Tics and Tourette Syndrome Singer, Harvey S
Continuum (Minneapolis, Minn.)
25, Številka:
4
Journal Article
The purpose of this article is to present current information on the phenomenology, epidemiology, comorbidities, and pathophysiology of tic disorders and discuss therapy options. It is hoped that a ...greater understanding of each of these components will provide clinicians with the necessary information to deliver thoughtful and optimal care to affected individuals.
Recent advances include the finding that Tourette syndrome is likely due to a combination of several different genes, both low-effect and larger-effect variants, plus environmental factors. Pathophysiologically, increasing evidence supports involvement of the cortical-basal ganglia-thalamocortical circuit; however, the primary location and neurotransmitter remain controversial. Behavioral therapy is first-line treatment, and pharmacotherapy is based on tic severity. Several newer therapeutic agents are under investigation (eg, valbenazine, deutetrabenazine, cannabinoids), and deep brain stimulation is a promising therapy.
Tics, defined as sudden, rapid, recurrent, nonrhythmic motor movements or vocalizations, are essential components of Tourette syndrome. Although some tics may be mild, others can cause significant psychosocial, physical, and functional difficulties that affect daily activities. In addition to tics, most affected individuals have coexisting neuropsychological difficulties (attention deficit hyperactivity disorder, obsessive-compulsive disorder, anxiety, mood disorder, disruptive behaviors, schizotypal traits, suicidal behavior, personality disorder, antisocial activities, and sleep disorders) that can further impact social and academic activities or employment.
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.
Tourette syndrome (TS) is a common, chronic neuropsychiatric disorder characterized by the presence of fluctuating motor and phonic tics. The typical age of onset is ∼5-7 years, and the majority of ...children improve by their late teens or early adulthood. Affected individuals are at increased risk for the development of various comorbid conditions, such as obsessive-compulsive disorder, attention deficit hyperactivity disorder, school problems, depression, and anxiety. There is no cure for tics, and symptomatic therapy includes behavioral and pharmacological approaches. Evidence supports TS being an inherited disorder; however, the precise genetic abnormality remains unknown. Pathologic involvement of cortico-striatal-thalamo-cortical (CSTC) pathways is supported by neurophysiological, brain imaging, and postmortem studies, but results are often confounded by small numbers, age differences, severity of symptoms, comorbidity, use of pharmacotherapy, and other factors. The primary site of abnormality remains controversial. Although numerous neurotransmitters participate in the transmission of messages through CSTC circuits, a dopaminergic dysfunction is considered a leading candidate. Several animal models have been used to study behaviors similar to tics as well as to pursue potential pathophysiological deficits. TS is a complex disorder with features overlapping a variety of scientific fields. Despite description of this syndrome in the late 19th century, there remain numerous unanswered neurobiological questions.
•Significant correlation between cortical endogenous opioids and repetitive behavior.•Frontal and prefrontal cortical GABA is influenced by endogenous opioids.•Altered cortical endogenous opioids ...contribute to an imbalance between goal-directed and habitual pathways.
Deer mice provide a non-pharmacologically induced model for the study of repetitive behaviors. In captivity, these animals develop frequent jumping and rearing that resemble clinical symptoms of obsessive-compulsive behavior (OCB), autism spectrum disorder (ASD), complex motor stereotypies (CMS), and Tourette’s syndrome (TS). In this study, we pursue the mechanism of repetitive behaviors by performing stereological analyses and liquid chromatography/ mass spectrometry (LC–MS/MS) measurements of glutamate (Glut), GABA, 3,4-dihydroxyphenylacetic acid (DOPAC), dopamine (DA), leu-enkephalin (leu-enk), and dynorphin-A (dyn-A) in frontal cortex (FC), prefrontal cortex (PFC), and basal ganglia. The only significant stereological alteration was a negative correlation between repetitive behaviors and the cell count in the ventromedial striatum (VMS). Neurochemical analyses demonstrated a significant negative correlation between repetitive behaviors and endogenous opioids (leu-enk and dyn-A) in the FC – the site of origin of habitual behaviors and cortical projections to striatal MSNs participating in direct and indirect pathways. The precise neurochemical process by which endogenous opioids influence synaptic neurotransmission is unknown. One postulated cortical mechanism, supported by our findings, is an opioid effect on cortical interneuron GABA release and a consequent effect on glutamatergic cortical pyramidal cells. Anatomical changes in the VMS could have a role in repetitive behaviors, recognizing that this region influences goal-directed and habitual behaviors.
