The interaction between the nervous system and the stomatognathic system: from development to diseases

The crosstalk between the nerve and stomatognathic systems plays a more important role in organismal health than previously appreciated with the presence of emerging concept of the “brain-oral axis”. A deeper understanding of the intricate interaction between the nervous system and the stomatognathic system is warranted, considering their significant developmental homology and anatomical proximity, and the more complex innervation of the jawbone compared to other skeletons. In this review, we provide an in-depth look at studies concerning neurodevelopment, craniofacial development, and congenital anomalies that occur when the two systems develop abnormally. It summarizes the cross-regulation between nerves and jawbones and the effects of various states of the jawbone on intrabony nerve distribution. Diseases closely related to both the nervous system and the stomatognathic system are divided into craniofacial diseases caused by neurological illnesses, and neurological diseases caused by an aberrant stomatognathic system. The two-way relationships between common diseases, such as periodontitis and neurodegenerative disorders, and depression and oral diseases were also discussed. This review provides valuable insights into novel strategies for neuro-skeletal tissue engineering and early prevention and treatment of orofacial and neurological diseases.


INTRODUCTION
With the advancement of brain science in recent years, the association between the nervous system and the stomatognathic system has become increasingly evident.To this effect, new concepts, such as neuromuscular dentistry 1,2 and stomatopsychology 3 have been proposed to explain the interaction between the two systems.Additionally, research has highlighted the importance of nerves in craniomaxillofacial development, 4 as well as the crosstalk between nerves and jawbone, 5 and the diseases that can arise from them.
Anatomically, the nervous and stomatognathic systems are evidently close in proximity.The nervous system consists of the central nervous system (CNS) and the peripheral nervous system (PNS).The former includes the brain and spinal cord, and the latter comprises cranial nerves (linking with the brain) and spinal nerves (linking with the spinal cord). 6The peripheral nerves associated with the oral and maxillofacial development region include the trigeminal nerve, facial nerve, glossopharyngeal nerve, vagus nerve, accessory nerve, hypoglossal nerve and even cervical spinal nerves. 7he nervous system regulates the stomatognathic system in a variety of ways, from maxillofacial bones to dental pulp, periodontal ligament (PDL), muscles, glands, oral mucosa, the tongue, the temporomandibular joint (TMJ), mouth, skin, and other structures. 8his intricate regulation of the nervous system is vital for the proper development and functioning of the maxillofacial system.Maxillofacial deformity and skeletal dysplasia are common comorbidities in neurodevelopmental deficit patients, such as trisomy 21 (ref. 9), neurofibromatosis, 10 and achondroplasia. 11e regulation between nerves and bones has been widely studied, 12 with intrabony nerves being found in cortical bone, 8 trabecular bone, periosteum, and bone marrow. 13,14The CNS regulates bone metabolism through the peripheral autonomic nervous system (ANS) and sensory nerves.The ANS comprises the sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS). 15,16All peripheral nerves regulate bone development and recover via neurotransmitters, neuropeptides, neurotrophins, and others. 17In the case of the jawbone, nerves not only distribute in the same parts as other bones, but also in special parts, such as the subchondral condyle, PDL, and dental pulp. 18In addition to classic targets, such as osteoclasts and osteoblasts, these parts are also targets of the nervous system that mediates jawbone remodeling.The regulation of nerves on the oral and maxillofacial systems is unique and significant due to the presence of more targets.Furthermore, because of the special anatomy of the jawbone-branches of the trigeminal nerve travel in the intraosseous canals and innervate peripheral tissues, 19 concomitant peripheral nerve injury can be caused by jawbone defects, and bone repair is accompanied by nerve repair. 20he proximity of anatomical structures, and the rich circulatory system of the brain and maxillofacial region, enable the nervous system and the stomatognathic system to interact with each other.The decline or loss of neurological function can result in some oral symptoms, such as facial paralysis 21 and salivation. 22onversely, oral diseases can influence the nervous system.If oral bacteria intrude into the brain via hematogenous spread, caries, periodontitis, and other oral infections may lead to intracranial infection and even neurodegenerative and neuropsychological diseases. 23Oral squamous cell carcinoma (OSCC) and adenoid cystic carcinoma (ACC) can lead to perineural invasion (PNI) of the head and neck as well, resulting in numbness, pain, or dysfunction. 24More importantly, the mechanism of some systemic diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are too complex to recognize their initiating lesions.Some nervous system diseases and stomatognathic diseases can promote each other, such as depression and periodontal disease, 25 and pain caused by neuropathy and stomatognathic lesions. 26Although abnormalities in the stomatognathic system are not the major cause of neurological diseases, it is important to note that the abnormalities can contribute to their progression.Therefore, understanding the potential links between these two systems is essential for early diagnosis and improved prognosis.
This review provides a comprehensive analysis of the cellular and molecular regulatory mechanisms between nerves and maxillofacial cells during growth and in both physiological and abnormal environments.It further examines the development of the oral and maxillofacial systems, wound healing, and other visible changes from a macro perspective.Additionally, it summarizes the nervous system diseases and disorders caused by the oral and maxillofacial systems, as well as the complex diseases that are strongly linked to the interaction between the nervous and stomatognathic systems.By gaining a better understanding of these complex scenarios, we can further investigate the underlying mechanisms and apply them to clinical settings for the early prevention and treatment of diseases in the future.

