Tourette's syndrome: what is this disease in simple words

Mental and neurological disorders are not uncommon in the modern world. Many of them were identified several centuries ago, but despite this, finding an effective way to treat them was not so easy.

Tourette's syndrome is one of these mysterious and complex disorders. Doctors have still not come to a consensus regarding the causes of its occurrence and methods of prevention. Moreover, according to statistics, 1 in 360 children has symptoms of the disease.

An additional difficulty is the presence of concomitant neurological disorders, which are not always possible to diagnose and treat.

In this article we will try to explain in simple terms what Tourette syndrome is, why it occurs and how you can help people with this disorder. Let's figure it out.

What is Tourette's syndrome?

Tourette syndrome is a common neurodevelopmental disorder that occurs in childhood or adolescence and is characterized by multiple motor tics and at least one vocal tic.

The syndrome was named by French neurologist Jean-Martin Charcot after his trainee Georges Gilles de la Tourette, who published a report in 1885 of nine patients with "convulsive tics".

Tourette syndrome is diagnosed based on clinical findings that detail the tics and the factors that trigger them. This diagnosis often occurs with a number of other neuropsychiatric conditions, including obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), anxiety disorders, mood disorders, impulse control and learning disorders.

The American Centers for Disease Prevention and Control conducted studies of children suffering from Tourette syndrome. The survey showed that every first child out of 360 children aged 6 to 17 years in the United States is diagnosed with this disease, and 37% of them suffer from a moderate or severe form of the disease [CDC, 2020].

According to researchers, boys are 3-5 times more likely to develop Tourette syndrome than girls, and adolescents 12-17 years old are 2 times more likely to develop it than children aged 6-11 years.

Another survey of parents of children with the disorder found the following:

• Parents usually first notice tics in children around the age of 6 years;
• the average time from initial identification of tics to diagnosis is 2 years;
• The average age at which Tourette's symptoms become most severe is 9 years;
• Nearly 70% of parents reported that major changes, such as moving to a new school, stress, or fatigue, worsened their child's tics [CDC, 2020].

Among children diagnosed with this diagnosis, 86% also had at least one additional mental or behavioral disorder. More than 30% of people with Tourette syndrome have obsessive-compulsive disorder, and 43% of them have at least one underlying chronic condition [CDC, 2020].

Diagnosis of the disease

The appearance of tics does not always mean that a person has Tourette syndrome3. This diagnosis is correct if:

• Symptoms first appear in childhood or adolescence (before 18 years of age).
• Simple or complex motor tics are accompanied by at least one vocal tic.
• Symptoms persist longer than 1 year.
• The disease progresses in waves, its manifestations become more or less pronounced.
• The appearance of symptoms is not associated with the use of psychoactive substances.

With temporary tic disorder, symptoms resolve in less than a year. Chronic (persistent) tic disorder lasts longer than a year, but the tics can only be motor or vocal. Temporary and chronic tic disorder is not Tourette's syndrome.

Diagnosis of the syndrome is performed by a neurologist or psychiatrist. He conducts a survey during which he needs to describe the manifestations of the disease, tell how long they last, how often they appear.

What signs indicate Tourette syndrome in a child?

Usually the disease becomes noticeable at the age of 5-7 years. You should consult a neurologist if you often experience rapid, repetitive, involuntary movements of the face, hands or body. It can be:

• blinking (Fig. 2);
• grimaces;
• nose twitching;
• movements of the neck, arms or legs.

Tics may change, but they persist and gradually intensify. Vocal tics appear later, but in some children they appear almost simultaneously with motor ones.

Figure 2. One of the signs of the syndrome is severe blinking.
Source: Tourette's Doesn't Have Me", HBO and the Tourette Syndrome Association / Wikipedia (Creative Commons Attribution-Share Alike 3.0 Unported) When diagnosing Tourette's syndrome, the following methods are used for examination:

• A clinical urinalysis is performed to determine the levels of catecholamines and metabolites in the urine. This allows you to evaluate the excretion of dopamine, norepinephrine, homovanillic acid in order to judge the violation of dopamine secretion.
• Electroencephalography is a study of the electrical activity of the brain, allowing one to evaluate the functions of its structures.
• Electromyography is a recording of myograms of muscles involved in motor involuntary movement.
• Computed tomography or magnetic resonance imaging to visualize the brain.

These methods are used in diagnosis only in cases where, in addition to tics, there are tremors, signs of epilepsy, visual or cognitive impairment. They help distinguish Tourette's syndrome from autism, epilepsy, schizophrenia and a number of other diseases.

Symptoms of Tourette's syndrome

The key features of the syndrome are tics—involuntary sounds and movements that must be present for at least 12 months to meet diagnostic criteria [Touretess action, 2021]. They usually appear in childhood between the ages of 2 and 14 (average around 6 years) and come in two types: physical and auditory (vocal).

Examples of physical tics include:

• flashing;
• eye rolling;
• involuntary grimaces;
• shrug;
• twitching of the head or limbs;
• jumping;
• whirling;
• touching objects and other people.

Vocal tics may manifest themselves in the following ways:

• throat clearing;
• whistling;
• frequent cough;
• tongue clicking;
• animal sounds (such as grunting);
• random words and phrases;
• repetition of a sound, word or phrase;
• swear words and profanity.

Tics are usually not harmful to overall health, but some, such as head jerking, can be very painful [NHS, 2021].

Tourette's syndrome was once considered a rare and bizarre disorder, and not everyone understood what kind of disease it was. It was commonly associated with coprolalia, a disorder that causes the utterance of obscene words or socially inappropriate and derogatory remarks. However, to date it has been scientifically established that coprolalia is rare - only 1 in 10 people suffering from the syndrome [Touretess action, 2021].

Tics can occur in almost any part of the body. Sometimes patients report “internal tics,” such as deep abdominal muscle tension and internal organ spasms.

Almost every person with the disorder experiences a physical sensation similar to itching, the need to sneeze, burning, or muscle spasms. As a rule, it appears before the tick itself and disappears immediately after.

Tics may worsen during periods of stress, anxiety, and fatigue. Some people may be able to control them for short periods of time in certain situations, such as while at school or work. This skill requires strong concentration and great effort from them. Moreover, according to some evidence, after such containment, tics begin to worsen when the person is in a calm environment [NHS, 2021].

