pain, where pain may be felt not only at the site of injury or pathology but also, or instead, at other distant sites. In addition, the facilitatory effects initiated by stimulation of orofacial tissues as a result of injury or inflammation of the tissues, for example,

may result in a prolonged increase in excitability of the trigeminal nociceptive neurons. This central sensitization is thought to be an important process contributing to the hyperalgesia and allodynia (see above) that characterizes pain resulting from an orofacial injury or inflammation. Furthermore, the development and maintenance of a central sensitization state is considered to underlie the manifestation of most chronic pain conditions. Central sensitization reflects a neuroplasticity of the nociceptive pathways in the CNS, and a number of brain chemicals such as those operating through glutamatergic, neurokinin, purinergic, opioid, gamma-aminobutyric acid, and 5-hydroxytryptamine receptor mechanisms have been shown to contribute to or modulate these central neuroplastic changes induced by peripheral injury or inflammation. These changes may also be influenced by other factors (e.g., genetic, environmental) as well as nonneural (e.g., glial) cells.

Orofacial Pain Conditions (for review, see Miles et al., 2004; Sessle et al., 2008) The orofacial region is a particular focus of pain, and a brief description and possible mechanisms are given for several of the most common or interesting pain conditions. The first is temporomandibular disorders, which present a variety of signs and symptoms. The most commonly reported symptoms are pain in the region of the TMJ or jaw muscles or both, limitation of jaw movement, and crackling (crepitus) or clicking in the joint. The pain can sometimes be referred to other structures such as the teeth and muscles of the jaw or neck. Salivation and lacrimation, possibly reflecting involvement of the autonomic nervous system are also frequently associated with the disorder (see Temporomandibular Disorders). The etiology, diagnosis, and treatment of the condition represent some of the most controversial aspects of dentistry. Occlusal factors related to the faulty interdigitation of upper and lower teeth were long considered to be the most important etiologic factors, but many studies now point to the importance of central factors (e.g., stress-related) in many patients. The enhanced pain sensitivity (reflected in allodynia and hyperalgesia) that is a clinical feature of this condition can be explained by peripheral and/or central sensitization phenomena. Treatment procedures are as varied and numerous as the various theories of its etiology, ranging from balancing the bite (i.e., occlusal equilibration) that has little scientific evidence to support its use, to the administration of muscle relaxants or anxiety-reducing drugs, to cognitive behavioral therapy and counseling. The etiology of trigeminal neuralgia (or tic douloureux) is also controversial. This disorder, which rarely occurs in persons <45 year of age, manifests as paroxysms of excruciating pain that usually last for a few seconds or minutes, with long periods of remission between attacks. It is said to be the most excruciating pain a human can suffer, yet a most interesting and puzzling feature is that the neuralgic attack is usually triggered not by a noxious stimulus but by a light, nonnoxious stimulus (e.g., puff of air, wisp of cotton) to certain trigger sites in the perioral region. Theories of its etiology relate to either peripheral or central factors. Some researchers believe that peripheral changes, such as compression of the trigeminal sensory nerve root in the vicinity of the trigeminal ganglion by aberrant