THE PHYSIOLOGICAL GROWTH AND DEVELOPMENTAL ANOMALIED OF NERVOUS AND CRANIOMAXILLOFACIAL SYSTEMS
Physiological growth of nervous and craniomaxillofacial systems It has been reported that cranial and maxillofacial development in vertebrates is closely related to neural growth. 4During this process, neural crest (NC) cells play a pivotal role, which are characterized by their multi-potential, migration, and differentiation abilities.In early embryonic development, NC cells first appear on the dorsal side of the neural tube and initiate the expression of NC signature genes (FoxD3, Sox10, etc.), signifying the formation of true NC cells. 27,28Subsequently, NC cells undergo an epithelialto-mesenchymal transition to migrate extensively during the entire embryonic development.NC cells can be divided into four main groups along the cephalic and caudal axis: cranial, vagal, trunk, and sacral ganglion subgroups. 29Among them, cranial neural crest (CNC) cells, derived from labeling NC cells with Wnt1, are the most significant group involved in craniofacial development, and the only group related to cranial bone formation. 30The migration of CNC cells is highly regulated and occurs along welldefined pathways, terminating in the ventral part of the brain and the branchial arch.CNC cells first migrate as continuous waves and rapidly split into three discrete streams to fill the first, second and third branchial arches.Subsequently, CNC cells contribute to various structures, including the skeletal system (cartilage and jawbone), cranial nerves and ganglia, as well as smooth muscle, vascular connective tissue, and the dermis of the head. 31oreover, CNC cells form multiple components of the tooth through sequential and induced epithelial-mesenchymal interactions between odontogenic mesenchymal cells derived from CNC and the covering ectoderm. 32Consequently, nerves play a crucial role in cranial and maxillofacial development.

Developmental anomalies of the nervous and craniomaxillofacial
systems.There are many congenital or genetic diseases that have multiple concurrent developmental alterations affecting the nervous system and stomatognathic system, some definitely serious for survival and others with less dramatic prognoses for life.Here are three of the typical diseases, and Table 1 lists additional ones.
Trisomy 21: Trisomy 21 (Down syndrome) is a genetic disorder resulting from an extra copy of human chromosome 21, occurring at a frequency of 1:600 to 1:2 000 (ref. 33 ).In fact, abnormal expression of non-HSA21 genes and deregulated non-coding genetic elements also influences brain and cognitive development in Trisomy 21.Patients with Trisomy 21 often suffer from mental retardation, neurodevelopmental disorders, and even AD with age. 9hey typically exhibit deficits in short-term memory and language abilities, as well as a variety of oral symptoms such as periodontitis, angular lip cheilitis, 34 missing teeth, malformed teeth, delayed tooth eruption, malocclusion, fissured lips and tongue, macroglossia, mouth breathing, and bruxism. 35The etiology of hypodontia abnormal development of the teeth may refer to alterations in the PNS 36 or the abnormalities in tooth germs. 37Inflammation, on the other hand, can be linked to alterations in patients' immune response 38 or various systemic or infectious diseases. 39Although novel treatments are being investigated, treatment of Trisomy 21 is largely based on approaches used for other diseases, such as AD. 40nd craniofacial or dentoalveolar aesthetics of patients with Trisomy 21 can be improved with surgical procedures and orthodontic treatments. 35,41urofibromatosis type 1: Many reports have demonstrated concomitant morpho-functional alteration in the stomatognathic system in individuals with neurofibromatosis.Neurofibromatosis is divided into two types: type 1 and type 2, the more common being Neurofibromatosis type 1 (NF1), which occurs at a frequency of 1 in 1000.NF1 is an autosomal dominant inherited disorder, and its pathogenesis is associated with mutations of the NF1 gene, which encodes the tumor suppressor neurofibromin. 42,43These mutations lead to the hyperactivation of the rat sarcoma mitogenactivated protein kinase (RAS-MAPK) pathway, which provokes cell hyperproliferation or tumorigenesis, like neurofibromas, optic pathway gliomas, astrocytomas, and malignant peripheral nerve sheath tumors. 10Because NF1 affects the underlying facial skeleton and can even directly infiltrate or pull down surrounding tissues, midface deformity is common in NF1 patients. 44Oral manifestations can be found in approximately 72% of NF1 patients, 45 with hard tissue (jawbone and teeth) malformations like intrabony cystic lesions, enlarged or branched mandibular canals 46 and malocclusion remaining prominent across the board. 47In addition, soft tissue deformities are frequently seen due to the morphological variations in particular sites.Examples of such deformities include malformed nose and upper lip areas, gingival enlargement, 48 gingival neurofibroma, 45 nodular lesions on the tongue, 49 and perineural fibrous thickening within the dental pulp. 50Due to a broad spectrum of lesions associated with NF1, surgical resection is usually used for therapy 44 Achondroplasia: The formation of mammalian skeletons occurs via intramembranous or endochondral ossification.The former occurs in the midface and the latter occurs in the skull base and nasal septum. 51Achondroplasia is the most prevalent genetic disorder of dwarfism, occurring at a frequency of 1 in 26,000 (ref. 52).Its pathogenesis is linked to activating mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3), 53 which is a pivotal regulator of endochondral bone growth.Activated FGFR3 signaling in chondrocytes increases the expression of Bmp ligand mRNA, which promotes osteoblast differentiation and accelerates bone formation and synchondrosis closure.Furthermore, the early closure of synchondroses may lead to the narrowing of the foramen magnum and spinal canals, 54 resulting in severe neurological complications, including radiculopathy, myelopathy, and neurogenic claudication.In terms of maxillofacial symptoms, achondroplasia patients may have a prominent The interaction between the nervous system and the stomatognathic system:. . .Wu et al.The interaction between the nervous system and the stomatognathic system:. . .Wu et al.
