Tic disorder (TD) is a chronic psychobehavioral disorder common in childhood and can be clinically classified into three types: transient tic disorder, chronic motor or vocal tic disorder (CT) and vocal and multiple motor combined tic disorder (Tourette’s syndrome (TS), of which TS is the most TS is the most typical. At present, the etiology and pathogenesis of TD in children are still not fully understood, but most scholars believe that the disease may be the result of a combination of factors, including genetic factors, biological factors, psychological and environmental factors, interacting with each other during the growth and development of children. 1, genetic factors A large number of studies have shown that TS is a neuropsychiatric disorder with an obvious genetic predisposition. It is generally believed that TS is inherited in an autosomal incomplete dominant or polygenic manner, and is an inherited disease with complex traits controlled by multiple micro-effect genes. It is more common in males than females, with a high male ectopic rate (nearly 100%) and a low female ectopic rate (70%). 1.1, Family and Twin Studies Clinical studies have found that TS has significant family “clustering”. The prevalence of TS and CT among first-degree relatives of TS is 10%-100% and 7%-22%, respectively, which is significantly higher than that of the general population. The prevalence of other psychiatric disorders, such as obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD), was also significantly higher among relatives with TSD. Clinically, it was found that most patients with TD have co-morbidity with various psychiatric disorders, with only 10%-15% with simple TS. more than 50% of TS have co-morbidity with psychiatric disorders such as OCD and ADHD, much greater than the general population, suggesting that there may be a common genetic basis between the two. Twin studies have found that monozygotic twins show a homozygous concordance rate for TS of 75% to 9O%, reaching 100% when the diagnosis is extended to all forms of tics, while the homozygous concordance rate for dizygotic twins is only 8% to 23%. 1.2, Chromosomal studies Recently, the Tic Disorders International Genetic Consortium (TSAICG) conducted a large sample TS genetic linkage analysis with 238 nuclear families, 18 families were a multiplex, and 2040 individuals. Results found that chromosomes 2p23.2, 1p, 3p, 5p, and 6p were linked across multiple generations, with each family having a positive linkage signal on chromosome 2. Another study found genetic heterogeneity also on chromosomes 2p, 4q34-35, 5q-35, 7q22-q31, 8q13-q22, l1q23, 13q3l, 17q25, and l8q22 in children with TS. Although the genetic linkage analysis identified some chromosomal regions linked to TS and also found some chromosomal aberrations, there was a lack of duplication between these linkages, and the possible association of susceptibility genes with TS in these regions remains to be further investigated. Many genes related to the dopamine and 5-hydroxytryptaminergic systems have been candidates for TD, such as the dopamine receptor family (DRD1-DRD5), dopamine transporter protein (DAT), noradrenergic genes (ADRA2a, ADRA2C), norepinephrine transporter protein ( NET), tyrosine-β-hydroxylase, catechol-O-methyltransferase (COMT), monoamine oxidase (MAO), dopamine-β-hydroxylase, and 5-hydroxytryptamine receptor family. Studies have shown that polymorphisms of DRD4 and MAOA may increase the risk of TS, and that Dde I polymorphism of DAT gene and 5-hydroxytryptamine receptor HTR2C gene (C-759T, G-697C) polymorphisms are associated with TS. Recently, SAP90/PSD95-associated protein 3 (SAPAP3/DLGAP3), a postganglionic linker protein, has been reported to be significantly highly expressed in striatal glutamatergic ganglia and is considered as a novel candidate gene for TS. The chromosome 13 SLIT and NTRK-like protein family member 1 (SLITRKI) genes have been reported as possible causative genes for TS and have been excluded. No positive results were found for other neurotransmitter candidate genes. In addition, studies of some neurodevelopment-related genes, such as brain-derived neurotrophic factor, mitochondrial endosomal peptidase-2-like protein, and neuroligins gene family, did not reveal an association with TS. Although some progress has been made in the genetic study of TD, the mode of inheritance of TD is still unclear and there is no clear causative gene, so further research is needed. 2, neurobiochemical factors The development of tic disorder may involve several neural systems and different neurotransmitters, including central dopaminergic, noradrenergic, 5-hydroxytryptaminergic, ¡-aminobutyric acidergic and opioid systems, etc. If one or some links in these neural networks become impaired, the neurotransmitter balance is disturbed, and thus neurological dysfunction occurs. 