Ann. N.Y. Acad. Sci. ISSN 0077-8923

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Childhood Onset Developmental Disorders

Motor control, habits, complex motor stereotypies, and Tourette syndrome Harvey S. Singer Johns Hopkins University School of Medicine, Baltimore, Maryland Address for correspondence: Harvey S. Singer, Rubenstein Child Health Bldg, 200 North Wolfe St, Suite 2158, Baltimore, MD 21287. [email protected]

Tourette syndrome (TS) and primary complex motor stereotypies (CMS) are two relatively common, distinctly different movement disorders of childhood. Despite their frequency, the precise underlying pathophysiological mechanism(s) for tics and stereotypies remains unknown. Both are likely to involve cortical–striatal–thalamo– cortical (CSTC) pathways or their interconnecting brain regions. In recent studies, distinct, separate cortical–striatal pathways have been identified for goal-directed and habitual behavioral activity with important influences from structures, such as the hippocampus, amygdala, dorsolateral prefrontal cortex, cerebellum, ventral tegmental area, and substantia nigra pars compacta. Determining the specific site of abnormality within these circuits remains an active area of research. At the synaptic level, numerous neurotransmitters are involved in the transmission of messages through CSTC pathways, and many have been proposed as potential pathophysiological mechanisms. Which, if any, transmitter is the primary pathological factor in TS and primary CMS remains to be definitively determined. Keywords: motor control; habits; motor stereotypies; tics; Tourette

Introduction Motor control is achieved through a complex network of informational processing activities involving numerous brain structures and pathways. Disruption of these interdigitated, yet incompletely defined systems leads to the development of movement disorders, that is, neurological abnormalities that affect the quality, fluency, speed, repetition, and ease of movements. At the most basic level, the signal for a volitional movement originates within neurons of the primary motor cortex (Brodmann area 4), descends via the pyramidal tract to lower motor neurons within the spinal cord, and ultimately innervates the muscles of the extremities. For more complex motor activities, the planning, performance, and reprogramming of actions involves a series of parallel circuits involving the frontal cortex, basal ganglia, thalamus, and cerebellum. Furthermore, within these circuits are brain regions and pathways that influence the learning and adaptation of movements performed in pursuit of a defined goal or as part of a repetitive habitual behavior.1,2

The habitual motor circuit has potential clinical relevance in two common childhood movement disorders, complex motor stereotypies (CMS) and motor tics, although they may have differences in the precise site of origin. This report defines goal-directed and habitual behaviors, reviews the clinical characteristics of primary CMS and Tourette syndrome (TS), discusses the anatomical pathways and neurotransmitters involved in goal-directed and habitual motor behaviors, and briefly reviews pathophysiological evidence supporting a circuit abnormality in CMS and TS. Goal-directed and habitual behaviors Drawing an analogy to investigations of behavior and learning, it is possible to conceptualize some repetitive movements as either goal directed or habitual. A goal-directed movement is an action that achieves a desirable goal. One that adapts quickly, is flexible, purposeful, cognitively controlled, and action–outcome oriented.1 In contrast, a habit is a repetitive, fixed, purposeful movement that is doi: 10.1111/nyas.12281

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performed automatically.2 The movement is slow to change, elicited by a particular context or stimulus, driven by reinforcement, and is stimulus responsive. In addition, habitual behaviors do not occur in relation to a current or future goal, although they might have been previously influenced by a past goal.3,4 For example, in initial stages of habit learning, animal studies show that food-reward behaviors may begin as goal directed, but with extensive training can be performed on cue, even if the reward is diminished or paired with a noxious outcome. Habitual clinical disorders Two clinical disorders, primary CMS and tics, have movements that can be best characterized as habitual behaviors.

Primary CMS CMS are defined in this manuscript as involuntary, rhythmic, repetitive, fixed (fashion, form, amplitude, and location) movements that appear purposeful, but are purposeless (serve no obvious adaptive function, or purpose), and stop with distraction.5,6 Frequently observed examples include bilateral flapping, waving, or rotating movements of the arms and hands, fluttering fingers in front of the face, opening and closing of the hands, and finger wiggling. Movements typically last for seconds to minutes, appear multiple times a day, and are associated with periods of engrossment, excitement, stress, fatigue, or boredom. Motor stereotypies are readily suppressed by a sensory stimulus (calling one’s name or touching) or distraction, though they may spontaneously reappear. Repetitive arm and hand movements may also be accompanied by neck extension, mouth opening, and jumping. Each child tends to have his/her own repertoire, some of which may evolve over time. CMS have been classified into two groups: primary, indicating an otherwise developmentally normal child; and secondary, for those with other development problems (e.g., autism, developmental delay, deafness, visual impairment, and Rett syndrome).7 Similar movements can occur in both primary and secondary groups and additional testing may be required to distinguish the appropriate classification. In the primary CMS group, movements typically begin within the first 3 years of life, 80% before age 2 years.8 Occasionally, affected individuals may