forehead, midface hypoplasia, occlusal abnormality, low nose bridge, narrow nasal passages, all of which are caused by defective endochondral ossification in craniofacial cartilage and premature closure of the growth center in craniomaxillofacial skeletogenesis. 11Due to critical illness in the nervous and orofacial system, any intervention ought to be implemented before the synchondrosis closure.

HOMESTASIS AND REGULATION BETWEEN THE NERVOUS SYSTEM AND JAWBONES Effect of nerves on jawbones
The anatomical structure of the jawbone is unique: the nerves travel in the bony ducts and send branches directly to surrounding tissues.The trigeminal nerve, the largest cranial nerve, comprises the ophthalmic, maxillary, and mandibular branches. 55The maxillary nerve innervates the maxilla, and the inferior alveolar nerve (IAN), which is the largest branch of the mandibular nerve, innervates the mandible. 56In addition to branches of the trigeminal nerve, ANS also plays a significant role in the physiology and pathology of the jawbone. 57xperimental animal studies have shown that the complex and intricate mechanism involves various nerves and bioactive factors secreted within the microenvironment. 57,58In particular, intrabony nerves regulate jawbone metabolism through neurotransmitters, neuropeptides, neurotrophins, and other signaling molecules. 59,60The tyrosine-hydroxylase-immunoreactive (TH-IR) fibers and vasoactive intestinal polypeptide (VIP)-IR fibers are sympathetic fibers.The TH-IR and VIP-IR fibers secrete norepinephrine (NE) and VIP respectively.Sensory neurons secrete calcitonin gene-related peptide (CGRP) and substance P (SP), so CGRP-IR fibers and SP-IR fibers are sensory fibers. 61The accumulation of various biological factors within the microenvironment of jawbones, along with the presence of their receptors in osteogenic and osteoblast lineage cells, [62][63][64] provides compelling evidence of bilateral homeostasis between nerves and the jawbone (Table 2 and Fig. 1).

Autonomic nervous system.
Animal experiments show that SNS negatively affects bone mass, 65 whereas PSNS does the opposite. 66revious research indicates that heightened SNS activity causes bone loss. 67SNS promotes bone resorption through the released NE and active β2-adrenergic receptors (β2-ARs), 62 as well as the receptor activator of nuclear factor kappa B ligand (RANKL)osteoprotegerin (OPG) system. 68The impact of SNS on the jawbone is more complicated than previously reported.Both TH-IR fibers and VIP-IR fibers distribute within the mandible periosteum and alveolar wall, but the distribution of TH-IR fibers is wider, and includes the mandibular endosteal retromolar zone.NE and VIP are two bioactive factors that contribute to osteoclast differentiation and bone resorption.Following sympathectomy, the number of TH-IR fibers and VIP-IR fibers declines, while the number of CGRP-IR fibers increases, 61 which is associated with sensory-sympathetic interactions mediated by neurotrophic factors. 69Sympathectomy changes the expression of NGF and semaphorin 3A (sema3a), leading to the increase of CGRP-IR fibers. 70Following a superior cervical ganglionectomy in female rats, bone mineral density increased significantly. 57This can be attributed to the inhibition of the SNS, which decreases the number of RANKL-expressing osteoblasts and preosteoclasts in the mandibular periosteum, thereby facilitating osteogenesis. 5Nerve fibers also innervate the TMJ, and active sympathetic signaling has been found to be related to bone loss during osteoarthritis of the TMJ, whereas the use of β2-ARs antagonists can suppress subchondral bone resorption and osteoclast function. 71Therefore, the metabolism of different regions of the jawbone is modulated by the sympathetic pathways.
In addition, the relationship between ANS and immune response has been investigated in the alveolar bone. 72Acetylcholine (a neurotransmitter secreted by PSNS) and its receptors have been found to be expressed in various non-neuronal cells including human keratinocytes, 73 fibroblasts, T cells, B cells and macrophages. 74,757][78] In fact, PSNS activation can promote osteoclast The interaction between the nervous system and the stomatognathic system:. . .Wu et al.
apoptosis to favor bone mass accrual. 66It has been found that electrical activation of the carotid sinus nerve can alleviate alveolar bone loss and periodontal disease in rats.This effect may be attributed to activation of PSNS and its anti-inflammatory response by provoking baroreflex and chemoreflex. 72However, comprehensive and thorough research investigating the regulation of ANS on the jawbone is relatively scarce.Therefore, further exploration is needed to understand the effect of ANS on the jawbone and its underlying mechanism.
