TICS: Transcranial Magnetic Stimulation for Children With Tourette's Syndrome
Phase: NA
Conditions: Tourette Syndrome
Sponsor: University of Calgary

                       
                                 
 
	  
	  
	  
Hotchkiss	  Brain	  Institute	  /	  Mathison	  Centre	  Pilot	  Research	  Fund	  Program	  (PFUN)	  
Application	  Form	  	  
Funding	  Competition	  2014	  
Deadline:	  December	  17,	  2014	  
	  
Instructions:	  Please	  complete	  all	  relevant	  sections	  and	  submit	  this	  form	  electronically	  to	  csjahrau@ucalgary.ca	  and	  
meredith.maloney@albertahealthservices.ca	  in	  either	  PDF	  or	  Word	  format.	  Please	  also	  include	  with	  your	  application	  a	  
Letter	  of	  Support	  from	  the	  Mathison	  Centre	  Director,	  outlining	  the	  benefits	  of	  the	  proposed	  research	  to	  their	  program,	  
and	  the	  roles	  of	  the	  pilot	  study	  within	  the	  larger	  research	  program.	  
	  
	  
	  
Principal	  Investigator:	  	  Frank	  P.	  MacMaster,	  PhD	  
Department/Affiliation:	  	  Psychiatry	  &	  Pediatrics	  
HBI	  Program:	  Brain	  &	  Behavior	  
Telephone:	  (403)	  955-­‐2784	  
Email:	  fmacmast@ucalgary.ca	  
Signature:	  
	  
	  
Co-­‐Investigators	  
Department	  
Signature	  
	  
Dr.	  Tamara	  M.	  Pringsheim	  
Clinical	  Neurosciences,	  Psychiatry,	  
Pediatrics	  and	  Community	  Health	  
Sciences	  
	  
	  
Dr.	  Adam	  Kirton	  
	  
Pediatrics	  and	  Clinical	  Neurosciences	  
	  
	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  	  
	  
Dr.	  Paul	  E.	  Croarkin	  
	  
Mayo	  Clinic	  
	  
	  
	  
Dr.	  Lisa	  Marie	  Langevin	  
	  
Psychiatry	  
	  
	  
	  
*	  The	  signature	  of	  each	  team	  member	  is	  required	  to	  indicate	  their	  willingness	  to	  participate	  in	  the	  project.	  This	  
requirement	  can	  also	  be	  met	  through	  the	  submission	  of	  a	  separate	  letter	  from	  the	  team	  member	  confirming	  their	  
involvement.	  	  
	  
Department	  Head:	  
	  
Name:	  	  	  Dr.	  Beverly	  L.	  Adams	  	  	  	  	  	  	  
	  
	  
Signature:	  	  
	  
	  
	  
	  
	  
	  
	  
*	  My	  signature	  above	  acknowledges	  and	  accepts	  the	  impact	  (clinical,	  financial,	  or	  otherwise)	  of	  this	  research	  on	  my	  
department/division/program/portfolio	  and	  I	  agree	  with	  the	  costs	  itemized	  in	  the	  study	  budget.	  
	  
Project	  Title:	  TICS:	  Transcranial	  Magnetic	  Stimulation	  for	  Children	  with	  Tourette’s	  Syndrome	  

                       
                                 
 
	  
