Abstract
Tics are unique from most movement disorders, in that they are partially suppressible. As part of the inhibitory motor network, the pre-supplementary motor area is engaged in motor control and may be involved in tic physiology. We used dual-site transcranial magnetic stimulation to assess inhibitory connectivity between right pre-supplementary motor area and left primary motor cortex, which has previously been demonstrated in healthy adults. We also used diffusion tensor imaging to investigate white matter connectivity in children with chronic tics. Twelve children with chronic tic disorder and fourteen typically developing controls underwent MRI with diffusion tensor imaging indices analysis followed by single and paired-pulse transcranial magnetic stimulation with conditioning pulse over the right pre-supplementary motor area followed by left motor cortex test pulse. Neurophysiologic and imaging data relationships to measures of tic severity and suppressibility were also evaluated in tic patients. Pre-supplementary motor area-mediated inhibition of left motor cortex was present in healthy control children but not in chronic tic disorder participants. Less inhibition correlated with worse tic suppressibility (ρ = − 0.73, p = 0.047). Imaging analysis showed increased fractional anisotropy in the right superior longitudinal fasciculus, corpus callosum, corona radiata and posterior limb of the internal capsule (p < 0.05) in tic participants, which correlated with lower self-reported tic suppressibility (ρ = − 0.70, p = 0.05). Physiologic data revealed impaired frontal-mediated motor cortex inhibition in chronic tic participants, and imaging analysis showed abnormalities in motor pathways. Collectively, the neurophysiologic and neuroanatomic data correlate with tic suppressibility, supporting the relevancy to tic pathophysiology.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Availability of data and material
The data that support the findings of this study are available upon reasonable request.
References
American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders: DSM-5. American Psychiatric Association, Washington, D.C.
Arai N, Muller-Dahlhaus F, Murakami T, Bliem B, Lu MK, Ugawa Y, Ziemann U (2011) State-dependent and timing-dependent bidirectional associative plasticity in the human SMA-M1 network. J Neurosci 31:15376–15383. https://doi.org/10.1523/JNEUROSCI.2271-11.2011
Arai N, Lu MK, Ugawa Y, Ziemann U (2012) Effective connectivity between human supplementary motor area and primary motor cortex: a paired-coil TMS study. Exp Brain Res 220:79–87. https://doi.org/10.1007/s00221-012-3117-5
Aron AR (2011) From reactive to proactive and selective control: developing a richer model for stopping inappropriate responses. Biol Psychiatry 69:e55-68. https://doi.org/10.1016/j.biopsych.2010.07.024
Aron AR, Poldrack RA (2006) Cortical and subcortical contributions to Stop signal response inhibition: role of the subthalamic nucleus. J Neurosci 26:2424–2433. https://doi.org/10.1523/JNEUROSCI.4682-05.2006
Banaschewski T, Woerner W, Rothenberger A (2003) Premonitory sensory phenomena and suppressibility of tics in Tourette syndrome: developmental aspects in children and adolescents. Dev Med Child Neurol 45:700–703
Baumer T, Thomalla G, Kroeger J et al (2010) Interhemispheric motor networks are abnormal in patients with Gilles de la Tourette syndrome. Mov Disord 25:2828–2837. https://doi.org/10.1002/mds.23418
Behler N, Leitner B, Mezger E et al (2018) Cathodal tDCS over motor cortex does not improve Tourette syndrome: lessons learned from a case series. Front Behav Neurosci 12:194. https://doi.org/10.3389/fnbeh.2018.00194
Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate—a practical and powerful approach to multiple testing. J R Stat Soc Ser B Stat Methodol 57:289–300. https://doi.org/10.1111/j.2517-6161.1995.tb02031.x
Bohlhalter S, Goldfine A, Matteson S et al (2006) Neural correlates of tic generation in Tourette syndrome: an event-related functional MRI study. Brain 129:2029–2037