Sensory nerves.The role of sensory nerves should not be ignored in bone regeneration.At the micro-level, these nerves promote bone recovery through the release of neuropeptides, such as CGRP and SP.Their receptors are expressed on bone cells, 5,63,64 indicating a strong association between the nervous system and bone metabolism in animal models.CGRP is a positive mediator for bone modeling, as it suppresses the number of osteoclasts by regulating the OPG/RANKL ratio.CGRP also promotes the osteogenic differentiation of human PDL stem cells to repair rat alveolar bone defects. 79However, the effect of SP appears to be contradictory.In vitro, studies indicate that SP can stimulate osteoblast and osteoclast differentiation and function. 80In vivo, studies show that a combination of SP and calcium phosphate cement can contribute to alveolar bone defect restoration. 81dditionally, SP has been found to hasten bone formation during mandibular distraction osteogenesis. 82Nonetheless, SP can inhibit osteogenesis induced by lipopolysaccharide from Porphyromonas gingivalis. 64Generally, CGRP and SP act synergistically since they are frequently co-localized in the same fibers and bone defect sites and released synergistically.After transection of the IAN, the secretion of CGRP and SP decreases, 58,59 which reduces the OPG/ RANKL ratio and promotes osteoclastogenesis.Thus, injured or transected IAN result in sensory nerve degradation and mandibular bone destruction.Nerve growth factor (NGF), a key neurotrophin released by sympathetic and sensory nerves, 83,84 has been found to stimulate bone formation by inducing regenerating axons, 85 and consequently, improving the density and quality of new bone in a rabbit model of mandibular distraction osteogenesis. 86Altogether, these findings indicate that sensory nerves play a significant role in bone formation and regeneration (Fig. 1a).
In addition to the classical pathways of neural regulation, such as those of limb bones, jawbone remodeling is also regulated by neural signals within the PDL. 87The PDL is the soft tissue between the teeth and alveolar bone, and it serves as a critical anatomical structure in orthodontic treatment.It has been reported that fibroblasts and osteoblasts in the PDL may respond directly to mechanical forces and initiate the remodeling of alveolar bone 88,89 through mechanotransduction 90,91 and intracellular signaling cascades. 92,93Additionally, the PDL is abundantly supplied with sympathetic, parasympathetic and sensory fibers, 94,95 which contribute to alveolar bone remodeling and tooth movement.As mentioned before, sympathetic fibers release NE and VIP to promote bone resorption, while parasympathetic fibers secret acetylcholine to inhibit bone resorption. 66Thinly myelinated and unmyelinated sensory fibers express CGRP and SP to facilitate osteogenesis. 878][99] This process activates an inflammatory cascade in the trigeminal spinal nucleus. 87It is mediated by the activation of neurons and inflammatory cells, 100,101 leading to an increase in the secretion of NGF, 102 CGRP, 103 SP 104 and various inflammatory molecules. 87In addition, the activated neural loop of the sensory-central-SNS influences orthodontic tooth movement. 105In summary, the PDL is a complex system, and nerves within it play a critical role in tooth movement and alveolar bone remodeling (Fig. 1b).

Regulation of jawbones to nerves
The condition of the jawbone can also affect the distribution of nerves.
Anatomical factors.The presence of teeth and the intraosseous canal makes the jawbone unique compared to other bones, and also affects nerve distribution.The mandibular canal is a compact bone canal in the cancellous bone of the mandible.The IAN runs through the mandibular canal and sends branches to control the teeth in what are known as mandibular canal branches.The number of these mandibular canal branches is largely determined by the number of teeth and occlusion elements in the human mandible. 106Since the presence of teeth helps to maintain the alveolar bone matrix, 107 when teeth are lost, nerve branches may disappear due to the absorption of alveolar bone. 106,108chanical factors.Actually, nerves can sense and respond to mechanical signals, which include the rigidity of the environment and press/traction exerted on the neurons by neighboring cells. 109The latter signal includes the tension of the jawbone and the orthodontic force of the teeth.After mandibular distraction osteogenesis, the elongation of the IAN occurs along with mandible regeneration in dogs. 110Aside from traction on the mandible, the orthodontic force on the teeth can also affect the distribution of nerves in the PDL, which is a specialized fibrous connective tissue, and dental pulp, which is connected to the PDL through the dentinal tubules and apical foramen.Dental pulp and PDL are richly supplied with sensory and sympathetic nerve fibers.They also feature immunoreactivity to protein gene product 9.5 and CGRP. 95,111It has been demonstrated that the reaction of the PDL is directly related to the duration, type, direction, and magnitude of the force on the teeth. 112,113Appropriate and intermittent orthodontic force will not cause permanent damage for the PDL and pulp. 114The density of nerve fibers in the pulp and PDL increases initially and then recovers as the duration of the force increases.However, constant, or excessive force may lead to irreversible damage of the PDL, and even cause pulp necrosis and root resorption. 115Injury to the IAN and related neuropathy is rare during orthodontic treatment.However, the roots of molar or premolar teeth are situated in close proximity to the IAN, the IAN may be injured. 116oactive factors.Bioactive signaling factors secreted by bone lineage cells have the potential to modulate the physiological activity of the nerves.Osteoblastic cells express NGF and sema3a.The former is a nerve attractant molecule involved in nerve fiber maintenance and plasticity, 117 and the latter is a repulsive molecule that inhibits fiber sprouting. 118,119The molecular network is disrupted after sympathectomy and the subsequent loss of VIP expression, leading to changes in the expressions of NGF and sema3a in rat mandible.As a result, CGRP-positive fibers invade the osteogenic layer due to the decrease in pro NGF and sema3a, and CGRP-positive fibers increase in the periosteum nonosteogenic layer due to an increase in mature NGF. 70

NON-DEVELOPMENTAL DISEASES CAUSED BY RECIPROCAL REGULATION BETWEEN THE NERVOUS SYSTEM AND THE STOMATOGNATHIC SYSTEM
Craniofacial diseases caused by neurological illnesses Several main oral symptoms arise from the decline or loss of neurological function, such as facial paralysis, facial spasm, salivation, and Frey syndrome (Fig. 2).