Motor control, habits, CMS, and TS

report receiving enjoyment from performing the movement, though the majority is unaware of their presence. Movements are absent in sleep and there is no premonitory urge. In a study of 43 primary CMS patients, ages 9–19 years, 96% continued to have symptoms, although many had a reduced frequency and intensity.9 Frequent comorbidities in children over age 7 years include attention deficit hyperactivity disorder (ADHD), tics, obsessive–compulsive disorder (OCD), and anxiety.8,10 By definition, individuals with primary CMS have a normal IQ, although many have motor performance issues that are unassociated with the presence of ADHD or the severity of stereotypic movements.11 The prevalence of primary CMS is unknown, but there are suggestions that it may be as high as 3–4% of preschool children in the United States. The etiology of motor stereotypies in normally developing children is unknown, although the possibility of a genetic predisposition has been suggested by data showing that 25–31% of primary CMS subjects have a positive family history of stereotypies.8,10 The absence of premotor Bereitschaftspotentials preceding the movements in children with primary CMS provides physiological evidence that motor stereotypies do not utilize typical voluntary motor pathways (E. Hondayer, personal communication). Therapeutically, for primary CMS, behavior therapy has been beneficial,12 but to date there is no good pharmacotherapy.

Tics and TS Tics, the cardinal feature of TS, are sudden, rapid, involuntary, nonrhythmic, and repetitive movements or vocalizations.13,14 Motor and phonic tics are each subdivided into simple and complex categories. Simple motor tics include eye blinking, facial grimacing, head jerking, shoulder shrugging, and abdominal tensing. Complex motor tics include clusters of simple movements or more prolonged, coordinated sequences that can appear nonpurposeful, such as facial or body contortions, or purposeful without actually serving a purpose, such as touching objects, clapping, hopping, echopraxia (repeating observed movements), or copropraxia (obscene gestures). Simple vocal tics include linguistically meaningless sounds and noises, such as throat clearing, coughing, grunting, barking, and yelping. Complex vocal tics include syllables, words, phrases, echolalia (repeating other’s words), palilalia

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(repeating one’s own words) and coprolalia (repeating obscene words). Tics typically have their onset between 4 and 7 years of age, with the majority manifesting by 11 years. They have a fluctuating, waxing, and waning course and are typically exacerbated by stress, anxiety, excitement, anger, or fatigue. Tics may diminish when the individual is absorbed in an activity, concentrating, focused, or emotionally pleased. Although tics can occur during sleep, they are not frequently reported. Many individuals with tics, especially older children and adults, describe a sensory phenomenon (premonitory urge), such as a tension, impulse, tingle, or feeling located in the relevant body part before the tic.15,16 While it is suggested that tics should be considered a habitual disorder, the presence of a premonitory urge and the suggestion that the performance of tics is reinforced by reduction of the premonitory urge17 may lead some to consider tics as a possible goal-directed behavior. The diagnosis of TS, known as Tourette’s disorder in DSM-5, requires a fluctuating, evolving course of multiple motor and at least one phonic tic, a duration of symptoms for greater than 1 year, an onset before age 18 years, and the absence of a provoking illness (such as encephalitis or degenerative disease) or tic-inducing medication. The male to female ratio is about 3–4:1. The course of TS is variable, but prognosis in the teenage or early adult years generally follows a broad rule of thirds: in one-third symptoms completely disappear, in one-third symptoms improve, and in one-third tics continue to fluctuate. The majority of individuals with TS have psychiatric comorbidities, such as OCD, ADHD, anxiety, mood, or personality disorders, episodic outbursts, and academic difficulties. These concomitant psychopathologies often have a later onset than tics (except ADHD, which may precede tics) and have been shown to significantly contribute to increased disability.18,19 A genetic basis for TS with a complex inheritance pattern is highly suspected, but environmental factors also appear to influence expression and outcome. Family studies show a 10- to 100-fold increased risk of TS in first-degree relatives. Monozygotic twins have a higher concordance rate (86%) for a chronic tic disorder as compared to dizygotic twins (20%).20,21 Tic suppression has been achieved through both behavioral and pharmacological approaches.22,23 24

Differences between motor stereotypies and tics Although both stereotypies and tics fit into the aforementioned definition of a habitual behavior, several characteristics differentiate these two conditions. Stereotypies have an earlier age of onset (

Motor control, habits, complex motor stereotypies, and Tourette syndrome.

Tourette syndrome (TS) and primary complex motor stereotypies (CMS) are two relatively common, distinctly different movement disorders of childhood. D...
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