1.	  Objectives:	  Tourette’s	  Syndrome	  (TS)	  is	  a	  neuropsychiatric	  disorder	  characterized	  by	  brief,	  repetitive	  movements	  and	  
vocalizations	  called	  tics.	  The	  effects	  of	  TS	  in	  children	  and	  youth	  are	  far-­‐reaching,	  with	  academic,	  occupational,	  and	  social	  
implications.	  Current	  treatments	  for	  TS	  remain	  limited,	  both	  in	  scope	  and	  efficacy.	  Pharmaceuticals	  prescribed	  to	  control	  
tics	  often	  have	  severe	  side	  effects	  with	  suboptimal	  benefit	  [1].	  Behavior	  therapy	  has	  limited	  efficacy	  in	  children	  and	  is	  
difficult	  for	  patients	  to	  access.	  Hence,	  there	  exists	  a	  salient	  need	  for	  the	  development	  of	  safe,	  accessible,	  and	  effective	  
treatments	  for	  young	  people	  with	  TS.	  Indeed,	  a	  recent	  study	  has	  suggested	  that	  the	  maturational	  reduction	  in	  tic	  
frequency	  that	  is	  sometimes	  seen	  in	  TS	  is	  due	  to	  a	  conscious	  effort	  directed	  at	  tic	  suppression,	  which	  develops	  over	  
time.	  Tic	  suppression	  is	  associated	  with	  an	  increase	  in	  tonic	  inhibition	  in	  the	  supplementary	  motor	  area	  (SMA),	  and	  
correlates	  with	  increased	  GABA	  neurotransmission	  and	  levels	  [2].	  Consequently,	  the	  SMA	  is	  a	  direct	  target	  for	  
therapeutic	  intervention.	  Repetitive	  transcranial	  magnetic	  stimulation	  (rTMS)	  involves	  a	  safe,	  non-­‐invasive	  application	  of	  
a	  magnetic	  field	  to	  a	  target	  brain	  area	  in	  order	  to	  change	  its	  activity	  and	  function.	  Our	  central	  hypothesis	  is	  that	  low	  
frequency	  rTMS,	  targeted	  to	  the	  SMA,	  will	  reduce	  tic	  severity	  through	  the	  potentiation	  of	  cortical	  GABAergic	  
neurotransmission.	  We	  propose	  the	  following	  specific	  objectives:	  
(Aim	  1)	  To	  characterize	  the	  effect	  of	  low	  frequency	  rTMS	  of	  the	  SMA	  on	  TS	  symptoms.	  We	  hypothesize	  that	  TS	  
symptom	  severity	  (as	  measured	  by	  the	  Yale	  Global	  Tic	  severity	  Scale	  or	  YGTSS)	  will	  decrease	  with	  low	  frequency	  rTMS	  
targeting	  the	  SMA.	  
(Aim	  2)	  To	  identify	  TMS-­‐mediated	  alterations	  in	  brain	  metabolites	  and	  functional	  connectivity	  that	  serve	  to	  normalize	  
cortical	  activity.	  We	  further	  hypothesize	  that	  improvement	  in	  TS	  symptoms	  will	  be	  moderated	  by	  TMS-­‐induced	  changes	  
in	  GABA	  and	  glutamate	  in	  the	  SMA	  assessed	  with	  proton	  magnetic	  resonance	  spectroscopy	  (1HMRS),	  potentiation	  of	  
GABAergic	  neurotransmission	  assessed	  with	  short-­‐interval	  cortical	  inhibition	  (SICI),	  and	  changes	  in	  the	  functional	  
connectivity	  between	  the	  SMA	  and	  primary	  motor	  cortex.	  
	  
2.	  Background:	  Tics	  in	  TS	  are	  thought	  to	  arise	  from	  1)	  dysregulation	  of	  excitation/inhibition	  in	  brain	  regions	  related	  to	  
motor	  function,	  and	  2)	  alterations	  in	  specific	  brain	  chemistry	  that	  potentiates	  overexcitability	  in	  the	  primary	  motor	  
cortex	  (M1),	  via	  input	  from	  the	  SMA.	  This	  results	  in	  the	  activation	  of	  striatal	  neurons,	  and	  hyper-­‐excitation	  of	  the	  M1,	  
leading	  to	  the	  expression	  of	  tics.	  It	  is	  hypothesized	  that	  TS	  is	  also	  associated	  with	  a	  reduction	  in	  GABA	  transmission	  
within	  the	  SMA	  and	  M1	  [3].	  One	  technique	  that	  has	  shown	  promise	  in	  normalizing	  brain	  function	  and	  reducing	  
symptoms	  of	  TS	  in	  children	  and	  adults	  is	  rTMS.	  While	  initial	  experiences	  with	  varied	  approaches	  were	  not	  encouraging	  
[4]	  [5]	  	  an	  effective	  approach	  is	  emerging	  	  [6]	  [7]	  [8].	  Furthermore,	  it	  is	  not	  known	  what	  effects	  this	  technique	  has	  on	  the	  
concentration	  of	  brain	  metabolites	  that	  mediate	  cortical	  hyperactivity	  and	  inhibitory	  neurotransmission.	  In	  this	  study,	  
we	  aim	  to	  investigate	  whether	  low	  frequency	  rTMS	  can	  improve	  TS	  symptoms	  in	  a	  pediatric	  population,	  and	  what	  effects	  
this	  technique	  has	  on	  the	  concentration	  of	  brain	  metabolites	  that	  mediate	  cortical	  hyperactivity.	  
	  