Facial paralysis.Facial paralysis is a typical neuro-stomatology disease that is divided into central facial paralysis and peripheral facial paralysis.Facial paralysis is caused by a dysfunction of the facial nerve, leading to the limitation of the activity of the facial muscles innervated by the nerve. 120Central facial paralysis lesions are located between the cerebral cortex and the facial nerve nucleus.2][123] Symptoms of central facial paralysis manifest in facial muscle palsies below the opposite palpebral fissure, disappearance of the nasolabial fold, and food retention in the oral vestibule.Peripheral facial paralysis is more commonly caused by extracranial etiologies, including viral infections (especially herpes zoster virus), 124 parotid malignant tumors, trauma, and even cold wind. 125,126Bell palsy is the most prevalent type of peripheral facial paralysis. 127Symptoms of Bell palsy include paralysis of all facial muscles on the lesion side, disappearance of forehead lines, inability to close the eyelids, sagging of the mouth angles, and even accompanying auditory changes and hypogeusia (Fig. 2a). 128cial spasm.Facial spasm refers to involuntary convulsions or spasms 129 of half of the facial muscles.It is classified as primary and secondary facial spasm. 130Primary facial spasm arises from demyelination caused by cerebellar pontine angle tumors 131 and vascular malformations that compress the facial nerve root. 132,133This demyelination disrupts the normal flow of action currents along the nerve fiber, resulting in overexcitation of the facial nerve and subsequent facial spasm. 134Secondary facial spasm is caused by facial nerve injury due to facial paralysis, trauma, inflammation, and other factors. 130The twitching typically begins with the orbicularis oculi muscle and gradually extends to other facial expression muscles on the affected side. 135And the twitching of the angularis oris muscle is the most prominent symptom (Fig. 2b). 129,136livation.Saliva is secreted by salivary glands, which are stimulated by the PSNS, but the contraction of the salivary duct's smooth muscle is controlled by the SNS.Therefore, neurological lesions can cause abnormal salivary secretion.The etiology of salivation may refer to weakness or poor coordination of bulbar or facial muscles, leading to poor lip seal, ineffective saliva control, and impaired swallowing mechanics. 137Therefore, neurological conditions like stroke, neuromuscular diseases like amyotrophic lateral sclerosis, and neurodegenerative diseases including PD, multiple system atrophy, and cerebral palsy can cause salivation. 22[140] Frey syndrome.The salivary glands receive signals from the PSNS, while the sweat glands and cutaneous blood vessels are regulated by the SNS. 141Physiologically, saliva secretion and sweating are two separate processes.The salivary gland secretes saliva in response to chewing stimulation, while there is no significant change in the skin condition.However, after parotid gland surgery, PSNS fibers can control denervated sweat glands and blood vessels in the skin. 142herefore, chewing can lead to not only saliva secretion from other salivary glands, but also sweating and flushing in the preauricular area due to increased PSNS activity.This phenomenon is known as Frey syndrome, 143 which is characterized by sweating and flushing in response to mastication or a salivary stimulus. 144In fact, it is common symptom following salivary gland surgery. 145And other symptoms include face rash, 146 burning, itching, forehead and scalp sweating 147 and neuralgia (Fig. 2d). 144urological diseases caused by an aberrant stomatognathic system While stomatognathic system abnormalities may not be the primary cause of neurological diseases, it is important to consider the potential links between them.Craniofacial symptoms or diseases, such as oral infection, OSCC, malocclusion and Sjogren syndrome (SS), can play a role in the development of neurological diseases.A comprehensive understanding of these links can aid early prevention and treatment of these neurological diseases (Fig. 3).