The term "tic attack" is used to describe attacks of severe, continuous, uncontrollable, and disabling tics that last anywhere from a few minutes to several hours. These attacks can cause great anxiety for the person experiencing them, as well as for those around them.

Up to 85% of people with Tourette syndrome have associated symptoms, including:

1. Attention deficit hyperactivity disorder is a group of behavioral symptoms that include inattention, hyperactivity and impulsivity that interfere with functioning or development.
2. Obsessive-compulsive disorder is an anxiety-related condition in which a person frequently experiences intrusive thoughts or compulsions that cause severe stress.
3. Anxiety disorder is a persistent feeling of worry that interferes with a person’s normal daily routine and does not go away with reassurance or reassurance.
4. Aggressive behavior that affects about 40% of people with Tourette syndrome.
5. Executive functional difficulties that affect a person's ability to regulate their behavior and reactions. There is good evidence to suggest that people with Tourette syndrome often have problems in this area.
6. Sensory processing difficulties may also be a sign of the syndrome. These include problems with any of the senses: taste, touch, hearing, vision, smell, proprioception (body awareness), vestibular (movement) and interoception (internal sensations such as thirst, hunger and pain).
7. Depression is a prolonged period of poor health. Often this condition is not provoked by anything.
8. Autism spectrum disorder (ASD) or autism is a lifelong developmental disorder that affects the way a person communicates and relates to others, as well as how they experience all their senses and interact with the world around them.
9. Sleep problems have been identified in both children and adults with Tourette syndrome. May include difficulty falling asleep and frequent awakenings at night.

Sometimes these additional symptoms are much more problematic than the tics themselves, as they can cause a lot more discomfort and complications to the person.

There is currently no technology that can predict how Tourette syndrome affects a person in the long term. According to some data, approximately half of children with this diagnosis significantly reduce their symptoms as they grow older [Movement Disorders Clinical Practice, 2019].

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Tourette's syndrome

- a disease of the nervous system, manifested by involuntary and abnormal muscle contractions (motor tics) and shouting of sounds or phrases (audio tics).

Causes of Tourette's syndrome

A large number of works have been written about Tourette syndrome, the authors of which tried to find out the reasons for its origin. Although the exact pathophysiology of the disorder remains incompletely understood, there is growing evidence that it results from complex interactions between multiple genes and environmental factors.

Tourette syndrome is known as a neurodevelopmental disorder because the predisposition to tics appears to develop as the brain develops. Scans have shown that people with the syndrome have certain areas of the brain that function differently or are a slightly different size (for example, some of the structures in the motor circuits that control movement).

Another disorder is likely an imbalance in the function of the brain's neurotransmitters—the chemical messengers that send signals between nerve cells.

Although tics are often inherited, to date no gene has been identified that causes Tourette syndrome. Other causes include environmental factors that may influence the risk of tics as the brain develops.

A large study of more than 6,000 pregnant women found that the strongest risk factor was poor maternal weight gain during pregnancy. Additionally, drug and alcohol use during pregnancy and whether the child was the firstborn were also associated with a higher risk of the child developing Tourette syndrome.

In recent years, much attention in both the medical literature and the mainstream media has been given to the hypothesis that some tics and neuropsychiatric disorders may be caused by an underlying autoimmune or autoinflammatory response associated with streptococcal infections [Tourette Association of America, 2021 ].

Treatment of Tourette's syndrome

To date, there is no scientific evidence confirming the effectiveness of any single treatment for Tourette syndrome. However, scientists and researchers have done a lot of work in this direction over the past 20 years and continue to study various options and ways to combat the syndrome.

One of the most popular and accessible treatments for the syndrome is behavioral therapy, which provides tools to help patients learn to change certain behaviors and attitudes about the tics themselves.

The best scientifically proven behavioral treatment is considered to be habit reversal therapy. Although the technique has been researched since the 1970s, it has only recently been shown to be effective as part of a comprehensive behavioral intervention for tics.

Habit withdrawal therapy consists of several stages in which the patient, together with the doctor, performs the following actions:

1. Identifies and describes all of his tics in detail.
2. Selects one specific tick to work on (usually the one that bothers him the most).
3. Describes in detail where in his body the tic occurs and what muscles and organs are involved.
4. Determines the triggers that provoke a given tic and the sensations that precede it.
5. Looks for an alternative way to satisfy the urge. It is important that the new movement does not look more unusual than the teak itself and does not interfere with human activity.

Once a new habit is formed, this approach is applied to all remaining tics.

The therapist also helps the patient understand what usually happens before and after an attack of tics (certain reactions to a situation, thoughts or feelings that he experiences in a certain place, and the reactions of others). He will then work to reduce the number of situations that trigger them. In this case, relaxation or the ability to look at the situation differently can help.

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If necessary, patients with Tourette syndrome are prescribed medications that can reduce symptoms and improve quality of life. Unfortunately, side effects from drug treatment are not uncommon and the effectiveness of drugs varies from person to person, so they are prescribed by a doctor after a detailed and serious examination.

The doctor and the patient should decide:

• Is it worth treating this disorder?
• what symptoms need to be treated;
• whether co-occurring conditions (such as ADHD or OCD) should be treated;
• whether a combination of medications is needed to treat different symptoms.

Assessing the effectiveness of treatment is complicated by the fact that the manifestation of tics weakens or intensifies over time. Sometimes the doctor may think that treatments are working well, but this may be a period when the tics have naturally decreased.

Treatment of Tourette's syndrome should begin with small doses of therapy, increasing them gradually. Thanks to this approach, side effects, if they occur, are easier to recognize and control. It is also recommended to make only one change at a time. If too many changes are made quickly and the symptoms of a disorder improve or worsen, it is difficult to understand why.

Stopping treatment suddenly is usually not a good idea, but sometimes it is necessary (for example, if a person has a severe reaction or worsening condition). This should only be done after consulting a doctor.

Although there is no medical evidence that a specific diet is better for people with the syndrome, many people find that their tics get worse when they eat foods that contain harmful additives, artificial colors and a lot of sugar.

