Merging the Pathophysiology and Pharmacotherapy of Tics

Abstract

Background: Anatomically, cortical-basal ganglia-thalamo-cortical (CBGTC) circuits have an essential role in the expression of tics. At the biochemical level, the proper conveyance of messages through these circuits requires several functionally integrated neurotransmitter systems. In this manuscript, evidence supporting proposed pathophysiological abnormalities, both anatomical and chemical is reviewed. In addition, the results of standard and emerging tic-suppressing therapies affecting nine separate neurotransmitter systems are discussed. The goal of this review is to integrate our current understanding of the pathophysiology of Tourette syndrome (TS) with present and proposed pharmacotherapies for tic suppression. Methods: For this manuscript, literature searches were conducted for both current basic science and clinical information in PubMed, Google-Scholar, and other scholarly journals to September 2018. Results: The precise primary site of abnormality for tics remains undetermined. Although many pathophysiologic hypotheses favor a specific abnormality of the cortex, striatum, or globus pallidus, others recognize essential influences from regions such as the thalamus, cerebellum, brainstem, and ventral striatum. Some prefer an alteration within direct and indirect pathways, whereas others believe this fails to recognize the multiple interactions within and between CBGTC circuits. Although research and clinical evidence supports involvement of the dopaminergic system, additional data emphasizes the potential roles for several other neurotransmitter systems. Discussion: A greater understanding of the primary neurochemical defect in TS would be extremely valuable for the development of new tic-suppressing therapies. Nevertheless, recognizing the varied and complex interactions that exist in a multi-neurotransmitter system, successful therapy may not require direct targeting of the primary abnormality.

Figure of Eight Stereotypies in a Young Girl With a Prenatal Cerebellar Injury

“…The cerebellum is capable of rapidly modulating basal ganglia activity in real time, leading to more‐precise motor control . This rapid modulation can instead lead to abnormal movements when cerebellar input is abnormal and may explain the roles for the cerebellum in several different motor disorders . Although this report provides additional support for an association between cerebellar pathology and head nodding/complex motor stereotypies, it is recognized that a direct causative effect has not been proven.…”

Controversies Surrounding the Pathophysiology of Tics

“…Lastly, there are those investigatorsincluding the authors-who have suggested that a disruption in multiple sites within the CBGTC circuit, or brain region inputting to the circuit, could lead to an aberrant message arriving at the primary motor cortex, thereby enabling the tic. Because several recent reviews [67][68][69] have extensively presented available clinical and animal model investigative data, only a more general overview is provided.…”

“…Recognizing the extensive data set for multiple transmitters, the identification of new complex synaptic chemical interactions, and our current space restrictions, the interested reader is referred to several recent reviews. [65][66][67] In the following sections, we focus on several specific transmitters and recent findings in animal models. One important takehome message is to recognize the significant interaction that exists among various neurotransmitters (Figure 3).…”

“…This is certainly not surprising, recognizing dopamine's well-established role in motor activity, movement disorders, temporal processing, regulating reward, reinforced learning, sensorimotor integration, cognitive function, and aversion. 67,[80][81][82] The dopaminergic system is divided into 3 categories: (1) the nigrostriatal system that projects from the substantia nigra pars compacta to various locations within the basal ganglia; (2) the mesolimbic system that arises in the ventral tegmental area and projects to the nucleus accumbens (ventral striatum) and amygdala; and (3) the mesocortical system arising from the ventral tegmental area and projecting to the frontal cortex. One frequently cited supporting factor for DA involvement in tics is the strong tic-suppressing effect of typical and atypical antipsychotic medications.…”

The Suppressive Effect of the Motor System on the Sensory System in Patients With Tourette Syndrome

“…Tourette syndrome (TS) is a complicated neuropsychiatric syndrome whose primary symptoms include chronic motor and vocal tics (1,2). Tics are defined as quick, rapid, recurrent, nonrhythmic, brief movements, or vocalizations with a waxing and waning course (3). TS is considered a complicated sensorimotor syndrome rather than a purely motor disease.…”