The link between oral infection and CNS infection.The presence of abundant microflora in the oral cavity, 148 combined with anatomical proximity of the brain and maxillofacial region, makes the CNS susceptible to infection.In analogy to the "gut-brain axis", the proposed concept of the brain-oral axis suggests the profound influence of an oral microbiome on the brain. 23,149Hematogenous spread is the predominant mode of intracranial dissemination, and caries with periapical involvement and periodontitis are the most frequently-triggering factors. 150In addition, other oral and maxillofacial specific infections, including herpes simplex, 151 herpes zoster, hand-foot-mouth disease, 152 and oral tuberculosis, 151 also invade the CNS along the peripheral nerve or bloodbrain barrier, causing pain, meningitis or intracranial infection.Notably, even oral manipulations, like endodontic treatments, tooth extractions, oral surgery, and simple toothbrushing, may cause acute or chronic infection. 153When oral pathogens spread through the blood system or nerve fibers into the brain, severe consequences may occur, such as chronic inflammation, brain abscesses, 150 ischemic stroke, 154 neurodegenerative diseases, neuropsychological diseases, 155 and even mortality.For instance, Porphyromonas gingivalis, a pivotal pathogen in gingivitis and periodontitis, can disrupt the blood-brain barrier via inflammation, which is a of small vessel disease, 154 thereby increasing the risk of acute ischemic stroke (Fig. 3a).
Perineural invasion resulting from tumors in the oral and maxillofacial regions.Certain types of oral tumors, such as ACC and OSCC, can invade nerves, leading to PNI, which is characterized by tumor cells tracking along nerves and/or enveloping at least one-third of the nerve's circumference. 156urthermore, ACC is one of the most common salivary gland tumors, particularly in the small salivary glands of the palate and parotid gland.Due to its high propensity for spreading along nerves, ACC is capable of causing PNI in the head and neck region. 157Facial nerve invasion caused by ACC leads to facial paralysis, while invasion of the trigeminal nerve causes facial pain.Additionally, invasion of the glossopharyngeal nerve and hypoglossal nerve may result in tongue numbness and tongue movement disorders. 24he sixth most common malignant tumor, OSCC, can infiltrate the CNS via the facial and trigeminal nerves, leading to the development of intracranial space-occupying lesions 24 and leptomeningeal disease. 158Although PNI in carcinoma of the lip is rare, malignant cells may trail along the IAN to the brainstem, resulting in leptomeningeal carcinomatosis. 158In addition, PNI appears in the advanced stages of tongue cancer. 159Patients may feel ear pain, throat pain, and pain in other areas involved in  160 Although its mechanisms are not yet understood, PNI has been shown to be linked to an elevated risk of recurrence, regional transfer, distant metastasis, and overall worse prognosis (Fig. 3b). 161errant stomatognathic system and headache.Headache is a prevalent condition that can be caused by various factors. 162ome studies have showed that malocclusion and sleep bruxism may contribute to the development of headache. 163Among different types of malocclusion, overbite, posterior crossbite, lingual crossbite, and lower crowding have been identified as potential risk factors for tension-type headaches in children and adolescents. 162,164The underlying mechanism may be related to the imbalanced bite, which can lead to tension in the masticatory muscles 165,166 and subsequently trigger headache. 167,168Sleep bruxism, which is characterized by tooth grinding and jaw clenching during sleep, 169 has also been associated with headache. 163This association may be due to the development of trigger points in the head and neck, 170 which are hyperalgesic zones that can induce headache (Fig. 3c). 171ogren syndrome.Although the abnormal oral and maxillofacial system in SS is not the direct cause of neuropathy, neurological oral symptoms often coexist in SS. 172 SS is a chronic inflammatory autoimmune disease characterized by mononuclear lymphocytic infiltration in lacrimal and salivary glands, 172,173 resulting in dry eyes and dry mouth.As the disease progresses, patients may experience various oral symptoms such as swallow dysfunction, oral malodour, rampant caries, periodontal disease, tongue papilla atrophy, sore tongue, salivary gland swelling or mumps, and poor denture retention. 174Additionally, orofacial myofunctional disorders and temporomandibular disorders (TMD) are common among SS patients, 175 with main symptoms including orofacial pain and mandibular function limitation. 176In addition to orofacial regions, the nervous system is affected in SS, with CNS lesions such as aseptic meningitis, 177 cerebellar syndromes 178 and neuromyelitis optica and others, as well as peripheral neuropathy including sensory neuropathy, sensorimotor neuropathies, and cranial neuropathies. 172SS can even increase the risk of PD, dementia 179 and depression (Fig. 3d). 180teraction effects of neurological diseases and craniofacial diseases The pathogeneses of some chronic diseases are exceedingly intricate, making it difficult to identify definitive instigating factors.In fact, in some cases, the diseases may mutually promote each other during their distinct stages.Consequently, this section aims to expound upon the plausible bidirectional associations between these diseases (Fig. 4).