Doctors recommend that patients with the disorder eat a diet rich in fresh and natural foods that contain large amounts of vitamins and minerals. Exercise greatly helps relieve symptoms of the disorder. However, some patients find that too much physical activity makes their tics worse. Therefore, you should limit exercises depending on what works in a particular case.

Since physical tics often lead to pain, gentle stretching every day can help keep your muscles relaxed and elastic. Yoga, meditation, aromatherapy and hypnotherapy can also have a positive effect on the symptoms of the disease. However, there is little evidence to support the effectiveness of complementary therapies in general.

Relaxation is essential to reduce the stress experienced by a person with a tic disorder. The most common relaxation training involves deep breathing combined with gradually tensing and relaxing different muscle groups. In 2021, Tourettes Action released a video of a guided relaxation system for people with Tourette's syndrome to help relieve tics. It can be found on the Internet.

In a small number of people with Tourette syndrome, tics may be so severe and painful that available treatment options, behavioral interventions, or medications cannot significantly reduce their severity. In this case, it is necessary to resort to more serious intervention.

Among neurosurgical methods, deep brain stimulation with implantation of electrodes into selected objects undoubtedly has advantages over traditional surgery, which is more invasive and irreversible.

This method was first tested in 1999. Its purpose is to provide continuous electrical stimulation to specific brain structures, thereby selectively simulating the activity of these areas, while avoiding widespread side effects by targeting other unused circuits [CDC, 2020].

Currently, such stimulation for the treatment of the syndrome is still in its infancy. Although preliminary studies show promising results in reducing tics, a number of questions still remain regarding optimal targets and suitable candidates. Moreover, the long-term impact of the procedure on other aspects of the syndrome (such as OCD, aggression, impulsivity, depression and anxiety) requires further study.

It should be noted that the surgical procedure carries a risk of complications (including death), and continued stimulation may have side effects. Analysis of the existing literature shows that in most cases, patients after surgery still require drug treatment, albeit in significantly reduced dosages. These and other important questions can only be resolved through future collaborative trials in sufficiently large patient samples [CDC, 2020].

Tics and Tourette syndrome (TS) represent an urgent problem in psychoneurology. The prevalence of transient tics among children in the Moscow region is 6%, chronic forms of the disease are 1%, and TS occurs with a frequency of 1 case per 1000 children [1]. In South Korea, the incidence of chronic tic disorders (CTD) in the population aged 2-19 years was 2.6 per 1000 per year, between 2009 and 2021 there was a slight increase in the incidence of CTD - from 1.9 to 2.9 per 1000 population per year [2]. In Norway, according to studies from 2008–2016, the prevalence of TS across the country varied from 0.15 to 1.23%, and on average, by the age of 12, TS was diagnosed in 0.43% of children, boys are 4 times more prevalent than girls [3]. It is likely that clinicians use different criteria for TS, resulting in chronic motor and vocal tics being interpreted as TS. CTE remains in 50% of adults [4], and M. Bloch et al. [5], indicate that 25% of tics persist in the adult population. In adults, TS occurs 5–10 times less frequently than in children; according to various estimates, from 50 to 659 cases per 1,000,000 adult population [6]. Thus, it is in childhood that patients with tics and TS are most likely to see doctors, and individual approaches to drug and behavioral therapy and observation algorithms are developed for such patients.

The disease is based on tic hyperkinesis - rapid stereotypical movements, reminiscent of voluntary ones, affecting the muscles of the face, body and limbs, changing in severity during the day, provoked by anxiety, mental and physical stress, disappearing in sleep. The main comorbid syndromes of tics and TS are attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCS), anxiety, mood swings, and sleep disorders. According to D. Martino et al. [7], isolated tics occur in 10-15% of cases. In the International Classification of Diseases, 11th revision (ICD-11), which will replace ICD-10 from 2022, tics and TS were placed in the section of diseases of the nervous system, which is true, since it is primarily parents with children who turn to a pediatric neurologist , patients with tics [8].