Bozkurt B, Yagmurlu K, Middlebrooks EH et al (2016) Microsurgical and tractographic anatomy of the supplementary motor area complex in humans. World Neurosurg 95:99–107. https://doi.org/10.1016/j.wneu.2016.07.072
Carvalho S, Goncalves OF, Soares JM, Sampaio A, Macedo F, Fregni F, Leite J (2015) Sustained effects of a neural-based intervention in a refractory case of Tourette syndrome. Brain Stimul 8:657–659. https://doi.org/10.1016/j.brs.2014.12.008
Chouinard PA, Paus T (2010) What have we learned from “perturbing” the human cortical motor system with transcranial magnetic stimulation? Front Hum Neurosci 4:173. https://doi.org/10.3389/fnhum.2010.00173
Civardi C, Cantello R, Asselman P, Rothwell JC (2001) Transcranial magnetic stimulation can be used to test connections to primary motor areas from frontal and medial cortex in humans. Neuroimage 14:1444–1453. https://doi.org/10.1006/nimg.2001.0918
Conelea CA, Woods DW, Zinner SH et al (2011) Exploring the impact of chronic tic disorders on youth: results from the Tourette syndrome impact survey. Child Psychiatry Hum Dev 42:219–242. https://doi.org/10.1007/s10578-010-0211-4
Conforto AB, Z’Graggen WJ, Kohl AS, Rosler KM, Kaelin-Lang A (2004) Impact of coil position and electrophysiological monitoring on determination of motor thresholds to transcranial magnetic stimulation. Clin Neurophysiol 115:812–819. https://doi.org/10.1016/j.clinph.2003.11.010
Cubo E (2012) Review of prevalence studies of tic disorders: methodological caveats. Tremor Other Hyperkinet Mov (N Y) 2
Cunnington R, Windischberger C, Deecke L, Moser E (2002) The preparation and execution of self-initiated and externally-triggered movement: a study of event-related fMRI. Neuroimage 15:373–385. https://doi.org/10.1006/nimg.2001.0976
Cunnington R, Windischberger C, Moser E (2005) Premovement activity of the pre-supplementary motor area and the readiness for action: studies of time-resolved event-related functional MRI. Hum Mov Sci 24:644–656. https://doi.org/10.1016/j.humov.2005.10.001
Debes N, Jeppesen S, Raghava JM, Groth C, Rostrup E, Skov L (2015) Longitudinal magnetic resonance imaging (MRI) analysis of the developmental changes of Tourette syndrome reveal reduced diffusion in the cortico-striato-thalamo-cortical pathways. J Child Neurol 30:1315–1326. https://doi.org/10.1177/0883073814560629
Draganski B, Martino D, Cavanna AE et al (2010) Multispectral brain morphometry in Tourette syndrome persisting into adulthood. Brain 133:3661–3675. https://doi.org/10.1093/brain/awq300
Draper A, Stephenson MC, Jackson GM, Pepes S, Morgan PS, Morris PG, Jackson SR (2014) Increased GABA contributes to enhanced control over motor excitability in Tourette syndrome. Curr Biol 24:2343–2347. https://doi.org/10.1016/j.cub.2014.08.038
Dum RP, Strick PL (1991) The origin of corticospinal projections from the premotor areas in the frontal lobe. J Neurosci 11:667–689
DuPaul GJ (1998) ADHD rating scale-IV: checklists, norms, and clinical interpretation. Guilford Press, New York
Eichele H, Plessen KJ (2013) Neural plasticity in functional and anatomical MRI studies of children with Tourette syndrome. Behav Neurol 27:33–45. https://doi.org/10.3233/BEN-120294
Ferbert A, Priori A, Rothwell JC, Day BL, Colebatch JG, Marsden CD (1992) Interhemispheric inhibition of the human motor cortex. J Physiol 453:525–546. https://doi.org/10.1113/jphysiol.1992.sp019243
Filevich E, Kuhn S, Haggard P (2012) Negative motor phenomena in cortical stimulation: implications for inhibitory control of human action. Cortex 48:1251–1261. https://doi.org/10.1016/j.cortex.2012.04.014
Fiori F, Chiappini E, Soriano M, Paracampo R, Romei V, Borgomaneri S, Avenanti A (2016) Long-latency modulation of motor cortex excitability by ipsilateral posterior inferior frontal gyrus and pre-supplementary motor area. Sci Rep 6:38396. https://doi.org/10.1038/srep38396
Franzkowiak S, Pollok B, Biermann-Ruben K et al (2012) Motor-cortical interaction in Gilles de la Tourette syndrome. PLoS ONE 7:e27850. https://doi.org/10.1371/journal.pone.0027850
Govindan RM, Makki MI, Wilson BJ, Behen ME, Chugani HT (2010) Abnormal water diffusivity in corticostriatal projections in children with Tourette syndrome. Hum Brain Mapp 31:1665–1674. https://doi.org/10.1002/hbm.20970