2.1, central dopamine (DA) Many studies have suggested that dysfunction of the cortical DA system in the basal ganglia and limbic system of the brain may be the main pathogenesis of TS. It has been suggested that the disease is due to excessive striatal DA activity or postsynaptic DA receptor hypersensitivity. It has been found that the amount of the main metabolite of DA in the cerebrospinal fluid of children with TS, high vanillic acid (HAV), is reduced, and the DA antagonists haloperidol and permethrin can suppress twitching; while drugs that increase central DA activity, such as Ritalin, amphetamine and cocaine, can aggravate twitching symptoms, suggesting that twitching may be related to abnormalities in the DA system. Some scholars have found that patients with TS have lower DA binding rates in the motor cortex, anterior cingulate gyrus and dorsomedial thalamus than normal controls. Some scholars found that monoamine transporter protein 2, which has the function of transporting DA in the brain of children with TS, has an abnormally enhanced signal in the striatum, which provides strong evidence for the theory of DA dysfunction in TS. However, some clinical cases of TS do not respond to antipsychotic drugs, while central stimulants improve their symptoms, challenging the central DA system hyperactivity theory of the cause of TD. 2.2. Hyperfunction of the norepinephrine (NE) adrenergic system also plays an important role in the pathogenesis of TS. The NEergic receptor agonists colistin and guanfacine have been clinically found to alleviate TS symptoms, and these drugs reduce central NE release while decreasing dopamine system activity. It has been found that tic symptoms are aggravated in stressful situations, and the level of 3-methylamino-4-hydroxyphenylethylene glycol (MHPG), a metabolite of NE, is increased in cerebrospinal fluid, while aniline imipramine, a drug that reduces central NE, improves tic symptoms. 2.3, 5-hydroxytryptamine (5-HT) Some scholars believe that hypofunction of 5-HT is also associated with TS. The pathogenesis of OCD is related to hypofunction of the 5-hydroxytryptaminergic system, and TS is often co-morbid with OCD, so it is presumed that the pathogenesis of TS and OCD are similar. In addition, it has been reported that the pathogenesis of TD is related to the dysfunction of g-aminobutyric acid (GABA), enkephalin, excitatory amino acids and sex hormones. 3, neuroanatomical factors In recent years, with the help of advanced imaging methods, many studies have found that many children with TD have developmental defects and anatomical abnormalities in the central nervous system, with lesions mainly in the basal ganglia, frontal cortex and limbic system. 3.1. Anatomical abnormalities Many children with TD have basal ganglia abnormalities. Basal ganglia lesions may contribute to the pathogenesis of TD and may also be the pathological and anatomical basis for the pathogenesis of many other psychiatric disorders, such as OCD and ADHD. Some scholars have performed electrical stimulation of deep brain tissue such as thalamus and pallidum in children with TS, with some therapeutic effects, suggesting the presence of basal ganglia lesions in children. Magnetic resonance (MR) studies showed that the volume of the caudate nucleus and pallidum decreased in children with TS, and the total number of neurons inside the pallidum increased, while the number of neurons outside the pallidum and inside the caudate nucleus decreased; the number of neurons positive for microclear binding protein inside the pallidum decreased. Plessen et al. found that children with TS had smaller total brain volumes than normal children, relatively smaller prefrontal and parietal cortices, and increased normal asymmetry (left > right) in the gray matter portion of the frontal lobes, with an increased white matter component in the right frontal lobe and smaller white matter volume in the deep left frontal lobe. Some scholars found abnormalities in the middle and lateral premotor cortex, anterior cingulate cortex, dorsolateral prefrontal cortex, and inferior lateral wall cortex in children with TS. Miller et al. found that children with TS also had abnormalities in the corpus callosum, hippocampus, and thalamus. 3.2. Functional abnormalities Functional imaging studies have shown reduced activity of basal ganglia neurons and increased activity of prefrontal, parietal, and temporal lobes in TS. Positron emission tomography (PET) showed that the glucose metabolic rate was significantly higher in TS patients with bilateral basal ganglia, frontal cortex and temporal lobe compared to the normal group. Using SPECT, some scholars found that cerebral blood perfusion values in the left caudate nucleus, cingulate gyrus, right cerebellum and left dorsolateral prefrontal regions were significantly lower in children with TS than in controls, and the severity of vocal twitch symptoms was positively correlated with blood flow in the mid-cerebellum, right dorsolateral prefrontal and left dorsolateral prefrontal regions. Marsh et al. showed that the activity of the ventral, middle prefrontal cortex gradually decreased, the functional activity of the right inferior prefrontal cortex