Neurodegenerative disorders.AD is the most common neurodegenerative disorder, its clinical characteristic is often manifested as progressive cognitive impairment. 181It has been discussed extensively that periodontitis is a risk factor for AD. 182,183acterial proteins and DNA from periodontal pathogens can provoke neuronal damage and cognitive impairment. 184Conversely, the severity of oral diseases is positively linked to AD, 185 because patients in the advanced stage of AD lose intellectual and social abilities, as well as the ability to maintain proper oral hygiene practices.This leads to oral lesions like caries, 186 periodontitis, 187 stomatitis, 188 ulcerations, angular cheilitis, candidiasis 189,190 and oral dysfunction. 191The second most common neurodegenerative disorder, PD, is characterized by motor dysfunction. 192Periodontal inflammatory disease is also linked to the morbidity of PD. 193 The pathogenic mechanism may involve neuroinflammation, which is a prevalent characteristic of various neurodegenerative disorders. 155[198] Psychological disorders.In addition to neurodegenerative diseases, there is mutual promotion between psychic disorders and stomatognathic diseases.1][202] Among these psychological factors, the dyadic relation between depression and periodontal disease has been extensively studied. 203Depression is a relevant pathogenetic factor for periodontitis, 25 and in turn, oral diseases can exacerbate the progression of depression (Fig. 4b).
Temporomandibular disorders.TMD are associated with an individual's mental state.6][207] Stress and negative affect are considered potentially important risk factors for TMD. 208ut the specific mechanism has not been fully clarified, which may refer to dysregulation of the hypothalamic-pituitary-adrenal 209 and aberrant secretion of cortisol. 210However, the effect of TMD and associated pain on the nervous system is relatively weak.Patients with painful TMD have been found that salivary levels of NGF and brain-derived neurotrophic factor (BDNF) are lower compared to healthy control subjects 211 NGF 212 and BDNF 213 are related to psychological impairment, which reflects a potential connection between an abnormal mental state and TMD.And patients suffering from painful TMD surely experience heightened self-perceived cognitive impairments and depressive symptoms. 214Furthermore, extensive alterations in brain structures have been observed in individuals afflicted with TMD pain, 215 including modifications in the trigemino-thalamo-cortical system, the lateral and medial pain systems, periaqueductal gray-raphe magnus pathway and the motor system.Nevertheless, the relation between these neuropeptides and psychological distress is more complicated than previously thought, and further research is required to understand the intricate interaction between TMD and psychological distress (Fig. 4c).
Pain.Oral and maxillofacial pain is a significant issue that perplexes many patients and seriously impacts their facial muscle movement and daily routines.Pain-sensitive structures in the oral and maxillofacial region are distributed in the intracranial trigeminal and glossopharyngeal nerves, and in the extracranial oral and maxillofacial skin, subcutaneous tissue, muscle, TMJ, dental pulp, and oral mucosa. 216Therefore, diseases that stimulate pain-sensitive structures may cause oral and maxillofacial pain.The most common facial pain is trigeminal neuralgia (TN), which is divided into primary TN and second TN. 26 Primary TN is typically caused by vascular compression with morphologic changes of the trigeminal nerve root. 217Second TN may be caused by an intracranial tumor, 218 such as those in the cerebellopontine angle or multiple sclerosis, infiltrative malignant tumors, trauma, and rheumatologic diseases.Even extracranial infections can lead to TN, especially odontogenic infections, such as endodontic infections, and periodontal infections or abscesses. 219Acute pulpitis is a distinct form of dental inflammation that can elicit severe and spontaneous sharp pain upon compression of the involved nerve without timely drainage.Patients experience radiating pain along the second or third branch of the trigeminal nerve to the ipsilateral head, ear, face, and temporal region, 220 often leading to secondary TN.Besides, herpes zoster infection can affect the trigeminal ganglion to trigger secondary TN. 219The underlying pathology of both primary TN and secondary TN is widely acceptable to be demyelination, 218 which triggers impulses with high-frequency afterdischarges. 221,222Therefore, innocuous mechanical stimuli in the trigeminal territory, including light touch, cold air, brushing teeth, and eating, can trigger severe pain. 217As a result, patients may avoid basic hygiene practices, like washing their face, brushing their teeth, and smiling, leading to poor facial and oral hygiene accompanied by calculus and stomatitis.Furthermore, during the pain attack phase, patients may vigorously rub their facial skin to alleviate the pain, leading to partial abrasion and secondary infection.
