Developing New Treatments for Tourette Syndrome: Clinical and Basic Science Dialogue
September 10, 2006 – September 12, 2006
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute of Mental Health (NIMH)
NIH Office of Rare Diseases (ORD)
Tourette Syndrome Association
In September, 2006, NINDS, NIMH, ORD, and the Tourette Syndrome Association (TSA) jointly sponsored a workshop to develop new and improved treatments for children and adults afflicted with Tourette syndrome (TS). The workshop included approximately 100 scientists, clinicians, and industry representatives in the fields of basic neurobiology, behavioral sciences, neurogenetics, neuroimaging, neurological disorders, motor disorders, and child psychiatry. The attendees convened with the express purpose of bridging the communication and information gap between basic and clinical science disciplines to evaluate existing TS treatments and to understand recent updates in the neurobiology of TS, in order to define new therapeutic directions. The following is a summary of the major themes discussed at the meeting.
Phenomenology of and Existing Treatments for TS
TS is characterized by an enduring pattern of motor and phonic tics that present during childhood. Estimates of TS prevalence range from 1 to 10 per 1000 children and adolescents1. The severity and frequency of tics peak early during the second decade of life, but then decline considerably in many individuals by their late teens and early 20s. Currently, there is no curative pharmacological treatment for TS, but several agents have proven successful at attenuating tics and improving psychosocial functioning. Since TS is associated with improper dopaminergic tone in the brain, doctors commonly prescribe atypical neuroleptics (e.g., risperidone) and typical neuroleptics (e.g., haloperidol), that function by blocking dopamine signaling at D2 receptors. Other commonly used agents include α2-adrenergic agonists (e.g., clonidine). Doctors have increasingly prescribed Botulinum toxin A to treat severe focal tics. In terms of behavioral approaches for tic control, habit reversal training, which employs competing responses to block tic manifestation, has appeared to be an effective technique in adults and seems to work in children as well. A handful of case studies suggest that deep brain stimulation, in which electrodes are implanted into specific brain regions to deliver electrical pulses to prevent tics, is a promising approach for controlling TS, but considerably more study of the technique is needed.
Brain Structure and Neural Circuitry
Research indicates that abnormal signaling between various brain circuits that manifests during development plays a causal role in TS. The chief circuit involves the cerebral cortex, basal ganglia, and thalamocortical regions, with the basal ganglia being the key node. Dopamine signaling within the basal ganglia serves to define the salience of information by filtering out "inappropriate" behaviors. Like anyone else, individuals with TS face a constant bombardment of information; unlike the efficient basal ganglia of their unaffected peers, however, the basal ganglia of individuals with TS have an impaired ability to discriminate between salient and non-salient signals. Importantly, it appears that the ventral striatum is the primary locus of dysfunction within the basal ganglia in individuals with TS. Although researchers do not have a clear understanding of the cause of basal ganglia dysfunction, some have looked for clues by examining the structure of TS brains. A comparison of postmortem basal ganglia tissue from patients with severe TS and normal controls indicates a below-normal density of inhibitory neurons in the striatum and an above-normal density in the internal segment of the globus pallidus within the basal ganglia.
Lessons Learned from Studies of Related Neural Processes and Abnormalities
Striatal neurons and dopamine signaling play a key role in the process of habit formation, particularly habits involving complex and socially relevant behavioral sequences, as is observed in people with TS. Certain areas of neural convergence in the striatum may be particularly sensitive to dopamine modulation during decision-making and habit formation – areas that may be hypersensitive or overactive in TS. Related to habit formation is the biology of addiction, which may parallel the neurobiochemical processes occurring in TS. Addiction studies have revealed that overlearning is associated with heavy dopamine release that activates the prefrontal cortex, which, in turn, releases a surge of glutamate on the nucleus accumbens that then drives drug seeking. In the case of TS, individuals with strong tics may have progressed through the process of overlearning such that they become "addicted" to tic behavior as a means to relieve the mounting internal stress or body tension often described as characteristic of TS.
Stereotypical Animal Behavior
There are no animal models for TS, but syntactic chain grooming in rats is a relevant behavior to study since it is sequential, rule driven, and predictable, yet flexible, much like tics. In addition, studies have shown that the ventral striatum of rats regulates this stereotypical movement. D1 receptor agonists dramatically up-regulate chain behavior, suggesting that D1 receptor antagonists may suppress this behavior. Because tics are often preceded by premonitory urges, additional insight into the neurobiology of TS and potential therapeutics may be gained by studying prepulse inhibition in rats, which is abrogated by increased dopamine signaling and/or disruption of the ventral striatum.
Pharmacological therapies for TS have traditionally focused on dopamine mechanisms. However, just as research has implicated different areas of the brain in TS, different neurotransmitter systems interact and overlap to contribute to the pathophysiology of TS. Salient interactions include those between dopamine and glutamate, dopamine and serotonin, and dopamine and gamma-aminobutyric acid (GABA).
Several potential pharmacotherapeutic targets for TS emerged during the workshop. These include compounds targeting monoaminergic systems (e.g., D1 receptor antagonists, serotonin agonists, or selective serotonin reuptake inhibitors), agents that regulate the prefrontal glutamatergic drive to the nucleus accumbens (e.g., N-acetylcysteine, modafinil), and agents that reinstate GABA receptor function or enhance GABA activity. The application of brain imaging, particularly between sibling pairs, and better identification of the genes involved in TS (e.g., SLITRK1) will facilitate and refine therapeutic approaches.
In order to better position the TS field to make substantial progress in translating research from the bench to the bedside, several individuals investigating other human disorders presented their experiences with coordinating and accelerating the therapy development process. One particular strategy that may bring TS therapeutics to the clinic relatively quickly and easily is to identify new applications for approved drugs or drugs that went through clinical trials but failed to receive FDA approval. Additionally, the NIH offers several resources to facilitate translational research.
Looking to the Future
In the concluding discussions, the workshop participants recognized two difficulties that hamper TS drug development: (1) there is no animal model of TS for preclinical analysis, and (2) it is difficult to enroll large clinical trials to assess a particular therapeutic intervention. To circumvent these difficulties, participants suggested the formation of a collaborative pilot study group to perform small experimental trials in people with TS in order to cultivate larger trials of appropriate drugs in appropriate patients. The formation of a pilot study consortium would serve to augment the TSA International Genetics Consortium, the TSA Behavioral Sciences Consortium, and the TSA Neuroimaging Consortium already in existence. Participants also stressed that larger clinical trials must be thoughtfully designed to enable researchers to discern which subgroups of people with TS (e.g., based on genetic polymorphisms, functional imaging profile, the type and severity of tics) derive benefit from a given therapeutic intervention. In addition, some suggested that other measures of improvement, aside from tics, be included in such analyses, such as improvements in quality of life. These ideas have the opportunity to gain further momentum since the TSA is planning another meeting in early 2007 that will focus on pragmatic approaches to clinical trial design and treatment exploration.
1. Leckman JF, Peterson BJ, Pauls DL, Cohen DJ (1997). Tic disorder. Psychiatric Clinics of North America, 20: 839-861.