gradually increased, and the activity of the right inferior prefrontal cortex gradually increased with age in normal controls, but this pattern was not found in the group of TS patients.The poorer performance of children with TS in the Stroop task was associated with the frontal striatal regions (including the inferior prefrontal cortex, middle frontal gyrus, dorsal The poorer performance of children with TS in the Stroop task was associated with increased activity in the frontal striatal areas (including the inferior prefrontal cortex, middle frontal gyrus, dorsal prefrontal cortex, nucleus accumbens, and thalamus). Using diffusion tensor imaging (DTI), Li Xuli et al. found that the anisotropy fraction (FA) of the left pallidum and bilateral thalamus were reduced and the apparent diffusion coefficient (ADC) values of the caudate nucleus, nucleus accumbens, and thalamus were increased bilaterally in children with TS, suggesting the presence of microstructural abnormalities in the basal ganglia of children with TS, which correlated with the severity of symptoms in TS patients. The results of the study are not entirely consistent because the methods of study are not identical among scholars. However, current neuroanatomical and functional imaging studies of TD suggest that the pathogenesis of TS is associated with abnormalities in the basal ganglia and prefrontal cortex, and that the lesions are centered on the basal ganglia, with abnormalities in the structure and function of the cortico-basal ganglia-thalamo-cortical neural circuit (CSTC). Some scholars believe that TS behavioral-motor abnormalities are related to the disorder of amygdala-striatal pathway, and involuntary vocalization may be related to the irregular discharge of cingulate gyrus, basal ganglia and brainstem. 4, psychosocial factors In recent years, the relationship between psychosocial factors and TD has received increasing attention, and psychosocial factors play an important role in the development of TD. 4.1, personality factors Studies have found that children with TD have different degrees of personality abnormalities, mostly avoidant and impulsive personalities, with a high incidence of behavioral problems. The Eysenck Personality Inventory (EPQ) survey shows that children with TD have high neuroticism and psychoticism T scores and low masking T scores, indicating that children with TD have poor self-control, irritability, anxiety, depression and low psychological maturity. They tend to overreact to external stimuli and do risky and novel things easily. Personality characteristics, as mediators of pathogenesis, may have a role in the development of TD and may be risk factors for its development. 4.2, emotional state People have found that trauma (family, social), excessive mental stress (such as academic pressure, work tasks, etc.), mood swings, fatigue and excitement (such as strenuous sports activities, long hours of computer games or watching TV, etc.), and excessive fright can trigger or aggravate tics. 4.3. Life events Some studies have shown that the presence of others around, receiving education, and conversations related to tics all have a certain influence on TD performance. Among different educational activities, twitching occurs most frequently during classroom assignments, least frequently during experimental activities, and more frequently when reading simple materials than when reading complex materials. patients with TD also have different responses to the external language environment, and the frequency of vocal symptoms increases when patients with TD are exposed to TD-related conversational content. 4.4. Surrounding environment In recent years, it has been found that the occurrence of TD is also related to the poor surrounding environment. 1. poor family environment, such as disharmony, more conflicts, less entertainment, low intimacy, less emotional communication, parental divorce, death of relatives, etc. 2. poor family education, such as too strict discipline, too critical, harsh, high rejection, more negativity, excessive interference and requirements exceeding the actual level, etc. 3. poor school environment The symptoms of tics are sometimes aggravated by examinations and classroom questions, such as teachers being too demanding, overly strict, ridiculing by classmates, and arguing with classmates. The specific mechanism of the role of psychosocial and environmental factors on TD is not clear. It may cause the occurrence of tics by affecting the neurochemical and neuroendocrine systems, increasing the level of stress-related hormones in the hypothalamic-pituitary-adrenal axis and cerebrospinal fluid, and increasing the excitability of the motor cortex. 