Etiology and pathogenesis

A significant role is assigned to disruption of dopamine (DA) metabolism, namely the excessive release of DA in the synapses of the striatum, which in turn disrupts the neurotransmitter balance in the cortex-striatum-thalamus-cortex system. Using positron emission tomography (PET) as an example in adult patients with TS, no signs of a significant increase in DA in DA2-DA3 receptors were found, and the analysis of changes in dopaminergic activity in the region of the caudate nucleus, taking into account the age of the patients, did not show significant differences from the control group [ 9]. Genetic studies of the association of TS with mutations in the DA receptor genes (DRA2, DRA4) and DA neurotransmitter genes have shown mixed results. For example, in a group of 674 patients with TS, positive associations with gene mutations were found, but in other studies in 343 patients with TS, the data were not confirmed. From a clinical point of view, such results make it possible to explain the lack of effect of antipsychotics in 40-60% of patients with TS; probably, with mutations in the DA2 receptor genes, antipsychotics do not have a blocking effect on excess DA activity. A mutation in the DAT1 gene, the DA transporter, was observed in 574 patients with TS versus 266 patients with TS in whom these data were not confirmed [10]. According to the ST model proposed by V. Tiago et al. [11], the interaction of DA1- and DA2-receptors, which realize the direct and indirect influence of signals from the “maternal neural network” in voluntary movements, DA emissions are phasic and tonic in nature, emissions may have pauses, hence the concentration of the transmitter cannot be constantly increased, which allows us to explain the contradictory data from studies of DA metabolism in the basal ganglia using PET. The role of the subthalamic nucleus in the pathogenesis of TS cannot be excluded, which can inhibit impulses from the orbitofrontal cortex, additional motor cortex to the basal ganglia, tonsils and nucleus accumbens. The key mechanism for selecting a dominant stimulus during the constant interaction of sensory and motor signals remains unclear [12]. Probably, at the level of the striatal system, an error in counting information occurs, which leads to involuntary movement, perceived in the CCST as voluntary. In this regard, it is assumed that deep brain stimulation can selectively influence subcortical structures and change the pathological program for choosing a dominant stimulus. The dopaminergic CSTPC is in constant interaction with the inhibitory function of gamma-aminobutyric acid (GABA) and serotonin. The role of serotonin in the development of tics and TS began to be discussed after mutations in the 5-HTTLPR and HTR2C receptor genes and polymorphisms in the SLC6A4 neurotransmitter transporter gene were discovered [13–15]. Our studies [16] on the neurotransmitter metabolism of DA, norepinephrine and serotonin in children with TS showed a connection between serotonin and vocal tics, and DA with motor ones, which allows for differentiated therapy depending on the severity of vocal and motor symptoms. The pathogenetic role of the mutation of adenosine 2A, a receptor that plays an important role in the regulation of glutamate and the release of DA, which in turn activates D2 receptors, is being considered [17]. The regulator of the activity of dopaminergic structures is histamine, synthesized in the tuberomammillary nucleus. Ascending projections of histamine (hundreds of thousands) are sent to the neurohypophysis, DA-containing areas of the ventral tegmentum of the midbrain and substantia nigra, the basal forebrain (magnocellular nuclei of the substantia innominate containing acetylcholine and GABA, striatum, neocortex, hippocampus, amygdala and thalamic nuclei of the midline ). A breed of mice with tic-like behavior was developed with a mutation in histidine hydroxylase, which normally provides the synthesis of histamine from histidine. The authors postulate a histamine hypothesis for the pathogenesis of TS, which does not exclude the development of treatment options in this animal model [18]. The histamine-3 receptor (H3R) is of particular interest due to its clinical effects in the treatment of neuropsychiatric disorders (sleep disorders, TS, parkinsonism, ADHD, ACS) and high expression in the brain. Histamine modulates, through histamine H3R receptors, the release of neurotransmitters in the striatal region of the brain. H3Rs are classically described as G protein-coupled receptors, although there is evidence that H3R forms heteromers with type 1 and type 2 DA receptors in medium spiny neurons, which alters signaling in the thalamocortical loop. Detailed time-dependent signaling in the two types of DA1 and DA2 receptors of medium-sized spiny neurons after H3R activation was presented for the first time [19]. The hypothesis of disturbances of noradrenergic receptor systems in TS was tested in studies [20, 21] using the example of a population of 180 patients with TS and a control group of 83 people; no significant differences in the polymorphisms of the norepinephrine receptor genes ADRA2A and ADRA2C were identified, which is a prerequisite for further study of norepinephrine complexes in pathogenesis diseases. Dysfunction of the brain's inhibitory system is considered one of the priority hypotheses for the pathogenesis of tics and TS. GABA receptors account for up to 40% of all neurotransmitter receptors in the central nervous system (CNS), including inhibitory interneurons in the cortex, striatum, cerebellum, and spinal cord. A study was undertaken to search for evidence of the concept of inhibitory dysfunction; as a result, data were obtained on the association of mutations in the GABA1, GABA4, and acetylcholine receptor (ACh) receptors with the severity of the clinical manifestations of TS. Several genes related to the GABA4 and GABA1 receptors and the nicotinic receptor ACh CHRNA4 were predicted to be abnormally spliced ​​in TS patients compared to controls [22]. The effect of cytokines was studied in mice by determining the expression of genes in the BDNF/NF-kB (brain-derived neurotrophic factor/nuclear transcription factor) pathway; with a decrease in BDNF expression in microglial cells of the striatum, DA and the number of DA2 receptors decreased. These results allowed the authors to suggest the influence of cytokines on DA activity in the basal ganglia [23]. DAergic neurotransmission is closely related to the endogenous opioid system. Thus, on the example of 170 patients, exome sequencing revealed rare, possibly pathological variants of 3041 genes, 54 of which were predominantly expressed in the basal ganglia. Comparison of frequency variants of selected candidate genes showed an excess of potentially disruptive variants in the OPRK1 gene, encoding the opioid kappa receptor in patients with TS [24]. Among the candidate genes for the development of TS, the SLITRK1 gene on chromosome 13q31.1 is considered, encoding the SLITRK1 transmembrane protein, which regulates neurite growth, is expressed in the embryonic and postnatal brain, including the cerebral cortex, thalamus and basal ganglia, which are associated with neuroanatomical regions, most often involved in TS [25]. It seems important to discuss de novo mutations in sporadic cases of tics and TS. Thus, in work [26], a variant of mutations of RPTOR polymorphisms, which encodes part of the cell growth regulation signaling pathway and is responsible for cell nutrition, was considered. RPTOR is an evolutionarily conserved protein with multiple roles in the MTOR pathway. RPTOR also plays an important role in maintaining cell size and MTOR protein expression. It is possible that RPTOR polymorphisms lead to the formation of neurons with abnormal hyperexcitability at the level of the somatosensory cortex and striatum. A mutation of the ASH1L gene was discovered, which is responsible for the expression of lysine-specific methyltransferase 2H, which affects brain development and increases the risk of developing autistic disorders, school learning defects, social adaptation and TS. Some ASH1L gene mutations associated with autism spectrum disorders change one building block (amino acid) in the enzyme lysine-specific methyltransferase 2H, others remove genetic material in the ASH1L gene sequence or result in an abnormally short enzyme. As a result of these mutations, the enzyme becomes nonfunctional, and its absence impairs histone methylation. Changes in the expression of genes regulated by lysine-specific methyltransferase 2H affect brain development and increase the risk of developing autistic disorders. 524 patients with TS who were found to have point mutations in the ASH1L gene were examined, then a transgenic line of mice was created, and a model of tic-like behavior was obtained, on which haloperidol had a therapeutic effect [27]. The ASH1L gene mutation led to a decrease in enzyme activity in the dorsal region of the striatum and an increase in DA release [27]. Probably, at the stages of ontogenesis of the formation of the striatal system, disturbances in the growth and size of neurons occur, which leads to an abnormal structure of the thalamo-striatal-cortical loop as a whole.

