!!"#$

!%"&##&'($!""#$%$""""""""&"'()""

*"#$%$"""""""*"'()""

!"#"$%"&'(&")*&+,--./&

!%)*+#%$

+ =

MTOFF MTON MTR

!"##$%"&#"'•  (%)'*+,-#.'*/'

01++1/'.2,0#'•  3#4/#'567.'

89:;<=''

>  ?#.)'*/'@*@1'#.A+,)#'1&'B#+C#D*/,A1/''

>  3#)#0A1/'1&'D#.*1/.'E*)F*/'-"#C'+,G#"''

!

"#$%&'(#')%!*+#%,-&+!.#')!/"*.0!!

!"#

$%#

$!#

$&#

$'#

$"#

&%#

&!#

&&#

&'#

&"#

!(# &(# '(# "(# )%(#

!"#$%

&'"&

($)*+"$,-%+).

"&()/+%#0($"

1)"2%+"#%3))

,454))

*+,-./#.001.,234#56271#-.81,##

96271#-.81,#/1:2+3:##

;,1<#-.81,##

=+7+,#>.3?#@,1.##

!" #!" $!!" $#!" %!!" %#!" &!!"

!" #!" $!!" $#!" %!!" %#!" &!!"

'("

')""

')""

!"

*"$"

*"%"

*"&"

$"

%"

&"

!"

*"$"

*"%"

*"&"

$"

%"

&"+,-""./0(1"""

+,-""./0(1"""

2-3"4"5!'(""""

2-3"4"6&'(""""

!"#$

!"#$

!"#$%%$&'((

!")*+%"(

!"#$%%$&'((

!"#$%&'(#"%)'&'*#%

+,-.#%&'(#"%)'&'*#%

/01%

2-*,%

3$&4.0&5%

3676

89:;%

,$-.!"(/0(+,-.#%&'(#"%<#5-0=5%0>>?""-=*%-=%@3%'"#%0A5#"B'A<#%-=%:C%@8%-&'*#5D%%

!"#$%%$&'((!"#$%%$&'((

!")*+%"(!")*+%"(

!")*+%"(

:9@6% 0  

20  

40  

60  

80  

100  

120  

Controls   RRMS  

cSP  du

ra7o

n  (m

s)    

cSP  lengthening  was  expected  to  be  propor7onal  to  the  total  amount  of  damage  throughout  the  brain.  Lower  cSP  and  sICI  were  predicted  to  be  correlated  with  more  extensive  damage  to  the  cor7cal  motor  hand  area.    

Neurology and Neurosurgery, McGill University McGill University Health Centre

1.  Caramia  MD,  Palmieri  MG,  Desiato  MT,  Boffa  L,  Galizia  P,  Rossini  PM,  Centonze  D,  Bernardi  G:  Brain  excitability  changes  in  the  relapsing  and  remi4ng  phases  of  mul8ple  sclerosis:  a  study  with  transcranial  magne8c  s8mula8on.  Clinical  neurophysiology  :  official  journal  of  the  Interna7onal  Federa7on  of  Clinical  Neurophysiology  2004,  115(4):956-­‐965.  

2.  Fisher  E,  Lee  JC,  Nakamura  K,  Rudick  RA:  Gray  ma>er  atrophy  in  mul8ple  sclerosis:  a  longitudinal  study.  Annals  of  neurology  2008,  64(3):255-­‐265.  3.  Vucic  S,  Burke  T,  Lenton  K,  Ramanathan  S,  Gomes  L,  Yannikas  C,  Kiernan  MC:  Cor8cal  dysfunc8on  underlies  disability  in  mul8ple  sclerosis.  Mul7ple  sclerosis  (Houndmills,  Basingstoke,  

England)  2012,  18(4):425-­‐432.  MTR  damage  paper  4.  Ziemann  U.  Pharmaco-­‐transcranial  magne8c  s8mula8on  studies  of  motor  excitability.  Handbook  of  clinical  neurology.  2013;116C:387-­‐97.  

Nantes JC*, Zhong J, Whatley B, & Koski L

Magne7c  resonance  imaging  techniques  provide  es7mates  of  the  severity  of  neural  atrophy  and  demyelina7on  occurring  the  in  the  brains  of  people  living  with  MS.    

9-hole peg test (9HPT)

Among  RRMS  pa7ents  experiencing  a  period  of  clinical  remission,  we  sought  to  es7mate  the  extent  to  which  intracor7cal  inhibi7on  (sICI,  cSP)  is  related  to  white  and  grey  mader  damage.  