Greene DJ, Schlaggar BL, Black KJ (2015) Neuroimaging in Tourette syndrome: research highlights From 2014–2015. Curr Dev Disord Rep 2:300–308. https://doi.org/10.1007/s40474-015-0062-6
Hampson M, Tokoglu F, King RA, Constable RT, Leckman JF (2009) Brain areas coactivating with motor cortex during chronic motor tics and intentional movements. Biol Psychiatry 65:594–599. https://doi.org/10.1016/j.biopsych.2008.11.012
Hua K, Zhang J, Wakana S et al (2008) Tract probability maps in stereotaxic spaces: analyses of white matter anatomy and tract-specific quantification. Neuroimage 39:336–347. https://doi.org/10.1016/j.neuroimage.2007.07.053
Ikeda A, Yazawa S, Kunieda T et al (1999) Cognitive motor control in human pre-supplementary motor area studied by subdural recording of discrimination/selection-related potentials. Brain 122(Pt 5):915–931. https://doi.org/10.1093/brain/122.5.915
Jackson SR, Parkinson A, Manfredi V, Millon G, Hollis C, Jackson GM (2013) Motor excitability is reduced prior to voluntary movements in children and adolescents with Tourette syndrome. J Neuropsychol 7:29–44. https://doi.org/10.1111/j.1748-6653.2012.02033.x
Kim JH, Lee JM, Jo HJ et al (2010) Defining functional SMA and pre-SMA subregions in human MFC using resting state fMRI: functional connectivity-based parcellation method. Neuroimage 49:2375–2386. https://doi.org/10.1016/j.neuroimage.2009.10.016
Kukaswadia S, Wagle-Shukla A, Morgante F, Gunraj C, Chen R (2005) Interactions between long latency afferent inhibition and interhemispheric inhibitions in the human motor cortex. J Physiol 563:915–924. https://doi.org/10.1113/jphysiol.2004.080010
Kunieda T, Ikeda A, Ohara S et al (2000) Different activation of presupplementary motor area, supplementary motor area proper, and primary sensorimotor area, depending on the movement repetition rate in humans. Exp Brain Res 135:163–172. https://doi.org/10.1007/s002210000519
Kurlan R, McDermott MP, Deeley C et al (2001) Prevalence of tics in schoolchildren and association with placement in special education. Neurology 57:1383–1388
Landeros-Weisenberger A, Mantovani A, Motlagh MG, de Alvarenga PG, Katsovich L, Leckman JF, Lisanby SH (2015) Randomized sham controlled double-blind trial of repetitive transcranial magnetic stimulation for adults with severe Tourette syndrome. Brain Stimul 8:574–581. https://doi.org/10.1016/j.brs.2014.11.015
Leckman JF, Riddle MA, Hardin MT, Ort SI, Swartz KL, Stevenson J, Cohen DJ (1989) The yale global tic severity scale: initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry 28:566–573
Leckman JF, Walker DE, Cohen DJ (1993) Premonitory urges in Tourette’s syndrome. Am J Psychiatry 150:98–102
Li CS, Huang C, Constable RT, Sinha R (2006) Imaging response inhibition in a stop-signal task: neural correlates independent of signal monitoring and post-response processing. J Neurosci 26:186–192. https://doi.org/10.1523/JNEUROSCI.3741-05.2006
Liu Y, Miao W, Wang J et al (2013) Structural abnormalities in early Tourette syndrome children: a combined voxel-based morphometry and tract-based spatial statistics study. PLoS ONE 8:e76105. https://doi.org/10.1371/journal.pone.0076105
Makki MI, Behen M, Bhatt A, Wilson B, Chugani HT (2008) Microstructural abnormalities of striatum and thalamus in children with Tourette syndrome. Mov Disord 23:2349–2356. https://doi.org/10.1002/mds.22264
Mars RB, Klein MC, Neubert FX, Olivier E, Buch ER, Boorman ED, Rushworth MF (2009) Short-latency influence of medial frontal cortex on primary motor cortex during action selection under conflict. J Neurosci 29:6926–6931. https://doi.org/10.1523/JNEUROSCI.1396-09.2009
Martino D, Delorme C, Pelosin E, Hartmann A, Worbe Y, Avanzino L (2017) Abnormal lateralization of fine motor actions in Tourette syndrome persists into adulthood. PLoS ONE 12:e0180812. https://doi.org/10.1371/journal.pone.0180812
Mills KR, Nithi KA (1997) Corticomotor threshold to magnetic stimulation: normal values and repeatability. Muscle Nerve 20:570–576
