title: Corticostriatal Divergent Function in Determining the Temporal and Spatial Properties of Motor Tics.
abstract: Striatal disinhibition leads to the formation of motor tics resembling those expressed during Tourette syndrome and other tic disorders. The spatial properties of these tics are dependent on the location of the focal disinhibition within the striatum; however, the factors affecting the temporal properties of tic expression are still unknown. Here, we used microstimulation within the motor cortex of freely behaving rats before and after striatal disinhibition to explore the factors underlying the timing of individual tics. Cortical activation determined the timing of individual tics via an accumulation process of inputs that was dependent on the frequency and amplitude of the inputs. The resulting tics and their neuronal representation within the striatum were highly stereotypic and independent of the cortical activity properties. The generation of tics was limited by absolute and relative tic refractory periods that were derived from an internal striatal state. Thus, the precise time of the tic expression depends on the interaction between the summation of incoming excitatory inputs to the striatum and the timing of the previous tic. A data-driven computational model of corticostriatal function closely replicated the temporal properties of tic generation and enabled the prediction of tic timing based on incoming cortical activity and tic history. These converging experimental and computational findings suggest a clear functional dichotomy within the corticostriatal network, pointing to disparate temporal (cortical) versus spatial (striatal) encoding. Thus, the abnormal striatal inhibition typical of Tourette syndrome and other tic disorders results in tics due to cortical activation of the abnormal striatal network.
  
  
  CONCLUSIONS
  The factors underlying the temporal properties of tics expressed in Tourette syndrome and other tic disorders have eluded clinicians and scientists for decades. In this study, we highlight the key role of corticostriatal activity in determining the timing of individual tics. We found that cortical activation determined the timing of tics but did not determine their form. A data-driven computational model of the corticostriatal network closely replicated the temporal properties of tic generation and enabled the prediction of tic timing based on incoming cortical activity and tic history. This study thus shows that, although tics originate in the striatum, their timing depends on the interplay between incoming excitatory corticostriatal inputs and the internal striatal state.
authors.affiliation: The Leslie and Susan Goldschmied (Gonda) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors.forename: Michal
authors.identifier: http://orcid.org/0000-0001-8703-7946
authors.initials: M
authors.lastname: Israelashvili
authors.affiliation: The Leslie and Susan Goldschmied (Gonda) Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan 52900, Israel izhar.bar-gad@biu.ac.il.
authors.forename: Izhar
authors.identifier: http://orcid.org/0000-0002-2999-4083
authors.initials: I
authors.lastname: Bar-Gad
mesh_terms: D000465:Algorithms; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002540:Cerebral Cortex / Q000503:physiopathology*; D003198:Computer Simulation; D003342:Corpus Striatum / Q000503:physiopathology*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D008297:Male; D009415:Nerve Net / Q000503:physiopathology; D051381:Rats; D020318:Rats, Long-Evans; D012032:Refractory Period, Electrophysiological; D013239:Stereotyped Behavior; D020323:Tics / Q000503:physiopathology*; D005879:Tourette Syndrome / Q000503:physiopathology
chemical_list: D018756:GABA Antagonists; D001640:Bicuculline
keywords: Tourette syndrome; animal model; basal ganglia; motor cortex; tic