Despite  persis7ng  brain  damage,  pa7ents  with  RRMS  experience  periods  of  clinical  remission  between  periods  of  symptom  exacerba7ons  (relapses).    

t(27)  =  2.35    p  <  .05  

*  

Email:  julia.nantes@mail.mcgill.ca    Lab  phone:  514-­‐934-­‐1934  ext.  34439  Website:  hdp://koskilab.mcgill.ca    

Thank  you  to  members  of  the  McConnell  Brain  Imaging  Center  (BIC)  of  the  Montreal  Neurological  Ins7tute,  for  training  and  assistance  with  the  neuroimaging  components  of  this  project.    

Lesion analysis

T1 T2 FLAIR PDW Volumetric analysis (normalized to size of skull)

T1

Cortical silent period (cSP) GABAB receptor activity biomarker

Short-interval intracortical inhibition (sICI) GABAA receptor activity biomarker

DEMYELINATION & NEURODEGENERATION

RELAPSING-REMITTING MULTIPLE SCLEROSIS (RRMS)

MAGNETIC RESONANCE IMAGING (MRI)

TRANSCRANIAL MAGNETIC STIMULATION (TMS)

MULTIPLE SCLEROSIS FUNCTIONAL COMPOSITE (MSFC)

NEUROIMAGING OUTCOMES

INTRACORTICAL INHIBITION OUTCOMES

White  maFer  

INTRACORTICAL INHIBITION CHANGES

C  

MTR & INTRACORTICAL INHIBITION

Magnetization Transfer Ratio (MTR)

B   RRMS  pa7ent    (in  remission)  

Timed 25-foot walk (T25FW) Paced Auditory Serial Addition Test (PASAT)

FIGURE  1.  Examples  of  cSP  traces  are  shown  from  a  control  (A)  and  from  a  RRMS  pa7ent  par7cipa7ng  during  a  period  of  clinical  remission  (B).  Compared  to  controls,  RRMS  par7cipants  had  significantly  longer  cSP  dura7ons  (C).  From  the  sICI  protocol,  an  example  of  a  motor-­‐evoked  poten7al  (MEP)  induced  by  a  single  supra-­‐threshold  TMS-­‐pulse  (D)  and  an  inhibited  MEP  (due  to  a  sub-­‐threshold  TMS  pulse  preceding  the  supra-­‐threshold  TMS  pulse)  (E)  are  shown.  Groups  did  not  differ  in  sICI  (F).    

0  

1  

2  

3  

4  

5  

6  

7  

8  

9  

10  

 White  mader  

 Grey  mader    

Brain  volume    

(normalize

d  voxels)  

x  100000  

0  

5  

10  

15  

20  

25  

30  

35  

40  

45  

50  

Normal  appearing  white  mader  

White  mader  lesions  

Grey  mader     M1  hand  area      

MTR

   (percent  units)  

CLINICAL OUTCOMES

FIGURE  2.  Compared  to  controls,  RRMS  par7cipants  had  lower  volumes  of  white  mader  (t(27)  =  -­‐2.75,  p  <  .01)  and  grey  mader  (t(27)  =  -­‐2.07,  p  <  .05)  (A).  Compared  to  white  mader  MTR  of  controls,  RRMS  par7cipants  had  significantly  lower  MTR  within  both  lesioned  (t(24)  =  -­‐5.48,  p  <  .0001)  and  normal  appearing  white  mader              (t(24)  =  -­‐1.96,  p  >  .05).  Cor7cal  MTR  within  the  primary  motor  cortex  (M1)  hand  area  was  lower  among  RRMS  par7cipants  compared  to  controls  (t(24)  =  -­‐1.99,  p  <  .05),  although  total  brain  grey  mader  MTR  did  not  differ  (t(24)  =  0.87,  p  >  .05)  (B).  