Misirlisoy E, Brandt V, Ganos C, Tubing J, Munchau A, Haggard P (2015) The relation between attention and tic generation in Tourette syndrome. Neuropsychology 29:658–665. https://doi.org/10.1037/neu0000161
Muller-Vahl KR, Riemann L, Bokemeyer S (2014) Tourette patients’ misbelief of a tic rebound is due to overall difficulties in reliable tic rating. J Psychosom Res 76:472–476. https://doi.org/10.1016/j.jpsychores.2014.03.003
Nachev P, Kennard C, Husain M (2008) Functional role of the supplementary and pre-supplementary motor areas. Nat Rev Neurosci 9:856–869. https://doi.org/10.1038/nrn2478
Neubert FX, Mars RB, Buch ER, Olivier E, Rushworth MF (2010) Cortical and subcortical interactions during action reprogramming and their related white matter pathways. Proc Natl Acad Sci U S A 107:13240–13245. https://doi.org/10.1073/pnas.1000674107
Neuner I, Kupriyanova Y, Stocker T et al (2010) White-matter abnormalities in Tourette syndrome extend beyond motor pathways. Neuroimage 51:1184–1193. https://doi.org/10.1016/j.neuroimage.2010.02.049
Picard N, Strick PL (1996) Motor areas of the medial wall: a review of their location and functional activation. Cereb Cortex 6:342–353
Picazio S, Veniero D, Ponzo V, Caltagirone C, Gross J, Thut G, Koch G (2014) Prefrontal control over motor cortex cycles at beta frequency during movement inhibition. Curr Biol 24:2940–2945. https://doi.org/10.1016/j.cub.2014.10.043
Rossi S, Hallett M, Rossini PM, Pascual-Leone A (2011) Screening questionnaire before TMS: an update. Clin Neurophysiol 122:1686. https://doi.org/10.1016/j.clinph.2010.12.037
Rushworth MF, Hadland KA, Paus T, Sipila PK (2002) Role of the human medial frontal cortex in task switching: a combined fMRI and TMS study. J Neurophysiol 87:2577–2592. https://doi.org/10.1152/jn.2002.87.5.2577
Saporta AS, Chugani HT, Juhasz C, Makki MI, Muzik O, Wilson BJ, Behen ME (2010) Multimodality neuroimaging in Tourette syndrome: alpha-[11C] methyl-l-tryptophan positron emission tomography and diffusion tensor imaging studies. J Child Neurol 25:336–342. https://doi.org/10.1177/0883073809339394
Scahill L, Riddle MA, McSwiggin-Hardin M et al (1997) Children’s Yale-Brown obsessive compulsive scale: reliability and validity. J Am Acad Child Adolesc Psychiatry 36:844–852
Serrien DJ, Orth M, Evans AH, Lees AJ, Brown P (2005) Motor inhibition in patients with Gilles de la Tourette syndrome: functional activation patterns as revealed by EEG coherence. Brain 128:116–125. https://doi.org/10.1093/brain/awh318
Shirota Y, Hamada M, Terao Y, Ohminami S, Tsutsumi R, Ugawa Y, Hanajima R (2012) Increased primary motor cortical excitability by a single-pulse transcranial magnetic stimulation over the supplementary motor area. Exp Brain Res 219:339–349. https://doi.org/10.1007/s00221-012-3095-7
Sigurdsson HP, Pepes SE, Jackson GM, Draper A, Morgan PS, Jackson SR (2018) Alterations in the microstructure of white matter in children and adolescents with Tourette syndrome measured using tract-based spatial statistics and probabilistic tractography. Cortex 104:75–89. https://doi.org/10.1016/j.cortex.2018.04.004
Smith SM, Nichols TE (2009) Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. Neuroimage 44:83–98. https://doi.org/10.1016/j.neuroimage.2008.03.061
Smith SM, Jenkinson M, Woolrich MW et al (2004) Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23(Suppl 1):S208-219. https://doi.org/10.1016/j.neuroimage.2004.07.051
Thomalla G, Siebner HR, Jonas M et al (2009) Structural changes in the somatosensory system correlate with tic severity in Gilles de la Tourette syndrome. Brain 132:765–777. https://doi.org/10.1093/brain/awn339
Wagner J, Wessel JR, Ghahremani A, Aron AR (2018) Establishing a right frontal beta signature for stopping action in scalp EEG: implications for testing inhibitory control in other task contexts. J Cogn Neurosci 30:107–118. https://doi.org/10.1162/jocn_a_01183
Wang Z, Maia TV, Marsh R, Colibazzi T, Gerber A, Peterson BS (2011) The neural circuits that generate tics in Tourette’s syndrome. Am J Psychiatry 168:1326–1337. https://doi.org/10.1176/appi.ajp.2011.09111692