Neural Basis of Oral and Facial Function

vessels or bony outgrowths, are the primary etiologic factor in triggering the painful attacks. Despite evidence in favor of a peripheral etiology, the signs and symptoms of the disorder are nonetheless suggestive of central neural changes, with imbalance in the functional organization of neurons in the trigeminal brain stem sensory complex. This view is compatible with the effectiveness of certain anticonvulsant or antiepileptic drugs in depressing the activity of trigeminal brain stem neurons. These drugs are now widely used for the clinical control of the disorder. Postherpetic neuralgia (shingles) differs from trigeminal neuralgia in that a definitive etiologic factor is known, namely, the herpes zoster virus that has gained access to the trigeminal ganglion. The pain usually involves the skin of the ophthalmic division of the trigeminal nerve (i.e., above and around the eye), and a selective loss of large myelinated fibers is apparent. Although this loss could, within the context of the gate control theory, lead to an imbalance of sensory input and an ‘opening of the gate’ (see above), the actual mechanisms responsible for the pain are still unclear. Another poorly understood condition is so-called atypical facial pain; atypical odontalgia or chronic continuous dentoalveolar pain are considered to reflect the same or related condition. This pain is diffuse, deep, and dull or throbbing in nature, and can be constant for many days. Unlike trigeminal neuralgia, trigger zones are typically not associated with the disorder. Its etiology is also uncertain, although it is often linked to a previous dental procedure (e.g., tooth extraction and root canal therapy) and its features suggest that central sensitization might be involved. Finally, the most common of orofacial pains is toothache. This pain is usually associated with trauma or dental decay affecting the ‘nerve’ of the tooth (the pulp) or the overlying hard tissue, the dentine. Much research has centered on the possible peripheral mechanisms of pulp and dentinal sensitivity. Figure 1 illustrates the innervation of the pulp; most of the nerves in the pulp are small-diameter afferent fibers associated with sensation, but some are autonomic efferent fibers thought to primarily control the blood supply of the pulp. The pulp afferent fibers can be excited by a variety of different types of stimuli (e.g., sugar and hot or cold drinks), as most people can attest to. While it is generally assumed that their excitation is exclusively related to pain, recent studies suggest that some pulp afferent fibers and their central connections in the brain may be involved in sensory functions other than pain. Many of the pulp afferent fibers terminate in close proximity to odontoblasts, but some enter the tubules in the dentine, occasionally in close contact with the process of the dentine-forming cell, the odontoblast (Figure 1). While these findings are considered by some researchers as evidence supporting a neural theory of dentinal sensitivity, the role of these intradentinal fibers in sensitivity is still unclear. Indeed, it is still conceivable that intradentinal neural processes contribute to the excitation of pulpal nerve fibers, or that intradentinal elements are involved by means of the odontoblast acting as a transducer, or by hydrodynamic processes, or both. More general acceptance exists for the hydrodynamic theory, which suggests that enamel or dentinal stimuli can cause a displacement of dentinal tubule contents; this, in turn, is thought to bring about a mechanically induced excitation of the nerves.

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Neuromuscular Functions (for Review, see Dubner et al., 1978; Miles et al., 2004; Sessle, 2009; Avivi-Arber et al., 2011) Muscle The orofacial region manifests a vast array of both simple and highly complex motor activities, which have important biological significance to the point of being among the most fundamental behaviors required for survival. Movements of the jaw and the surrounding musculature are integrally involved in human behaviors as diverse as mastication (chewing), drinking and suckling, manipulation of objects with the tongue, cheeks, and lips, communication through facial expressions, and speech production. The peripheral motor components of these activities are the muscles of the jaw, face, tongue, pharynx, larynx, and palate. Like muscles elsewhere in the body, they consist basically of a passive elastic component (e.g., tendon, ligaments) and an active contractile component; the latter is composed of numerous individual striated muscle fibers. These so-called extrafusal muscle fibers are connected to the axons of alpha motoneurons present in the brain stem; a single alpha motoneuron plus the muscle fibers that it supplies are known collectively as the motor unit. Impulses from the motoneuron are conducted along its axon (the alpha efferent or motor axon) to the muscle fibers and bring about muscle contraction through the process of neuromuscular transmission. The peripheral sensory components of muscle are receptors. For example, muscle contains free nerve endings and these receptors are associated with muscle pain and possibly responses to stretch. In addition, there are also specialized receptors (e.g., the Golgi tendon organ, which is particularly sensitive to muscle tension and the stretch-sensitive muscle spindle). In addition to a dual afferent supply, the muscle spindle receives a motor innervation from the gamma (fusimotor) efferent fibers of small gamma motoneurons, which modify the sensitivity of the afferent fibers to stretch, thereby indirectly assisting or maintaining muscle contraction. In contrast to muscles in most other places of the body, these specialized receptors have a limited distribution in the craniofacial region.

Central Mechanisms There are only limited details available of the primary muscle afferent pathways and central connections of most of the orofacial musculature, except for the trigeminal mesencephalic nucleus, which contains the cell bodies of jaw-closing muscle spindle primary afferent fibers (and some other orofacial primary afferent fibers). This location of primary afferent cell bodies is the only place in the body where primary sensory cell bodies are located within the CNS. Other major distinguishing features of the orofacial motor systems include the following. (1) Many orofacial muscles lack muscle spindles and Golgi tendon organs, as noted above. (2) A fusimotor (gamma-efferent) control system is absent due to the lack of muscle spindles in many muscles. (3) Reciprocal innervation, where muscle afferent fibers have reciprocally opposite effects on antagonistic spinal motoneurons, is