Table  1.  Mean  ±  SD  score  on  the  Mul7ple  Sclerosis  Func7onal  Composite  (MSFC)  and  raw  scores  on  each  MSFC  subscale.  *  p  <  .01        **p  <  .05  

BRAIN VOLUME & INTRACORTICAL INHIBITION SIENAx

0  

20  

40  

60  

80  

100  

120  

140  

-­‐6   -­‐5   -­‐4   -­‐3   -­‐2   -­‐1   0   1   2  

cSP  du

ra7o

n    

(ms)    

White  mader  volume  (z-­‐score)  

0  

20  

40  

60  

80  

100  

120  

140  

-­‐2.5   -­‐2   -­‐1.5   -­‐1   -­‐0.5   0   0.5   1  

cSP    dura7

on    

(ms)    

Grey  mader  volume  (z-­‐score)  

29  

31  

33  

35  

37  

39  

41  

43  

45  

47  

0   50   100   150  Magne

7za7

on  Transfer  R

a7o  

(percent  units)  

cSP  (ms)  

FIGURE  4.  Trends  toward  nega7ve  correla7ons  were  observed  between  cSP  dura7on  and  white  mader  MTR  signal  within  normal  appearing  white  mader  (r(15)  =  -­‐0.25,  p  =  0.18),  lesioned  white  mader  7ssue  (r(15)  =  -­‐0.31,  p  =  0.12),  grey  mader  volume  (r(15)  =  -­‐0.26,  p  =  0.17),  and  grey  mader  MTR  (r(15)  =  -­‐0.23,  p  =  0.20).  Conversely,  MTR  within  the  M1  hand  area  trended  in  a  posi7ve  direc7on  with  cSP  (r(15)  =  0.23,  p  =  0.19).      

FIGURE  5.  Qualita7ve  model  of  interac7ons  between  intracor7cal  inhibi7on  and  brain  damage  of  persons  with  mul7ple  sclerosis.    

0  10  20  30  40  50  60  70  80  90  100  

Controls   RRMS  

sICI  (%

inhibi7o

n)  

!" #"

!"#$$% !"#&% !"'%

$%&&'(%)&%"•  *(+",-./&0",1"

23--31"04.2&"•  5&61&"7890"

:;<=>?""

@  A&0+",1"B,B3"&0C-.+&"3)"D&-E&F,1.C31""

@  5&+&2C31"3)"F&0,310"G,+H,1"/%&E"-.I&%""

%

!()*+,-(,.*%"/(*01+/%'(,.%2!"'3%%

!"#$%%$&'((

!")*+%"(

!"#$%%$&'((

!"#$%&'(#"%)'&'*#%

+,-.#%&'(#"%)'&'*#%

/01%

2-*,%

3$&4.0&5%

3676

89:;%

,$-.!"(/0(+,-.#%&'(#"%<#5-0=5%0>>?""-=*%-=%@3%'"#%0A5#"B'A<#%-=%:C%@8%-&'*#5D%%

!"#$%%$&'((!"#$%%$&'((

!")*+%"(!")*+%"(

!")*+%"(

FreeSurfer

!"#

$%#

$!#

$&#

$'#

$"#

&%#

&!#

&&#

&'#

&"#

!(# &(# '(# "(# )%(#

!"#$%

&'"&

($)*+"$,-%+).

"&()/+%#0($"

1)"2%+"#%3))

,454))

*+,-./#.001.,234#56271#-.81,##

96271#-.81,#/1:2+3:##

;,1<#-.81,##

=+7+,#>.3?#@,1.##

cSP DURATION IS RELATED TO BRAIN DAMAGE

METHODS

DISCUSSION

BACKGROUND RESULTS

OBJECTIVE

INTRACORTICAL INHIBITION ALTERATION DURING THE REMISSION PHASE OF MULTIPLE SCLEROSIS: RELATION TO WHITE AND GREY MATTER DAMAGE

HYPOTHESIS

Grey  maFer  

A   Healthy    control  

D   E  

F  

*  

t(27)  =  0.15    p  >  .05  

!"

#"

$!"

$#"

%!"

%#"

&!"

&#"

'!"

'#"

#!"

()*+,-",../,*012"

3405/"+,6/*"

7405/"+,6/*"-/80)18"

9*/:"+,6/*"" ;$"4,1<",*/,"""

!"#$%

&'"&

($)*+"$,-%+).

"&()

=)15*)-8"

>>;?"!"

#"

$!"

$#"

%!"

%#"

&!"

&#"

'!"

'#"

#!"

()*+,-",../,*012"

3405/"+,6/*"

7405/"+,6/*"-/80)18"

9*/:"+,6/*"" ;$"4,1<",*/,"""

!"#$%

&'"&

($)*+"$,-%+).