Wen H, Liu Y, Wang J et al (2016) Combining tract- and atlas-based analysis reveals microstructural abnormalities in early Tourette syndrome children. Hum Brain Mapp 37:1903–1919. https://doi.org/10.1002/hbm.23146
Wolff N, Luehr I, Sender J, Ehrlich S, Schmidt-Samoa C, Dechent P, Roessner V (2016) A DTI study on the corpus callosum of treatment-naive boys with “pure” Tourette syndrome. Psychiatry Res Neuroimaging 247:1–8. https://doi.org/10.1016/j.pscychresns.2015.12.003
Woods DW, Piacentini J, Himle MB, Chang S (2005) Premonitory Urge for Tics Scale (PUTS): initial psychometric results and examination of the premonitory urge phenomenon in youths with Tic disorders. J Dev Behav Pediatr 26:397–403
Wu SW, Maloney T, Gilbert DL et al (2014) Functional MRI-navigated repetitive transcranial magnetic stimulation over supplementary motor area in chronic tic disorders. Brain Stimul 7:212–218. https://doi.org/10.1016/j.brs.2013.10.005
Xu B, Sandrini M, Wang WT et al (2016) PreSMA stimulation changes task-free functional connectivity in the fronto-basal-ganglia that correlates with response inhibition efficiency. Hum Brain Mapp 37:3236–3249. https://doi.org/10.1002/hbm.23236
Yazawa S, Ikeda A, Kunieda T et al (2000) Human presupplementary motor area is active before voluntary movement: subdural recording of Bereitschaftspotential from medial frontal cortex. Exp Brain Res 131:165–177. https://doi.org/10.1007/s002219900311
Zhang S, Ide JS, Li CS (2012) Resting-state functional connectivity of the medial superior frontal cortex. Cereb Cortex 22:99–111. https://doi.org/10.1093/cercor/bhr088
Acknowledgements
We appreciate participants and families who took time to participate in this study.
Funding
This research was supported in part by The Sage Foundation (Brighton, MI), Cincinnati Children’s Research Foundation, Tourette Association of America and National Institutes of Health.
Author information
Authors and Affiliations
Contributions
ABB: research project—organization and execution; statistical analysis—review and critique; manuscript preparation—writing of the first draft, review and critique. WY: research project—conception, organization, and execution; statistical analysis—design, execution, review and critique; manuscript preparation—review and critique. DLG: research project conception, and organization; statistical analysis—review and critique; manuscript preparation—review and critique. PSH: statistical analysis—design, execution, review and critique; manuscript preparation—review and critique. HSJ: research project—organization and execution. DAH: research project—organization and execution. SWW: research project—conception, organization, and execution; statistical analysis—design, execution, review and critique; manuscript preparation—writing, review and critique.
Corresponding author
Ethics declarations
Conflict of interest
DG has received honoraria and travel support from the Tourette Association of America and has received research support from the National Institutes of Health. PH has received research support through the National Institutes of Health. SW received funding support from Cincinnati Children’s Research Foundation, has received salary support from Tourette Association of America and the National Institute of Health, and received funding for equipment used in this study from The Sage Foundation (Brighton, MI). The rest of the authors have no disclosures relevant to this study. On behalf of all authors, the corresponding author states that there is no conflict of interest.
Ethics approval
This study was approved by the CCHMC Institutional Review Board.
Consent to participate
A parent or legal guardian of pediatric participants gave written informed consent. Children also gave written assent for the study.
Additional information
Communicated by Winston D Byblow.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Bruce, A.B., Yuan, W., Gilbert, D.L. et al. Altered frontal-mediated inhibition and white matter connectivity in pediatric chronic tic disorders. Exp Brain Res 239, 955–965 (2021). https://doi.org/10.1007/s00221-020-06017-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00221-020-06017-0