5, neuroimmune factors In recent years, there have been more and more studies on the relationship between immune factors and TS, and it has been reported that about 20% to 35% of TD onset is related to autoimmune damage after infection, of which about l0% is related to Group A beta-hemolytic streptococcal (GABHS) infection. Streptococcal infection has been reported to cause associated pediatric autoimmune neuropsychiatric disorders (PANDAS), which may be associated with anti-neuronal antibody-mediated central neurological dysfunction, and is considered a distinct subtype of TD. Some scholars have found a significant increase in serum antibody titers against streptococcal Ml2 and M19 proteins in children with TD, which are major virulence factors of GABHS and can cross-react immunologically with antigenic determinants of human tissues, including brain tissue, resulting in increased tyrosine hydroxylase activity and increased dopamine release from neuronal synapses. Anti-streptococcal antibodies and anti-basal ganglia antibodies (ABGA) have been found to be elevated in the sera of TS patients, and if this serum was administered to the ventral extremity of the striatum of experimental rats, the rats showed a significant increase in oral stereotypic symptoms, further suggesting a correlation between TS and immune system dysfunction. However, almost everyone has a history of GABHS infection, but more than 95% do not develop twitchy symptoms, suggesting that there is also a predisposing factor of the host itself in the pathogenesis of TD. Some studies have found that cellular immune dysfunction may also be associated with the susceptibility of some children to TD. CD4+ cells, CD4+/CD8+ ratio and NK-positive cells are significantly lower in children with TD compared with normal controls, while CD8+ cells are significantly higher and NK cells lower than in controls, indicating that children with TD have immune dysfunction based on cellular immune dysfunction. Immunomodulatory treatment such as sedative immunoglobulin can reduce twitching symptoms to a certain extent, further suggesting that infection and immune dysfunction may be factors influencing the development of TD. Clinical studies have found that patients with frequent upper respiratory tract infections, sore throat, and chronic tonsillitis are prone to twitching TD, and children with TD often have a history of bacterial or viral infections 4-6 weeks before the onset of the disease. In addition, spirochetes, mycoplasma, Helicobacter pylori, cytomegalovirus, herpesvirus, and HIV infections have also been reported to cause TS. The relationship between infectious factors and twitching is unclear. It is possible that various pathogens cause damage to the corresponding neural structures (e.g., basal ganglia and CSTC) through direct attack or cross-immune reactions, thus causing twitching. 6. Other factors 6.1. Perinatal abnormalities Studies have found that there are more perinatal abnormalities in TD patients, so it is thought that perinatal factors may also be related to the development of TD. Such as prematurity, twin births, severe reactions in the first 3 months of pregnancy, maternal factors (bad mood, smoking, alcohol consumption, coffee drinking, very low frequency magnetic field exposure, etc.), fetal or neonatal diseases (intrauterine asphyxia, intrauterine infection, cord winding, neonatal asphyxia, low birth weight, neonatal hypoxic-ischemic encephalopathy and intracranial hemorrhage, etc.), these factors easily lead to fetal or neonatal brain damage and are risk factors for the development of TD Factors. 6.2. Diet Clinical findings show that the onset and exacerbation of TS are also related to diet. There is a positive correlation between the consumption of foods containing caffeine, refined sugar and sweeteners and the worsening of TD. It has been reported that the consumption of colorings, additives and beverages may also aggravate tic symptoms, and it is possible that some of the ingredients in these foods, after digestion and absorption, can interact with the dopaminergic and 5-hydroxytryptaminergic systems, leading to the imbalance of neurotransmitters in the brain. Frequent consumption of Western fast food and puffed food has also been reported to be associated with tic symptoms, which may be related to the high levels of lead in these foods. However, it is generally believed that dietary factors play a minor role in the etiology of TD, but have some influence on the severity of twitching. 6.3, Drugs It has been reported that long-term, high-dose application of antipsychotic drugs or central stimulants may cause TD, including clozapine, stimulants (Ritalin, amphetamine, pemoline), antiepileptic drugs (carbamazepine, phenytoin, lamotrigine), etc. It has also been reported that the use of androgens, aminophylline, cocaine, morphine, etc. can cause twitching. Various kinds of poisoning (such as wasp poisoning, tribute poisoning, carbon monoxide poisoning, etc.) may also cause twitching. 6.4.Other children with TD have EEG abnormalities of 12.5%-66%, and dynamic EEG ( AEEG ) abnormalities of up to 5%, which are mostly non-specific. Many children with TD have a history of febrile convulsions, head trauma or cervical spine injury. In addition, elevated blood lead levels and zinc or iron deficiency have also been reported to be associated with TD.