Glossopharyngeal neuralgia (GPN) is a relatively rare condition that may be affected by both the nervous system and oral structure.Patients with GPN experience paroxysmal pain in the tonsils, pharynx, tongue base, and other areas.Similar to TN, one of the recognized lesions associated with GPN is nerve compression by a blood vessel at the root entry zone of the brainstem. 223,2246][227] Also, GPN has trigger points that can elicit pain, such as swallowing, chewing, coughing, yawning, and talking.In addition to neuralgia, other symptoms may occur, such as excessive saliva, throat spasm, 228 twitch, and epilepsy (Fig. 4d). 229

CONCLUSIONS AND FUTURE PERSPECTIVES
This review summarizes the connection between neurodevelopment and craniofacial development, highlighting the intricate crosstalk between nerves and jawbones, as well as diseases among the two systems.The current research on the association between the nervous system and the stomatognathic system is extensive and intricate; however, it also has limitations.The underlying causes of congenital diseases in the stomatognathic system, such as Moebius syndrome, Parry-Romberg syndrome, and AS, remain unclear.Moreover, the connection between facial deformities and other neurodevelopmental disorders has not been established; this lack of understanding causes more complex disease management and higher costs, particularly without the aid of genetic screening.There is also a scarcity of studies that incorporate pathways related to the immune system and cation channels in jaw-regulating nerves.Research about the regulation of the CNS on the jawbone is also inadequate.At the molecular level, there is a lack of in-depth studies regarding the effect of acetylcholine and SP on the jawbone.In particular, the regulation of SP on the jawbone is perplexing, as opposing effects of SP have been observed at different concentrations.Interestingly, even at the same tested concentration, SP exerts different effects on the regulation of the jawbone.The role of SP may be strongly influenced by the specific surrounding environment, the duration of exposure, and the state of the jawbone.In addition, the interaction of neurological diseases and craniofacial diseases further complicates the issue, and the initial factors and the specific mechanism remain unclear.Therefore, prioritizing neurodevelopment and neurological diseases related to the stomatognathic system is crucial for the timely prevention and treatment of oral diseases.It is imperative to investigate the contribution of published gene mutations to congenital diseases in both systems and expand the scope of gene mutation research.Such work would enhance the efficiency of prevention and treatment through embryo intervention and prenatal screening for dysplasia, as well as the early detection and diagnosis of refractory diseases, such as AD and TN.In addition, further investigations are necessary to examine the effects of bioactive factors, such as acetylcholine and SP, in regulating jawbone acquisition and loss.Furthermore, neural pathways mediated by the immune system and cation channels within jawbones are worth investigating.This may lead to the development of innovative strategies for neuro-bone tissue engineering.
Moreover, we found that the relationship between these two systems was far more complicated than what has been previously demonstrated.Based on existing research and obvious controversy, it is evident that the interaction mechanism between the nervous system and the stomatognathic system merits further investigation and potentially opens new research avenues.

Fig. 1
Fig. 1 Effect of nerves on jawbones.a Effect of ANS and sensory nerves on jawbones.VIP and NE released from sympathetic nerves can activate corresponding receptors and upregulate RANKL in OBs, and RANKL contributes to OC maturation.All of them lead to bone resorption.Ach released from parasympathetic nerves may contribute to anti-inflammatory activity and osteoclast apoptosis.CGRP and SP released from sensory nerves downregulate RANKL and upregulate OPG in OBs, thereby hastening bone formation.b The neurofeedback in the PDL under the induction of orthodontic force.Orthodontic force triggers nociceptors in sensory fibers, leading to inflammatory cascade mediated by CGRP and SP, as well as the activated neural loop of the sensory-central-SNS.Orthodontic force also activates sympathetic nerves and promotes osteoclast activity.The neurofeedback influences alveolar bone remodeling and tooth movement.PGE 2 prostaglandin E2, IL-6 interleukin-6, Ach acetylcholine, NK1R neurokinin 1 receptor, CRL+RAMP1 calcitonin receptor-like receptor+receptor activity-modifying protein 1, V trigeminal nerve

Fig. 2
Fig. 2 Craniofacial diseases caused by neurological illnesses.a Facial paralysis.Lesions located between the cerebral cortex and the facial nerve nucleus lead to central facial paralysis.Extracranial lesions cause peripheral facial paralysis.b Facial spasm.Demyelination cause primary facial spasm and facial nerve injury may result in secondary facial spasm.c Salivation.Weakness or poor coordination of bulbar or facial muscles resulted from neurological diseases can cause salivation.d Frey syndrome.After parotid gland surgery, PSNS fibers can control sweat glands and blood vessels in the skin, leading to sweating and flushing during chewing.Created with BioRender.com

Fig. 3
Fig. 3 Neurological diseases caused by an aberrant stomatognathic system.a The link between oral infection and CNS infection.Oral microbes are easy to invade the brain via hematogenous spread.b Perineural invasion resulting from tumors in the oral and maxillofacial regions.c Headache caused by malocclusion and sleep bruxism.d Sjogren syndrome.Mononuclear cells and lymphocytes invade lacrimal and salivary glands.Created with BioRender.com

Fig. 4
Fig. 4 Interaction effects of neurological and craniofacial diseases.a The interaction between neurodegenerative disorders and stomatognathic diseases.Periodontitis is conducive to the development of AD and PD, which increase the risk of stomatognathic diseases conversely.b Mutual promotion between psychic disorders and stomatognathic diseases.c The potential connection between abnormal mental state and temporomandibular disorders.d The link between pain and oral symptoms.Vascular compression leads to primary TN.And the etiology of secondary TN is various.No matter what kind of TN, it can cause a series of oral symptoms.P. gingivalis Porphyromonas gingivalis, LPS lipopolysaccharide, HPA hypothalamic-pituitary-adrenal.Created with BioRender.com

Table 1 .
Congenital diseases with neurologic disorder and cranio-facial abnormalities