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Accumulated evidence from pharmacological trials and postmortem analyses suggests that abnormalities of dopaminergic neurotransmission play a key role in the pathogenesis of TS. A substantial body of evidence has also accrued to implicate regions outside the striatum in the generation of tics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We initiated an [11C]FLB 457 positron emission tomography study in conjunction with an amphetamine challenge to evaluate extrastriatal dopamine (DA) D2\/D3 receptor binding and DA release in a group of treatment\u2010naive, adult TS patients compared with a group of age\u2010 and sex\u2010matched controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>At baseline, TS patients showed decreased [11C]FLB 457 binding potentials bilaterally in cortical and subcortical regions outside the striatum, including the cingulate gyrus, middle and superior temporal gyrus, occipital cortex, insula, and thalamus. Amphetamine challenge induced DA release in both control and TS subjects bilaterally in many cortical regions; however, in TS patients, regions of increased DA release were significantly more widespread and extended more anteriorly to involve anterior cingulate and medial frontal gyri. Conversely, and in contrast to healthy controls, no significant DA release was noted in the thalami of TS patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These abnormalities of dopaminergic function localize to brain regions previously implicated in TS and suggest a mechanism for the hyperexcitability of thalamocortical circuits that has been documented in the disorder. 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