3.	  Novelty	  (What	  will	  we	  learn	  that	  we	  don’t	  already	  know?):	  The	  neurobiological	  study	  of	  the	  novel	  application	  of	  
rTMS	  in	  pediatric	  TS	  allows	  us	  to	  map	  the	  trajectory	  of	  adaptive	  changes	  in	  the	  brains	  of	  children	  with	  TS,	  and	  to	  attempt	  
to	  speed	  up	  these	  processes	  as	  they	  relate	  to	  decreasing	  cortical	  hyper-­‐excitability,	  modulating	  GABAergic	  
neurotransmission,	  increasing	  inhibitory	  metabolite	  levels	  within	  affected	  brain	  regions.	  Our	  multimodal	  approach	  
allows	  us	  to	  gain	  critical	  insight	  into	  the	  structural,	  functional,	  and	  metabolic	  correlates	  of	  TS	  symptoms	  within	  the	  
pediatric	  brain,	  an	  area	  that	  currently	  remains	  underexplored.	  
	  
4.	  Methods	  	  
Sample:	  A	  pilot	  cohort	  of	  11	  males	  with	  TS	  (7-­‐12	  years,	  right	  handed,	  no	  comorbid	  ADHD)	  will	  be	  recruited	  through	  the	  
Calgary	  Tourette	  Syndrome	  Clinic	  (Alberta	  Children’s	  Hospital,	  Calgary,	  Alberta).	  Participants	  will	  continue	  prescribed	  
medication	  regimes	  during	  the	  trial	  at	  the	  discretion	  of	  individual	  medical	  care	  professionals.	  
Measurements:	  To	  establish	  diagnosis	  and	  ascertain	  treatment	  response,	  we	  will	  conduct	  assessments	  at	  baseline,	  
weekly	  during	  treatment	  (including	  the	  final	  week)	  and	  at	  8	  week	  and	  6	  month	  follow-­‐ups.	  Measures	  used	  include	  the	  
Yale	  Global	  Tic	  severity	  Scale	  (YGTSS),	  Present	  and	  Lifetime	  version	  of	  the	  Kiddie	  Schedule	  for	  Affective	  Disorders	  and	  
Schizophrenia	  (K-­‐SADS-­‐PL),	  Multidimensional	  Anxiety	  Scale	  for	  Children,	  the	  Children’s	  Depression	  Rating	  Scale-­‐Revised,	  
and	  the	  General	  Behavior	  Inventory	  (P-­‐GBI).	  

                       
                                 
 
	  
MRI	  Acquisition:	  Participants	  will	  undergo	  both	  baseline	  and	  post-­‐treatment	  MRI	  scans.	  MR	  data	  will	  be	  acquired	  on	  a	  
GE	  3T	  Discovery	  750W	  scanner,	  and	  include	  a	  high-­‐resolution	  anatomical	  scan	  for	  use	  in	  the	  rTMS	  procedure.	  Voxels	  
within	  the	  M1	  and	  SMA	  will	  be	  targeted	  by	  short	  echo	  (TE=	  30msec,	  TR	  =	  2000	  msec)	  and	  MEGA	  PRESS	  proton	  magnetic	  
resonance	  spectroscopy	  (1H-­‐MRS)	  protocols.	  Analysis	  of	  MRS	  will	  be	  completed	  using	  the	  LCModel	  method,	  which	  
converts	  the	  in	  vivo	  spectrum	  to	  a	  linear	  combination	  model	  for	  each	  metabolic	  solution	  [9,	  10].	  The	  SMA	  will	  be	  
confirmed	  during	  the	  scan	  with	  a	  brief	  right	  and	  left	  finger	  tapping	  functional	  magnetic	  resonance	  imaging	  (fMRI)	  task	  
[11].	  We	  will	  also	  collect	  resting	  state	  fMRI	  and	  diffusion	  tensor	  imaging	  (DTI).	  Total	  time	  in	  the	  scanner	  is	  less	  than	  60	  
minutes.	  Our	  established	  acquisition	  is	  well	  tolerated	  from	  ages	  5	  through	  adulthood.	  
Single	  and	  Paired-­‐Pulse	  TMS	  (Neurophysiology):	  Using	  established	  lab	  protocols,	  the	  following	  motor	  neurophysiology	  
measures	  (and	  their	  possible	  neurotransmitter	  system	  correlates)	  will	  be	  defined	  for	  M1	  bilaterally	  at	  baseline	  and	  1	  
week	  post-­‐intervention:	  rest	  and	  active	  motor	  thresholds	  (RMT,	  AMT),	  stimulus	  response	  curve	  (100-­‐150%RMT),	  short-­‐
interval	  intracortical	  inhibition	  (SICI,	  GABAA),	  cortical	  silent	  period	  (cSP,	  GABAB),	  ipsilateral	  silent	  period	  (iSP,	  
interhemispheric	  inhibition),	  and	  intracortical	  facilitation	  (ICF,	  glutamatergic	  NMDA)[12].	  	  
Low-­‐Frequency	  rTMS	  (Neuromodulation):	  Baseline	  T1	  MR	  images	  will	  allow	  individualized	  neuronavigation	  (Brainsight	  
2,	  Rogue	  Research,	  Montreal	  QC)	  to	  coregister	  the	  rTMS	  Airfilm	  coil	  (Magistim,	  UK)	  precisely	  to	  the	  SMA	  as	  defined	  by	  
fMRI.	  Interventional	  rTMS	  parameters	  will	  be:	  intensity	  100%	  RMT,	  frequency	  1Hz,	  duration	  20	  minutes	  (1200	  
stimulations).	  Treatments	  will	  occur	  on	  each	  weekday	  at	  the	  same	  time	  of	  day	  for	  three	  weeks	  (15	  total).	  
Analysis:	  Statistical	  analyses	  will	  be	  performed	  using	  SPSS	  for	  Windows	  22.0	  (SPSS	  Inc.,	  Chicago,	  IL).	  For	  aim	  1,	  to	  test	  for	  
differences	  in	  tic	  symptoms	  (YGTSS)	  with	  rTMS,	  a	  repeated	  measures	  analysis	  of	  variance	  (rmANOVA)	  will	  be	  performed.	  
A	  similar	  approach	  will	  be	  used	  for	  assessing	  glutamate	  concentration	  in	  the	  SMA,	  SICI,	  ICF,	  CSP	  (Aim	  2).	  Furthermore	  for	  
Aim	  2,	  functional	  connectivity	  changes	  with	  rTMS	  will	  be	  examined	  using	  Statistical	  Parametric	  Mapping	  (SPM)	  
approaches.	  Pearson	  correlations	  between	  clinical	  and	  neurobiological	  variables	  controlling	  for	  age	  will	  be	  explored.	  
	  