"&()

=)15*)-8"

>>;?"A   B  

**  *  

*  ****  

*  NS  

MSFC   9HPT  (dominant)    

9HPT    (non-­‐dominant)    

T25FW   PASAT  

Controls   0.62  (0.27)   18.2  (1.9)   17.85  (1.6)   3.6  (0.6)   46.9  (8.9)  

RRMS   0.27  (0.53)*   21.1  (3.8)**   20.5  (3.8)*   4.4  (1.1)*   42.8  (11.2)  

A   B  r(15)  =  -­‐0.69  p  <  .01  

r(15)  =  -­‐0.26  p  >  .05  

MTR

Caramia  et  al.  (2004)    

cSP  =  40  ms    

cSP  =  93  ms    

!"#$%&'($)*(+,-./0!.#",*)...

123.

&123.

3.

324.

324.

56..

5*.3. 43.74. 84. 133.

!"#$%&'($)*(+,-./0!.#",*)...

!"1&'($)*(+,-./0!.#",*)...

234.

&234.

4.

435.

435.

6*.4. 54.75. 85.

69..

244.

!"

#"

$!"

$#"

%!"

%#"

&!"

&#"

'!"

'#"

#!"

()*+,-",../,*012"

3405/"+,6/*"

7405/"+,6/*"-/80)18"

9*/:"+,6/*"" ;$"4,1<",*/,"""

!"#$%

&'"&

($)*+"$,-%+).

"&()

=)15*)-8"

>>;?"!"

#"

$!"

$#"

%!"

%#"

&!"

&#"

'!"

'#"

#!"

()*+,-",../,*012"

3405/"+,6/*"

7405/"+,6/*"-/80)18"

9*/:"+,6/*"" ;$"4,1<",*/,"""

!"#$%

&'"&

($)*+"$,-%+).

"&()

=)15*)-8"

>>;?"

!"#

$%#

$!#

$&#

$'#

$"#

&%#

&!#

&&#

&'#

&"#

!(# &(# '(# "(# )%(#

!"#$%

&'"&

($)*+"$,-%+).

"&()/+%#0($"

1)"2%+"#%3))

,454))

*+,-./#.001.,234#56271#-.81,##

96271#-.81,#/1:2+3:##

;,1<#-.81,##

=+7+,#>.3?#@,1.##

!"#

$%#

$!#

$&#

$'#

$"#

&%#

&!#

&&#

&'#

&"#

!(# &(# '(# "(# )%(#

!"#$%

&'"&

($)*+"$,-%+).

"&()/+%#0($"

1)"2%+"#%3))

,454))

*+,-./#.001.,234#56271#-.81,##

96271#-.81,#/1:2+3:##

;,1<#-.81,##

=+7+,#>.3?#@,1.##

!"#$%&'(#"%)'&'*#%

+,-.#%&'(#"%)'&'*#%

/$&0.1&%2#3#"-.$%%

4/5%)6"'718%%%

                                                                     profile  name:    JULIA  CHRISTINE  NANTES  

 

ACKNOWLEDGEMENTS CONTACT INFORMATION

REFERENCES

#  441.19  

!"#$%&"'!"#$%$&'"()

'

*$+,)))

--./) /0./)

!"#$%&"'!"#$%$&'")()

!"()&&)*+'!"#$%$&'")1)

!"()&&)*+'!"#$%$&'")1)

!"()&&)*+'!"#$%$&'")1)

2'3)

4$5#) %!*,!"&&)-"'!"#$%$&'")()

'

/676

-!*8)

sICI  &    cSP  are  biomarkers  of  intracor7cal  inhibitory  neurotransmission  resul7ng  from  ac7vity  at  GABAA  and  GABAB  receptors,  respec7vely.      Ziemann    (2013)  

N/A  

•  RRMS  par7cipants  (in  clinical  remission)  have  cSP  prolonga7on,  indica7ng  that  ac7vity  at  intracor7cal    GABAB  receptors  may  be  abnormally  high.  

•  Low  white  mader  volume  is  related  to  cSP  prolonga7on  during  RRMS  clinical  remission  phases.  

 

•  Preliminary  evidence  that  damage  within  the  primary  motor  cortex  hand  region  lowers  intracor7cal  inhibi7on.    

E  

Caramia  et  al.  (2004)  Fisher  et  al.  (2008)      Vucic  et  al  (2012)    

FIGURE  3.  Lower  white  mader  volume  predicted  longer  cSP  dura7on  (A).  The  rela7onship  between  grey  mader  volume  and  cSP  dura7on  did  not  reach  significance  (B).  Z-­‐scores  compare  individual  RRMS  par7cipants  to  the  mean  ±  SD  of  the  control  group.        

Motor  hand  area