Tics are sudden, rapid, recurrent, nonrhythmic motor movements or vocalizations (phonic productions) that are commonly present in children and are required symptoms for the diagnosis of Tourette ...syndrome. Despite their frequency, the underlying pathophysiology of tics/Tourette syndrome remains unknown. In this review, we discuss a variety of controversies surrounding the pathophysiology of tics, including the following: Are tics voluntary or involuntary? What is the role of the premonitory urge? Are tics due to excess excitatory or deficient inhibition? Is it time to adopt the contemporary version of the cortico-basal ganglia-thalamocortical (CBGTC) circuit? and Do we know the primary abnormal neurotransmitter in Tourette syndrome? Data from convergent clinical and animal model studies support complex interactions among the various CBGTC sites and neurotransmitters. Advances are being made; however, numerous pathophysiologic questions persist.
Movement disorders secondary to autoantibodies in children represent a rapidly expanding group of conditions. Once considered to be limited to poststreptococcal Sydenham's chorea or rare cases of ...childhood systemic lupus erythematosus, a variety of antibody-related movement abnormalities are now seen as part of noninfectious autoimmune encephalitis or within an expanding list of postinfectious disorders. In this article, several proposed autoantibody-mediated movement disorders in children are reviewed. In each one, there is a hypothesized antibody biomarker that is believed to be pathogenic and cause the clinical symptoms. As will be discussed, in some, such as anti-NMDA receptor encephalitis, the strength of supporting evidence is strong. In others, antibodies have been identified, but their role as the pathophysiological mechanism remains undetermined. Lastly, there are proposed disorders, such as PANDAS, that are controversial on both a clinical and autoimmune basis.
Motor stereotypies are common in children with autism spectrum disorder (ASD), intellectual disability, or sensory deprivation, as well as in typically developing children ("primary" stereotypies, ...pCMS). The precise pathophysiological mechanism for motor stereotypies is unknown, although genetic etiologies have been suggested. In this study, we perform whole-exome DNA sequencing in 129 parent-child trios with pCMS and 853 control trios (118 cases and 750 controls after quality control). We report an increased rate of de novo predicted-damaging DNA coding variants in pCMS versus controls, identifying KDM5B as a high-confidence risk gene and estimating 184 genes conferring risk. Genes harboring de novo damaging variants in pCMS probands show significant overlap with those in Tourette syndrome, ASD, and those in ASD probands with high versus low stereotypy scores. An exploratory analysis of these pCMS gene expression patterns finds clustering within the cortex and striatum during early mid-fetal development. Exploratory gene ontology and network analyses highlight functional convergence in calcium ion transport, demethylation, cell signaling, cell cycle and development. Continued sequencing of pCMS trios will identify additional risk genes and provide greater insights into biological mechanisms of stereotypies across diagnostic boundaries.
Complex motor stereotypies are rhythmic, repetitive, fixed, and non-goal directed movements (e.g., bilateral flapping/waving movements of the hands/arms). Movements typically begin in early childhood ...and can occur in otherwise normally developing ("primary") or autistic ("secondary") children. Stereotypies persist, occur multiple times a day, have prolonged durations, can be socially stigmatizing, and may lead to bullying and isolation. Prior behavioral treatment studies have focused on older children (ages 6-12) and report modest reductions in stereotypy (i.e., between 14% and 33%). The current study involves the functional assessment and treatment of five children with Primary Complex Motor Stereotypy using a modified awareness training procedure, differential reinforcement of other behavior, and schedule thinning in a nonconcurrent multiple baseline design. Results suggest a 99% reduction of motor stereotypy from baseline across all participants.
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