5.	  Sample	  size	  with	  justification:	  Estimating	  the	  sample	  size	  needed	  was	  based	  on	  similar	  studies.	  For	  the	  primary	  
outcome	  measure	  (aim	  1)	  of	  a	  reduction	  in	  tic	  severity	  (Yale	  Global	  Total	  Tic	  Severity	  Scale),	  we	  set	  p	  <	  0.05	  (two	  tailed),	  
d	  =	  0.47,	  power	  =	  0.80,	  rendering	  a	  need	  for	  a	  minimum	  of	  10	  subjects.	  Clinically	  meaningful	  change	  in	  the	  YGTSS	  will	  be	  
defined	  at	  a	  23%	  or	  greater	  reduction	  in	  total	  score	  [13].	  
	  
6.	  Anticipated	  Results:	  We	  predict	  this	  novel	  treatment	  will	  demonstrate	  reduction	  in	  tic	  severity	  and	  intrusiveness.	  
Potential	  pitfalls	  include	  (1)	  intolerance	  to	  rTMS,	  (2)	  inadequate	  MRI	  data	  quality	  and	  (3)	  non-­‐response	  to	  treatment.	  For	  
TMS	  tolerability,	  most	  do	  very	  well,	  with	  a	  low	  incidence	  of	  side	  effects	  [14].	  Moreover,	  low	  frequency	  rTMS	  is	  the	  most	  
well	  tolerated	  type	  of	  rTMS.	  With	  regard	  to	  motion	  during	  the	  MR	  scan,	  our	  group	  has	  scanned	  over	  200	  subjects	  at	  the	  
Alberta	  Children’s	  Hospital	  to	  date.	  Data	  loss	  from	  motion	  accounts	  for	  less	  than	  5%.	  To	  improve	  data	  quality,	  we	  have	  a	  
mock	  scanner	  that	  helps	  acclimatize	  children	  to	  the	  scanning	  procedure.	  Given	  our	  collaboration	  with	  the	  Calgary	  
Tourette	  Syndrome	  clinic,	  we	  anticipate	  robust	  recruitment	  (over	  1,000	  patients	  associated	  with	  the	  clinic).	  
	  