Neurobiological and neurophysiological aspects of tics and TS

The functional activity of the somatosensory cortex is of increased interest to neurologists, since its study opens up the possibility of psychotherapeutic and volitional control over tics. A study of connections between the somatosensory cortex and the basal ganglia using functional magnetic resonance imaging (fMRI) led to unique results: it turned out that metabolic activation of the left somatosensory cortex, posterior parietal cortex, putamen and amygdala was significantly higher and longer lasting in patients during tics than in a control group of individuals who reproduced voluntary movements similar to tics [28]. The neuroanatomy of the pathogenesis of tics corresponds to the hypotheses of stress provocation through the limbic system with hyper-DA activation of the sensorimotor cortex. Studies using fMRI confirm the participation in the pathophysiology of tics of the additional zone of the sensorimotor cortex in close connection with the insular region during a stressful situation (test of viewing gloomy faces) with activation of the thalamus and putamen. The study of connections between the basal ganglia and the cortex demonstrated persistent and functional disorganization of neuronal networks in patients with TS [29]. According to studies using fMRI, it has become possible to clarify the disruption of connections in the basal ganglia, thalamus and cerebellum in patients with TS. The most notable changes were found in the basal ganglia (motor control), insular cortex (thirst, emotional processing), nucleus accumbens (tics caused by emotional distress) and cerebellum (coordination, accuracy, learning). The results obtained reflect a very complex process leading to the formation of a tic: basal ganglia - insula - nucleus accumbens - cerebellum [30]. The fMRI data was supplemented by the following work with the conclusion that TS is characterized by increased functional integration of several basal ganglia-thalamocortical circuits, which indicates the predominance of excitatory neurotransmission and insufficient brain maturation with a decrease in cortico-cerebellar connections. A comparison of the clinical syndromology of tics and the phenomena of “premonition” of hyperkinesis on the part of the patient showed a close connection between the insular and somatosensory cortex. In patients with CTE with motor impulsivity, high functional connections of the frontal-temporo-basal ganglia - cerebellar pathway were identified, which were inhibited when prescribed atypical antipsychotic drugs [31, 32]. In patients with TS and ACS, the topography of functional connections of brain structures is expanded. Recent work has shown the interest of not only the area of ​​the insular and sensorimotor cortex, but also the supramarginal, inferior frontal gyri, and precuneus. It should be noted that the severity of ACS corresponded to the activation of precisely these areas of the brain [33, 34]. The severity of hyperkinesis was more correlated with activity in the anterior cingulate cortex [35]. The use of MRI spectroscopy with assessment of the GABA spectrum in the somatosensory cortex showed increased accumulation of this transmitter, which was regarded as a compensatory inhibitory reaction in response to DA hyperactivation [36]. Studies using evoked somatosensory potentials in patients with TS have made it possible to establish a connection between hyperamplitude signals in the sensorimotor cortex and the severity of tic hyperkinesis; this finding is considered by the authors as a neurophysiological marker of the severity and prognosis of the disease [37]. Thus, the data obtained reflect the complex process of the formation of hyperkinesis and psycho-emotional reactions in patients with TS, in which it is possible to distinguish the main (motor) loop: sensorimotor cortex - striatum - thalamus - sensorimotor cortex, an additional (emotional-stress) loop: sensorimotor cortex - cingulate gyrus - insula - nucleus accumbens - cerebellum - sensorimotor cortex. When ACS and ST are combined, the supramarginal gyrus and precuneus of the parietal lobe and the inferior frontal gyrus are involved.

Clinical symptoms, course and outcomes

Tics debut in children aged 3 to 7 years, the expression of symptoms is observed from 8 to 12 years with a maximum exacerbation of symptoms at 10-11 years, it is during this age period that the transformation of tics into TS occurs.

TS is characterized by daily multiple motor tics with one vocal symptom or more for 12 months, is not associated with medications and diseases of the central nervous system, manifests itself before the age of 18, and is caused by a developmental disorder of the central nervous system, according to DSM-V [38]. In our opinion, the criteria for TS in the DSM-V are simplified in comparison with the versions of DSM-III and IV, in which the diagnosis of TS is established in cases of generalized motor hyperkinesis, meaning by generalization the participation in hyperkinesis of the muscles of the lower extremities: jumping, curling the toes, pelvic movements . Another important criterion for diagnosing TS in adult patients in DSM-III was impairment in occupational performance due to tics, which in children can be equated to school or college learning. Based on many years of research, we have developed a classification of tics according to etiological and topical principles, indicating the severity and stages of the process [39].

Classification of tic hyperkinesis

I. Etiology:

1. Primary (hereditary).

2. Secondary, symptomatic, medicinal (psychostimulants, valproate).

3. Cryptogenic (without established etiology or sporadic).

II. Topical and clinical manifestation of tics:

1. Local - in one muscle group.

2. Common - more than two muscle groups.

3. Generalized, involving the muscles of the lower extremities in combination with vocal tics. - ST.

3.1. Infantile benign form of TS.

III. Severity (calculated by the researcher over 20 minutes of observation):

1. Single - <10.

2. Serial - >10<50.

3. Status - from >50 to 600-1200.

IV. Flow:

1. Transient - complete reversibility of hyperkinesis, observation of the patient for 3 years.

2. Remitting - reduction to single tics or complete regression for weeks and months.

3. Stationary - chronic hyperkinesis is constantly present.

4. Progressive—increasing symptoms, no remissions, drug resistance.

V. Stages:

1. Debut (3 years - 7 years).

2. Expression of symptoms (8-12 years) - exacerbation of the disease in the form of status motor-vocal hyperkinesis.

3. Residual (13-15 years) - regression of symptoms or their complete disappearance.

At the onset of the disease, most children experience local motor tics: blinking, squinting, turning their gaze, tilting and turning their head. Simple vocal tics of coughing and nose sniffing can be the first symptoms in up to 20% of cases, which are not perceived by parents as obsessive movements, and in some cases children undergo treatment for months from allergists and pediatricians. In most patients, vocal tics join motor tics at the stage of symptom expression. Complex vocal tics include coprolalia, palilalia, echolalia; in our observations, they were noted in 6% of cases and are characteristic only of ST. The severity of tics is determined by counting hyperkinesis over 20 minutes by a doctor at an appointment or by parents at home; the objective picture is made up of 3 counts over 1 week. We characterized severe exacerbations as tic status, when the total number of tics reaches more than 50, can reach 600-1000 in 20 minutes, they exhaust the child, and frequent head movements cause pain in the cervical and occipital regions [39]. In the kinematics of tics, clonic (fast) and dystonic (slow) hyperkinesis can be distinguished (Table 1) [40].