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limited due to the sparsity of muscle spindle and tendon organ afferent fibers. This lack may be compensated for by the powerful regulatory influences afforded by afferent inputs from facial skin, mucosa, TMJ, and teeth (see below). (4) Coordinating pathways and mechanisms exist to allow for the bilateral activity of muscles; although activity of a particular limb or trunk muscle can occur on both the left and right sides of the body in some movements, this bilateral activation (or depression) is particularly prominent in orofacial movements (e.g., chewing, swallowing, speech, coughing). The muscle afferent fibers, along with cutaneous, joint, and intraoral afferent fibers, make excitatory reflex connections with brain stem motoneurons located within one or more cranial nerve motor nuclei (Figure 4); these connections are usually indirect and involve interneurons in the trigeminal spinal tract nucleus, the solitary tract nucleus, and the reticular formation. Examples of such ‘simple’ reflexes are the jawclosing, jaw-opening, and horizontal jaw reflexes; facial muscle reflexes; tongue reflexes; and laryngeal, pharyngeal, and palatal reflexes. In addition to these excitatory reflex effects of various oral–facial stimuli, inhibitory effects are also expressed on the reflexes by sensory stimuli and by descending regulatory influences arising from higher brain centers such as the cerebral cortex (Figure 4). The excitatory and inhibitory influences are especially involved in protection of the masticatory apparatus (e.g., from biting the tongue during chewing) and in providing much of the neural organization upon which are based more complicated motor activities such as the protective reflex synergies of coughing and gagging. An even higher level of complexity of organization is seen with the rhythmic, automated activities of mastication, suckling, and swallowing; speech is another complex sensorimotor behavior utilizing this neural organization.

Figure 5 Electromyographic activity of various muscles recorded during a natural chewing cycle in a human subject: jaw (1–6); tongue (7); and facial (8). Vertical line indicates onset of activity in right anterior temporalis muscle. M and B indicate, respectively, onset and offset of contact of the opposing incisor teeth. AT, anterior temporalis; PT, posterior temporalis; MA, masseter; PI, medial (internal) pterygoid; PX, lateral (external) pterygoid; D, digastric; MY, mylohyoid; UL, upper lip; LL, lower lip; 1C, incisor contact. Reproduced, with permission, from Moller, E.,1966. The chewing apparatus. Acta Physiol. Scand. 69 (Suppl. 280), 1–229.

Cerebral cortex somatosensory and motor areas

Planning, initiation, and modulation of voluntary and involuntary movements; sensory-motor integration; motor learning

Thalamus Basal ganglia Sensory-motor integration; motor learning

Cerebellum Other subcortical areas (e.g., red nucleus, reticular formation)

Muscle contraction Sensory receptors

Brain stem Central pattern generators

Involuntary movements, initiation, and modulation of semiautomatic movements

Motor V,VII,XII Sensory V/ mesencephalic

Figure 4 Diagram showing the principal inputs of orofacial sensorimotor system. There are extensive interconnections, both excitatory and inhibitory, between the different cortical and subcortical regions, and commissural fibers are responsible for bilateral coordination. The central pattern generators provide the programmed motor output to muscles active in chewing (the ‘chewing Center’) and swallowing (the ‘swallowing Center’). Reproduced, with permission, from Avivi-Arber, L., Martin, R., Lee, J.C., Sessle, B.J., 2011. Face sensorimotor cortex and its neuroplasticity related to orofacial sensorimotor functions. Archs. Oral Biol. 56, 1440–1465.

Neural Basis of Oral and Facial Function

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Figure 6 The orchestrated sequence of events characterizing a single swallow. At the start of the swallow, the soft palate acts as a partition up to the base of the tongue (a, b) and elevates to engage the posterior pharyngeal wall and close off the nasopharynx as the food bolus (black) moves backward over the tongue surface (c–e). The tongue acts as a piston to squeeze the bolus into the pharynx, and the bolus is conveyed down the pharynx by pharyngeal muscle contractions (f–j); note that the epiglottis is tilted backward (e.g., to protect the entrance into the laryngeal airway (white)); the glottis (not shown) also serves to close off the entrance into the airway. Then, the bolus is slightly delayed at the upper esophageal sphincter (k), which then relaxes to allow the bolus into the upper esophagus (l, m) before closing again to prevent reflux (regurgitation). As the bolus moves down the esophagus (n–t), the soft palate relaxes and the epiglottis resumes its position and the airway is reopened. Reproduced, with permission, from Bradley, R.M., 1984. Basic Oral Physiology. Year Book Medical, Chicago; adapted from Rushner, R.F., Hendron, J.A., 1951. The act of deglutition; a cinefluorographic study. J. Appl. Physiol. 3 (10), 622–630.