7.	  Likelihood	  of	  Generating	  New	  Funding:	  In	  Canada,	  there	  are	  only	  5	  active	  operating	  CIHR	  grants	  with	  any	  conceptual	  
relationship	  (however	  remote)	  with	  TS.	  Only	  two	  examine	  treatment	  (both	  behavioral	  interventions)	  and	  only	  one	  
targets	  children,	  but	  simply	  as	  a	  sub-­‐population.	  ClinicalTrials.gov	  has	  only	  two	  actively	  recruiting	  studies	  of	  TS	  listed	  in	  
Canada	  as	  well	  (physical	  activity,	  pharmacological).	  Despite	  the	  severity,	  prevalence,	  onset	  in	  childhood,	  and	  
limitations	  of	  current	  interventions,	  there	  is	  little	  active	  research	  in	  TS	  in	  children.	  Furthermore,	  despite	  the	  recent	  
evidence	  described	  above	  implicating	  the	  SMA	  and	  indicating	  the	  promise	  of	  rTMS,	  no	  study	  is	  currently	  combining	  
neurobiological	  measures	  with	  brain	  stimulation	  to	  target	  symptoms	  in	  TS.	  We	  believe,	  given	  our	  infrastructure	  and	  
expertise,	  we	  are	  well	  suited	  to	  take	  leadership	  in	  this	  area	  internationally.	  Initial	  data	  will	  be	  applied	  to	  funding	  
applications	  for	  the	  Thrasher	  foundation	  ($300,000	  over	  3	  years)	  and	  the	  Tourette	  Syndrome	  Association	  Research	  Grant	  
($150,000	  over	  2	  years).	  Similar	  funding	  will	  be	  sought	  from	  CIHR,	  AIHS,	  and	  NIH	  as	  appropriate.	  We	  have	  also	  formed	  a	  
new	  collaboration	  with	  the	  Mayo	  Clinic,	  University	  of	  Cincinnati,	  CAMH,	  and	  others	  through	  our	  CAIRNS	  (Child	  and	  
Adolescent	  International	  Research	  into	  Neuro-­‐Stimulation)	  research	  program.	  This	  collaboration	  can	  help	  in	  developing	  
larger	  scale	  trials.	  	  

                       
                                 
 
	  
Budget	  (How	  will	  the	  funds	  be	  spent?	  Include	  discussion	  of	  overlap	  with	  existing	  projects,	  if	  appropriate.	  Provide	  
a	  justification	  and	  indicate	  the	  amount	  to	  be	  spent	  on	  each	  budget	  item).	  
	  
Personnel	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
	  
Overlap	  
There	  is	  no	  overlap	  with	  existing	  projects.	  This	  direction	  into	  Tourette’s	  Syndrome	  is	  entirely	  novel.	  
Please	  note	  that	  supplementary	  or	  “top-­‐up”	  funding	  is	  not	  permitted	  for	  this	  competition;	  projects	  must	  explore	  a	  
new	  avenue	  of	  research	  for	  the	  investigator.	  	  
Are	  there	  any	  other	  sources	  of	  funding?	  Yes:	  X	  -­‐	  If	  yes,	  from	  where:	  Dr.	  MacMaster’s	  start	  up	  funds	  ($4,950)	  
References:	  
1.	  
Pringsheim	  T,	  et	  al;	  Canadian	  journal	  of	  psychiatry	  Revue	  canadienne	  de	  psychiatrie	  2012,	  57(3):133-­‐143.	  
2.	  
Draper	  A,	  et	  al;	  Current	  biology	  :	  CB	  2014,	  24(19):2343-­‐2347.	  
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Franzkowiak	  S	  et	  al;	  PloS	  one	  2012,	  7(1):e27850.	  
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20(2):257-­‐262.	  
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Kwon	  HJ	  et	  al;	  Neuroscience	  letters	  2011,	  492(1):1-­‐4.	  
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Mantovani	   A	   et	   al;	   The	   international	   journal	   of	   neuropsychopharmacology	   /	   official	   scientific	   journal	   of	   the	  
Collegium	  Internationale	  Neuropsychopharmacologicum	  2006,	  9(1):95-­‐100.	  
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Provencher	   SW.	   Magnetic	   resonance	   in	   medicine	   :	   official	   journal	   of	   the	   Society	   of	   Magnetic	   Resonance	   in	  
Medicine	  /	  Society	  of	  Magnetic	  Resonance	  in	  Medicine	  1993,	  30(6):672-­‐679.	  
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Provencher	  SW.	  NMR	  in	  biomedicine	  2001,	  14(4):260-­‐264.	  
11.	  
Hiroshima	  S	  et	  al;	  Neurologia	  medico-­‐chirurgica	  2014,	  54(7):511-­‐520.	  
12.	  
Bunse	  T	  et	  al;	  Brain	  stimulation	  2014,	  7(2):158-­‐169.	  
13.	  
Jeon	  S	  et	  al;	  Contemporary	  clinical	  trials	  2013,	  36(2):414-­‐420.	  
14.	  
Anderson	  B	  et	  al;	  The	  journal	  of	  ECT	  2006,	  22(1):49-­‐53.