Table 1. Semiotics of tic hyperkinesis

Fast - clonic tics are represented by blinking, shuddering of the shoulder girdle, twitching of the corner of the mouth and wings of the nose, contraction of the abdominal muscles, twitching of the hands (9.3%). Slow - dystonic tics manifested themselves in the form of closing their eyes, raising their shoulders, turning the head to the side, opening the mouth with the lower jaw moving forward, grimacing, throwing back the head, movement in the shoulder girdle - adducting the shoulders, throwing the arm to the side, flexion and extension of the hand and fingers. It is difficult to classify ritual movements, especially squatting (4.6%) and jumping (3.8%), which are observed only in patients with TS. During electromyography with cutaneous electrodes from the muscles of the face and shoulder girdle, various signals were recorded depending on the semiotics of hyperkinesis: for clonic tics, spindle-shaped volleys lasting 10-30 ms with an amplitude of 500-2500 μV are characteristic, and for dystonic tics, diamond-shaped tics lasting 100-1000 ms with an amplitude 1000-3000 µV [37].

Dystonic tics are observed in 76% of children and adults with TS and are unfavorable prognostic signs of the chronic course of the disease [40, 41]. At the age of 10-11 years, patients begin to complain of a feeling of discomfort, tightening in a certain muscle group, a premonition of a tic, which disappears after hyperkinesis for a short time, then the premonition appears again in the same area along with the desire to “make a tic” [42]. Hypothetically, this fact can be explained by excessive impulses in the sensorimotor cortex and a local deficit of inhibitory influences. The role of the insular cortex is suggested in the pathophysiology of “premonition” of tics, voluntary suppression of hyperkinesis, used in behavioral therapy. The role of the temporal lobe in the pathophysiology of tics is also important. Thus, it was noted that when mentioning aloud about tic disorders, the patient developed symptoms of the disease [43]. The complex phenomenology of tics and stereotypies is constantly enriched by the characteristics of new variants, for example, tics caused by auditory stimuli in combination with misophonia (intolerance to the sounds of chewing, noise, creaking, etc.) and stereotypies associated with intense educational activity are observed. Tics and motor stereotypies can be recognized by the location and duration of the motor act. Stereotypes - slow movements (opening the mouth, licking lips, biting nails and cuticles) - are better controlled by the child and practically do not occur during tasks and enthusiastic activities. Animal studies and fMRI of the brain of TS patients with severe stereotypies confirm the involvement of all three main loops: sensorimotor, associative and limbic [44]. The differential diagnosis of TS and chronic motor tics in the absence of vocalisms remains a difficult issue. It was proposed to take into account the severity of tics, the diverse semiotics of hyperkinesis, comorbidity with ADHD and ACS, copropraxia - they significantly prevailed in children with TS [45]. These data are useful in cases where there are no vocal manifestations of the disease to determine the prognosis and decide on the duration of therapy. Comorbid syndromes in patients with tics and TS include ADHD, OCD, and anxiety disorders [46]. In the pediatric population, ADHD is combined in 56% of cases, anxiety manifestations in 90%, in 1/2 of patients ADHD is combined with anxiety, and a direct correlation has been identified between the severity of tic hyperkinesis and the severity of comorbid symptoms [41]. In this regard, we have developed the following therapeutic strategy: step 1 - drug correction of tics; Step 2 - solving questions about the treatment of comorbid pathology. Emotional hyperexcitability in patients with tics and TS is manifested in the sensations of smell and taste; differences in the food selectivity of patients with TS relative to healthy children when choosing food and fruits have been shown [47].

According to long-term (from 25 to 32 years from the onset of tics) observations of patients with TS, the outcomes are generally positive, observed in 82% of cases. The evaluation criteria included academic performance, paid work, marriage and quality of life, and 20–40% of patients had mild discomfort from hyperkinesis [48]. Predictors of the chronic course of TS in adults are the early onset of tics, status hyperkinesis, the presence of ADHD, OCD, and emotional disorders [49]. We distinguish a benign childhood form of TS with regression of tic disorders after 15 years according to the following criteria: 1) autosomal dominant type of inheritance of motor tics in the male line; 2) high clinical effect from the use of antipsychotics; 3) absence of ADHD, OCD and cognitive impairment [39].

Treatment

The goal of therapy is for a child with tics and TS to receive education, and therefore the teacher must create a comfortable environment around the child; Drug therapy is currently not able to completely relieve patients from hyperkinesis. Behavioral therapy is the first line treatment. Behavioral therapy is used in adolescents when the child has experience anticipating tics. The most common behavioral intervention to reduce tics is habit modification training, which is based on the concept that patients learn to perceive the anticipation of a tic and use antagonistic, competitive muscle activity (movement or tension) to suppress or counteract the onset of hyperkinesis. In the work of V. Petruo et al. [58] have proven the effectiveness of reducing the severity of tics using this technique, as well as increasing the level of attention to the indicators of the control group. It is noteworthy that in the studies of S. Hall et al. [59] proved the possibility of conducting behavioral therapy remotely with a similar effect as in face-to-face sessions. The doctor’s task is to prepare parents for the long journey of adaptation of a child with tics to learning and completing school assignments. The doctor selects a drug treatment regimen to reduce the severity and frequency of motor and vocal hyperkinesis. Treatment of comorbid syndromes such as ADHD, ACS, anxiety, mood disorders, destructive behavior, schizotypal traits, suicidal behavior, personality disorder, antisocial behavior and sleep disorders, which may be more important than motor and vocal symptoms, is relevant [50]. The model of motor behavior regulation provides for two pathways: direct and indirect. Both pathways have opposite effects on spontaneously firing thalamocortical neurons and hyperkinetic activity, i.e. activation of the direct pathway facilitates motor activity by disinhibiting thalamocortical neurons, whereas activation of the indirect pathway reduces motor activity by increasing the inhibition of thalamocortical neurons [51]. The complexity of motor behavior disorders is manifested by a multi-level system of movement regulation, including the sensorimotor cortex, thalamus, subthalamic nucleus, nucleus accumbens, and amygdala complex. In table Table 2 presents drugs that have a long history of use in the treatment of tics and TS, as well as new generation ones [51].

