Tourette Syndrome Association Neuroimaging Consortium Pilot Study

Sponsored by TSA-WU-12-91.

Important research on Tourette Syndrome (TS) is proceeding along several fronts, from gene-hunting to controlled trials of new treatments. The TSA has fostered collaborative research in these areas among several centers of excellence. The TSA Genetics Consortium and the TSA Behavioral Sciences Consortium have delivered remarkable results. For example, the Behavioral Sciences Consortium delivered a 1700 percent return on TSA's investment, producing $6 million in NIH research funding from an initial TSA investment of about $330,000. At the same time the consortium improved an existing treatment, published a treatment manual, and conclusively demonstrated the treatment's effectiveness. Recruitment for the treatment study in children proceeded quickly, but three academic centers were needed to keep up that pace. Similar success was seen in the study of adults with tics, which ran simultaneously thanks to participation of an additional three sites. By laying the groundwork for a successful collaboration, TSA produced two of the largest tic treatment studies ever completed, and did so at remarkable speed.

Similar success may result from bringing multicenter collaborative TS research to neuroimaging. Neuroimaging studies have contributed to our understanding of TS pathophysiology, but essentially all of these research studies were performed in isolation, each at a single site. There are scientific obstacles that may have driven that isolation. Methods for brain imaging are complex and in some cases equivalent scans simply cannot be performed on magnets from different MRI manufacturers. Additional complications include subtle but consistent inter-site differences in image acquisition and reconstruction, subject placement, noise volume, brightness of visual stimulus presentation, and so on. However, recent developments have allowed successful multicenter collaborative brain imaging studies in Alzheimer's disease and schizophrenia.

This raises the question, what important questions about TS could best be answered by a multicenter imaging study? We discuss this question in detail below, but examples include the following: What is the developmental course of the delayed and aberrant functional connectivity recently demonstrated in TS adolescents? What clinical features are most closely associated with these findings? Can we predict which children with recent-onset tics will go on to develop a chronic tic disorder, compared to the majority whose tics will disappear forever after a few months? Why do some children with chronic tic disorders, but not others, outgrow them in adulthood? How does behavior therapy such as CBIT affect the brain, and do subject factors such as brain activity predict who will respond? Together, the PIs and collaborators have expertise and funding in these areas, and these are studies whose completion could be substantially speeded with a multi-site design.

However, the first step is to demonstrate that we can collect and analyze data of high quality across several sites. Scientists from the fBIRN (Function Biomedical Informatics Research Network) neuroimaging consortium, discussing the challenges of multisite MRI studies, concluded it is highly recommended that you conduct a methodological inter-site reliability study before you proceed with the main (scientifically substantive) study. We agree with this advice.

Therefore we propose to develop a TS neuroimaging consortium at a few carefully selected sites, demonstrate that we can achieve adequate quality control so that our results are reliable whether done at one center or another, and show that including more than one site boosts the overall recruitment rate. We will also develop procedures that will allow other sites to qualify to join the consortium. In the process we will gather the required preliminary data to apply to NIH for funding of a multicenter neuroimaging study of TS.

Hypotheses:

• Multicenter TS imaging studies have practical advantages and are scientifically appropriate:
  • Recruitment rate and demographic diversity are improved by adding research sites;
  • With careful, prospective quality control, the methods proposed for this study can be implemented reliably across several sites.

Specific Aims:

• Demonstrate feasibility and reliability of methods across sites:
  • Demonstrate increased rate of recruitment by a multi-site approach; and
  • Demonstrate cross-site reliability of clinical, MRI and other experimental measures.
• Create rules and structures that will facilitate:
  • Continued peaceful and efficient collaboration across sites, and
  • An orderly and appropriate process whereby additional sites may join the consortium.
• Write an application for NIH funding of a multisite study of TS.