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Neural Basis of Oral and Facial Function

Mastication, Swallowing, and Related Neuromuscular Functions Mastication Mastication serves to break down foodstuffs for subsequent digestion by means of the masticatory forces generated between the teeth. It is characterized by cyclic jaw movements in three dimensions (vertical, lateral, and anteroposterior) and less rigid facial and tongue motility patterns. These various movements are produced by the coordinated contraction of the jaw, face, and tongue muscles (Figure 5). Masticatory forces on the teeth are usually in the 5- to 10-kg range, but can vary depending on such factors as the teeth concerned (molars exert the greatest force, incisors the lowest), practice, toughness of the diet, tooth-cusp configuration, the wearing of dentures, presence of pain or periodontal disease, and the distance that the jaws are separated when the forces are applied. Even greater forces are developed during biting; maximal biting forces on a tooth usually range from approximately 20–200 kg (the Guinness world record is over 400 kg!). Although mastication was originally thought to be based on alternating simple jaw reflexes of jaw opening and closing, the current concept is that the cyclic, patterned nature of chewing depends on a subcortical center comprising a central neural pattern generator, the brain stem ‘chewing center.’ This generator is sensitive to descending regulatory influences from higher brain centers and to sensory inputs from oral–facial receptors; the sensory inputs may be particularly critical in the learning of mastication and acquisition of masticatory skills, in actively (i.e., reflexly) guiding masticatory movements, and in guiding the position of the jaw when the teeth come into occlusion and when the jaw is at ‘rest.’ The clinical significance of the sensory influences is further exemplified by their probable involvement, along with central influences, in the etiology of pathophysiologic conditions such as temporomandibular disorders and bruxism (tooth grinding).

Swallowing In contrast to mastication, swallowing is an innate, reflexly triggered, all-or-none motor activity that is relatively insensitive to sensory or central control. In addition to its obvious alimentary function, swallowing also serves as a protective reflex of the upper airway because it reflexly interrupts respiration and prevents the intake of food or fluid into the airway. Swallowing consists of a rigid, temporal pattern of muscle

activities that appears to depend on a brain stem pattern generator, the ‘swallow center,’ for its expression. The coordinated muscle activities provide the means for the propulsion of a food or liquid bolus from the oral cavity to the stomach (Figure 6) and also afford mechanisms for protection of the airway and prevention of reflux (regurgitation). Some of the muscles are ‘obligate’ swallow muscles (i.e., they always are active in swallowing), whereas others show a variable participation in swallowing (the facultative muscles). The latter muscles especially may be sensitive to alterations in the oral environment and to maturational changes, and thus their participation can vary depending, for example, on the volume or consistency of a foodstuff, or whether the subject is an infant or adult.

Other Functions Mastication, suckling, and swallowing are themselves components of even more complex behaviors. They are associated with feeding and drinking, which are particularly dependent on the function of higher centers of the brain such as the hypothalamus. Sensory feedback, however, is also utilized for the initiation, maintenance, and cessation of these ingestive behaviors (e.g., a ‘full stomach’ stretches gastrointestinal receptors, which, through their central connections, can inhibit feeding). Many of these higher brain centers are also concerned with other complex functions involving the oral cavity, including oral aggression (e.g., biting), facial expression, and speech.

Bibliography Avivi-Arber, L., Martin, R., Lee, J.C., Sessle, B.J., 2011. Face sensorimotor cortex and its neuroplasticity related to orofacial sensorimotor functions. Archs. Oral Biol. 56, 1440–1465. Dubner, R., Sessle, B.J., Storey, A.T. (Eds.), 1978. The Neural Basis of Oral and Facial Function. Plenum, New York. Miles, T.S., Nauntofte, B., Svensson, P. (Eds.), 2004. Clinical Oral Physiology. Quintessence, Copenhagen. Sessle, B.J., 1987. The neurobiology of facial and dental pain: present knowledge, future directions. J. Dent. Res. 66, 962–981. Sessle, B.J., 2000. Acute and chronic craniofacial pain: brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit. Rev. Oral Biol. Med. 11, 57–91. Sessle, B.J., 2009. Orofacial motor control. In: Squire, L. (Ed.), Encyclopedia of neuroscience, vol. 7. Academic Press, Oxford, pp. 303–308. Sessle, B.J., Lavigne, G., Lund, J.P., Dubner, R. (Eds.), 2008. Orofacial Pain: From Basic Science to Clinical Management, second ed. Quintessence, Chicago.