Table 2. Pharmacological drugs and target receptors in the treatment of tics and TS [51]

Note. * - drugs registered in Russia for use in children. Receptors: DA - dopamine, Glut - glutamate, GABA - gamma-aminobutyric acid, Hist - histamine, 5-HT - serotonin, Ach - acetylcholine, Opiod Rs - opioid, CB Rs - cannabinoid.

Our experience shows that baclofen is most effective for motor facial tics, while topiramate is most effective for status hyperkinesis, including blinking, blepharospasm, flinching, and head turning [52]. Haloperidol reduces to a greater extent the motor symptoms of the disease in patients with TS, and rispolept reduces vocal tics and obsessive-compulsive symptoms [53]. In children aged 5-8 years, it is advisable to start initial therapy with hopantenic acid 50 mg/kg/day in double doses for a course of 4-6 months; after 1 month of use, along with regression of tics, a decrease in the level of anxiety and severity of ADHD manifestations is observed. In some cases, tiapride is effective in doses of 100–300 mg/day [54]. Taking into account the pathogenetic concept of tics and TS as a result of neurological development disorders, the study of L.S. is of great interest. Chutko et al. [55], devoted to the use of Cortexin administration courses in age-related dosages in patients with tic hyperkinesis. The study was carried out in two groups: in the 1st group there were patients with motor tics who were prescribed phenibut, and in the 2nd group, comparable in age and severity of hyperkinesis, Cortexin was added to phenibut. When assessing the results in the 1st group, an effect was noted in 60% of cases, and in the 2nd group - in 83%. Probably, the peptides of the drug, interacting with the molecular partners of the brain (β5 tubulin, 14-3-3 α/β protein, actin, creatine kinase type B) [56] influence neuroplasticity and neurotransmitter metabolism. Our data from a multicenter study assessing the effectiveness of Cortexin in the treatment of cognitive dysfunctions allow the drug to be used in cases of comorbidity of tic disorders and attention deficit disorder [57]. A promising method, according to K. Dyke et al. [60], is transcranial magnetic stimulation. Using the example of patients aged 16-33 years with TS, results were obtained in which, after a single stimulation of the additional motor cortex, a decrease in the severity of hyperkinesis was determined without excitability of the primary motor cortex. Regular activities, adequate sleep and physical activity play a significant role. Physical activity can reduce vocal phenomena and increase social adaptation; the load should be at least 12,000 steps per day [61]. To understand the volitional control of tics and improve behavioral therapy, further research in this area is necessary, especially important is the identification of the form of “voluntary” volitional control and “premonition” of hyperkinesis [62]. In this regard, data on the use of relaxation therapy is of interest, especially in patients with an exacerbation of the disease after a stressful situation, however, a comparative analysis with other techniques showed that relaxation therapy is the least effective intervention, as it reduces the number of tics by 32% compared to 44%. with self-control and 55% with habit change [63]. Dental splints, which are used to treat temporomandibular joint disorders and bruxism, may be helpful in reducing the severity of auditory and motor facial tics. The effect is explained by additional sensory effects on the insular cortex and the placebo phenomenon. Thus, a decrease in the severity of hyperkinesis was demonstrated by 72% of participants in the general observation group (average age 17 years) [64].

The possibilities of botulinum therapy in the treatment of patients with chronic motor tics and TS are actively discussed in the literature. A 2021 Cochrane review on this issue concluded: Level C evidence, recommending further research. At the same time, doctors can use botulinum therapy for severe local disabling tics in adults and adolescent patients, but the patient should be warned that the effect is temporary and side effects such as weakness and dysphonia are likely [65].

Thus, according to modern literature on tic hyperkinesis and TS, there is progress in research: the search for mutations in neurotransmitter receptors, the use of functional neuroimaging methods. The ultimate goal of the research is to substantiate the drug effect on the target receptors of neurotransmitters. PET studies of dopamine mediation in the striatum of the brain did not show significant differences with the control group, at the same time, the GABA spectrum was significantly increased in the sensorimotor cortex, in which there is hyperactivation and a local excess of the inhibitory transmitter is a compensatory reaction. An important step is to prove the participation in the pathogenesis of tics of the insular cortex and nucleus accumbens, which are responsible for the psycho-emotional sphere, which makes it possible to explain the significant role of stress factors in the onset and exacerbation of the disease. Neurotransmitters involved in cortico-thalamo-striatum-basal ganglia-cortical connections, such as DA, glutamate, GABA, norepinephrine, serotonin, histamine, acetylcholine, endogenous opioids and cannabinoids, have been studied. Studies have been carried out on specific neurotransmitters, but the relationships of the entire neuromediation panel have never been studied, although it is hypothetically clear that a change in inhibition and hyperactivation in one link leads to desynchronization of the entire network. It is probably necessary to create a program for processing scientific information for the study of ST based on artificial intelligence. In practical terms, an important step was the development of computer analysis of cutaneous electromyography, which makes it possible to classify clonic and dystonic tics. The therapy formulates the concept of basic behavioral therapy with the possibility of drug correction of severe hyperkinesis. At the same time, behavioral therapy methods can be used in adolescents, and tics debut at the age of 3 and reach their maximum peak by 10-11 years. Botulinum therapy methods are recommended only in adolescence, but have a low level of evidence to date. Progress in the treatment of TS is represented by cannabinoids and blockers of vesicular transport of DA, which are not registered for use in children. As data accumulate at the intersection of neurogenetics, neuromediation, and functional neuroimaging, taking into account developmental neuroscience, new approaches will emerge for the treatment of tics and TS in children.

The authors declare no conflict of interest.

The authors declare no conflicts of interest.

Living with Tourette Syndrome

The Conversation recently conducted a mini-study in which it surveyed 16 UK residents on the topic “How does Tourette Syndrome affect your life?”

In an interview with journalists, some of the respondents said that they live a full life, having a job they love and a happy family. They claim that this condition has helped them grow emotionally and find more meaning in their lives. One of the respondents about [The Conversation, 2019].

