**3.1 Mechanism and pathways of tics and comorbidities**

Figure 1 is a practical schema explaining the mechanism and pathways of tics and related disorders based in experimental models resulting of neuroanatomy and neurobiology grounds.

Fig. 1. Cerebral cortex giving glutamatergic excitatory projections to striatum. Abbreviations: Glu: glutamate, DR: dopamine receptors, DA: dopamine, GABA: gamma aminobutiric acid, enk: encephaline K, SNpc: substantia nigra pars compacta, SNpr: substantia nigra pars reticulata, Sust P: susbstantia P, GPe: external globus pallidus, GPi: internal globus pallidus, NST: nucleus subthalamic, VA: ventral anterior, VT: ventral nuclei, CM-PF: centromedian -parafascicular nuclear complex.

The cerebral cortex provides excitatory glutamatergic projections to striatum. The striatum has a topographic distribution as follows: somatosensorial dorsolateral, intermediate / associative and a centromedial / limbic.

Five parallel circuits connecting the cortex to the striatum27 28:


Epidemiology of Tics 167

level. Clinicians should remember that tics characteristically wax and wane in severity, so sometimes just waiting for some period of time can result in a lessening of tics and avoid

Tics that interfere with school or other daily activities or are disabling because of social embarrassment, physical discomfort or self-injury must be treated. Tic-suppressing medications should be dosage titrated to identify the lowest one that will produce resolution

Usual medication treatment for tics centers in alpha agonists and antipsychotics. However, other types of drugs may be of benefit for patients having an inadequate response or problems with tolerability. Clonazepam has had reported modest ticsuppressing effects in published case series32.This drug may be particularly useful in patients with an associated anxiety disorder. The dopamine-depleting drug tetrabenazine has possible efficacy. The drug is marketed with restriction in some countries. In an openlabel study the drug showed sustained moderate to marked reduction in tics over an average of 2 years' follow-up33. However, only 22% of subjects were free of side effects. The most common side effects are sedation, depression, insomnia, and parkinsonism. Children may tolerate higher doses of tetrabenazine than adults34. Tetrabenazine does not cause tardive phenomena but dopamine-depleting agents can cause neuroleptic

Local injections of botulinum toxin can be considered when one or a few dystonic tics are present in patient's repertoire, such as holding of a sustained neck posture or sustained eye closure36, cervical tics associated with myelopathy37 and laryngeal injections for severe vocal

Deep brain stimulation surgery (DBS) is an approach used to treat other movement disorders including tremor and may be effective for selected patients with severe, disabling and medication-refractory tics. Have been open-label reports of tic reduction following transcranial magnetic stimulation (TMS) of the supplementary motor area39 40. To date, most reported cases involve bilateral targeting of the centro-median parafascicular and ventralis oralis complex or central nuclei of the thalamus41, the globus pallidus internus42 and nucleus

Although sustained benefit has been reported to at least 17 months and most patients continue to require some medication for tics44, more careful investigation of their efficacy,

The ''Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS)'' hypothesis suggested that chronic, recurrent tics and OCD can arise as an autoimmune sequel of infection with group A beta-hemolytic streptococcus45. Actually, there is insufficient evidence to conclude that streptococcal infection has a true

medication use or increases.

**4.1 Tic-suppressing drugs** 

tics, including copralalia38.

**4.2 Deep brain stimulation surgery** 

malignant syndrome even after years of use35.

accumbens/anterior limb of the internal capsule43.

safety, and tolerability of DBS for the treatment of tics is needed.

**4.3 Treatment of tics associated with streptococcal infection** 

of disability.

5. Anterior cingulate circuit: is part of limbic system and is associated to silence, apathy and tics. This circuit is originated in anterior cingulate gyrus and connects with ventral striatum, which is formed by olfactory tubercle, nucleus accumbens, caudate and putamen. Moreover, the striatum receives additional inputs of hippocampus, amygdala and entorhinal cortex.

Although the hypothesis of neural circuit was developed for tics and movement disorders, it is possible that this fundamental principle works for limbic and cognitive aspects. Gangliobasal outputs to frontal lobe via thalamus provide an anatomical substrate for the production of simple and complex tics and compulsions. Thus, abnormal activation of the motor cortex via thalamocortical circuit can cause motor and vocal tics. Abnormal activation of the supplementary area and gyrus cinguli can cause complex tics. Abnormal activation of orbitofrontal cortex can cause compulsions.