However, some survey participants reported that the syndrome made them feel lonely. Even those who were accustomed to their disorder felt the need to hide their tics in public. They have learned to control and suppress them in every possible way, fearing condemnation and bullying. To avoid public ridicule and bullying, they preferred to isolate themselves from others.

Most respondents reported being bullied as children and sometimes as adults. Some of them even experienced a negative reaction from their parents to their condition. One of the survey participants recalls: “I was forced to hide in closets and rooms when guests came to us. I was never taken out in public. I was even kept away from my own family, with the exception of my grandparents” [The Conversation, 2019].

Another participant said: “Imagine working in a bar, stressful nights and stuff like that. You start to have tics. Drunk visitors start asking stupid questions and making fun of you. You try to talk to your employer about it, arguing that you need to rest or you'll get worse. But he doesn’t understand it because he doesn’t care” [The Conversation, 2019].

People in the study said they wanted to be “normal” in order to achieve all their goals. They feel that Tourette's syndrome is holding them back from being who they want to be and doing what they want to do.

The lives of people suffering from the syndrome are often complicated by public attitudes towards this diagnosis. For example, 15-year-old American Emily Womack, who suffers from vocal tics, was asked to leave the cinema while watching trailers.

Emily explains that she "let go of her tics" before the film started so that while watching it her screams would not disturb her and those around her. Emily's mother Tina said the family were sitting watching trailers when the theater director approached them: “He told me that nine people had complained about Emily's noises. I explained that she suppresses noise during the show and there is nothing to worry about since that is what she does during every movie she goes to."

“It was a crowded theater with people laughing loudly, talking loudly, and even kids throwing popcorn and annoying people. But Emily was chosen out of everyone solely because of her disability,” says Tina Womack [BBC News, 2019].

The Tourette Syndrome Association of America posted a video of Emily on their Facebook page where she talks about what happened. The post, which was viewed by several thousand people, prompted many with the disorder to share their own stories.

Association CEO and President Amanda Talty says, “Being asked to leave created an environment in which Emily and her family felt unwelcome due to her disability under the Americans with Disabilities Act. Offering free movie tickets and popcorn will not relieve the embarrassment and shame that a person feels in such situations. Unfortunately, this is a familiar story for most people with Tourette's syndrome, and this moment will stay with Emily for the rest of her life" [BBC News, 2019].

In the last 20 years, a large number of films have appeared that describe the lives of people suffering from Tourette syndrome . Here are just a small part of them:

• Before the Class (2008).
• Inner Road (2014).
• Vincent wants to go to the sea (2010).
• I am a teacher (2018).
• It's not me, it's my tick (2011).

The purpose of this movie: to popularize the disorder in order to show the world that it does not harm others, and people suffering from it are exactly the same members of society as everyone else. The more people know about Tourette's syndrome, the more tolerant they will be.

American singer and songwriter Billie Eilish made an official statement several years ago that she suffers from Tourette syndrome, which she was diagnosed with as a child. “I never mentioned my syndrome online because I never wanted people to think about it every time they think about me,” the singer admitted [Billboard, 2018].

The singer went on to say that her disorder was a constant part of her life from an early age. “I have learned to suppress my tics and have learned certain techniques that help reduce them when I don’t want to be distracted in certain situations,” she wrote on her social media page.

The singer's parents were shocked when they learned about their daughter's illness. Thanks to her fighting spirit and the support of her loved ones, Billie was able to turn this disorder into a feature. She realized that her tics made her truly unique. Faced with the fact that those around her turned their backs on her, she realized in time that she could be strong without people who cared only about her appearance and behavior [Life, 2020].

This is precisely what her songs are dedicated to, which made her famous throughout the world. Now, with an audience of millions of fans, Billy openly talks about his illness and encourages people with the same syndrome not to give up.

Billie Eilish's confession has helped people suffering from Tourette syndrome find hope. The star openly spoke about her disorder because she is confident that spreading information about it will improve the quality of life for people suffering from it and their loved ones [Billboard, 2018].

In addition, identifying with a celebrity will help people with the syndrome increase their self-confidence. They will no longer be ashamed of their diagnosis and will believe in making their dreams come true, just like Billie Eilish.

In addition to Billie Eilish, American football player Tim Howard and screenwriter and comedian Dan Aykroyd suffer from Tourette syndrome. According to some sources, the famous Austrian composer Wolfgang Amadeus Mozart and the Roman Emperor Claudius also had this disorder.

Prognosis and course of the disease

Tics occur in many children, but they often go away so quickly that they are not even diagnosed. Only 0.3-0.8% of children are diagnosed with Tourette's syndrome, and 1% of these continue to have it into adulthood6. This disease is not dangerous to health, does not affect development, but can cause behavioral and social problems. It is more severe at high levels of stress, if a person tries to suppress tics, if he does not receive support, if the disease is not treated.

Tourette's syndrome and learning

If a child with Tourette syndrome has multiple motor and vocal tics, he can be homeschooled. To do this, you need to pass a psychological-medical-pedagogical commission (PMPC). This commission will assess the child's health status. She may recommend further schooling, training according to an individual plan or an adapted program, or transfer to home schooling. If the disease persists into adulthood, severe cases may result in disability. This will provide a number of social benefits, including exemption from conscription and the right to receive benefits.

The prognosis will be favorable if:

• contact a neurologist and psychotherapist as soon as possible;
• apply ways to manage stress, emotions, self-esteem;
• use techniques to “replace” or weaken tics;
• treat concomitant diseases or disorders.

Sometimes Tourette's syndrome greatly reduces the quality of life, affects the psychological state, and interferes with social adaptation. It is important to treat this disease and remember that even with it, a person can lead a normal life and achieve success.

Billie Eilish has Tourette's syndrome

The story of the famous American singer Billie Eilish confirms that Tourette syndrome can be controlled and you can lead a full life (video 2).

Video 2. Billie Eilish has Tourette syndrome.

Billie Eilish hid the disease for a long time, but in 2021 she admitted that she has Tourette syndrome. After this, the singer received many messages from fans who also have this disease or simply support her. The singer says that she has lived with the syndrome all her life, has learned to control it well, and her loved ones perceive its manifestations as something normal.

Billie Eilish lives with Tourette syndrome. Photo: benhoudijk/Depositphotos