Accepted Manuscript Safety of primed repetitive transcranial magnetic stimulation and modified constraintinduced movement therapy in a randomized controlled trial in pediatric hemiparesis Bernadette Gillick, PhD, MSPT, PT Linda E. Krach, MD Tim Feyma, MD Tonya L. Rich, OTL/R Kelli Moberg, OTL/R Jeremiah Menk, MS Jessica Cassidy, DPT Teresa Kimberley, PhD, PT James R. Carey, PhD, PT PII:
S0003-9993(14)01118-6
DOI:
10.1016/j.apmr.2014.09.012
Reference:
YAPMR 55977
To appear in:
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
Received Date: 20 May 2014 Revised Date:
8 September 2014
Accepted Date: 9 September 2014
Please cite this article as: Gillick B, Krach LE, Feyma T, Rich TL, Moberg K, Menk J, Cassidy J, Kimberley T, Carey JR, Safety of primed repetitive transcranial magnetic stimulation and modified constraint-induced movement therapy in a randomized controlled trial in pediatric hemiparesis, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2014), doi: 10.1016/ j.apmr.2014.09.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Safety rTMS mCIMT
Title: Safety of primed repetitive transcranial magnetic stimulation and modified constraintinduced movement therapy in a randomized controlled trial in pediatric hemiparesis
SC
RI PT
Authors: Bernadette Gillick, PhD, MSPT, PT1 Linda E Krach, MD1,2 Tim Feyma, MD2 Tonya L Rich, OTL/R2 Kelli Moberg, OTL/R2 Jeremiah Menk, MS1 Jessica Cassidy, DPT1 Teresa Kimberley, PhD, PT1 James R Carey, PhD, PT1
M AN U
Location of Work: 1)University of Minnesota, Medical School, Department of Physical Medicine and Rehabilitation, Minneapolis, MN 2)Gillette Children’s Specialty Healthcare, St. Paul, MN Presentation of Work: Gillick BT, Krach LE, Moberg K, Rich T, Carey JR. Pediatric Hemiparesis: Repetitive Transcranial Magnetic Stimulation and Constraint-Induced Therapy. AACPDM Annual Conference, September 13, 2012, Toronto, Canada.
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Gillick BT, Ellsworth ST, Elmajri L, Henneman ES, Carey JR.Pediatric Hemiparesis: Synergistic Treatment Using Repetitive Transcranial Magnetic Stimulation and Constraint-Induced Therapy. APTA Combined Sections, 2012, Chicago, IL , Student co-authors: Ellsworth, Elmajri, Henneman.
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Acknowledgment of financial support: This study was funded by NIH grant #1 RC1HD06383801. This publication [or project] was also supported by Grant Number 1UL1RR033183-01from the National Center for Research Resources (NCRR) and by Grant Number 8 UL1 TR000114-02 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) to the University of Minnesota Clinical and Translational Science Institute (CTSI). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the CTSI or the NIH. The University of Minnesota CTSI is part of a national Clinical and Translational Science Award (CTSA) consortium created to accelerate laboratory discoveries into treatments for patients. University of Minnesota Center for Magnetic Resonance Research funding supported the imaging work #P41 EB015894. Dr. Gillick was supported by the Foundation for Physical Therapy Promotion of Doctoral Studies during this thesis work. No author has a conflict of interest.
ACCEPTED MANUSCRIPT Safety rTMS mCIMT
RI PT
Author for Correspondence and Reprints: Name: Bernadette T. Gillick, PhD, MSPT, PT Address: University of Minnesota- Medical School- Program in Physical Therapy 420 Delaware Street SE, MMC 388 Minneapolis, MN 55455 Telephone: 612.626.3121 Email: [email protected]
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The study is registered on clinicaltrials.gov (# NCT01104064) of the United States National Institutes of Health.
ACCEPTED MANUSCRIPT Safety rTMS mCIMT 1
Title: Safety of primed repetitive transcranial magnetic stimulation and modified constraint-
2
induced movement therapy in a randomized controlled trial in pediatric hemiparesis
3
RI PT
4 5 6
SC
7 8
M AN U
9 10 11 12
16 17 18 19
20
EP
15
AC C
14
TE D
13
21
22
1
ACCEPTED MANUSCRIPT Safety rTMS mCIMT
ABSTRACT
24
Objective. To investigate the safety of combining 6-Hz primed low-frequency repetitive
25
transcranial magnetic stimulation (rTMS) intervention in the contralesional hemisphere with a
26
modified constraint-induced movement therapy (mCIMT) program in children with congenital
27
hemiparesis.
RI PT
23
Design. Phase 1 randomized, double-blinded, placebo-controlled pretest/posttest trial.
M AN U
29
SC
28
30
31
Setting. University academic facility and a pediatric specialty hospital.
32
Participants. Nineteen subjects aged 8 to 17 years with congenital hemiparesis due to ischemic
34
stroke or periventricular leukomalacia. No subject withdrew due to adverse events. All subjects
35
included completed the study.
EP AC C
36
TE D
33
37
Interventions. Subjects were randomized to one of two groups: either rTMSreal with mCIMT (n =
38
10) or rTMSsham with mCIMT (n = 9).
39
2
ACCEPTED MANUSCRIPT Safety rTMS mCIMT
Main Outcome Measures. Adverse events, physician assessment, ipsilateral hand function,
41
stereognosis, cognitive function, subject report of symptoms assessment and subject
42
questionnaire.
RI PT
40
43
Results. No major adverse events occurred. Minor adverse events were found in both groups.
45
The most common were headaches (real: 50%, sham: 89%, p=0.14) and cast irritation (real:
46
30%, sham: 44%, p = 0.65). No differences between groups in secondary cognitive and
47
unaffected hand motor measures were found.
M AN U
SC
44
48
Conclusions. Primed rTMS can be used safely with mCIMT in congenital hemiparesis. We
50
provide new information on the use of rTMS in combination with mCIMT in children. These
51
findings could be useful in research and future clinical applications in advancing function in
52
congenital hemiparesis.
53
Key Words Hemiparesis, Transcranial Magnetic Stimulation, stroke, safety, pediatrics
EP AC C
54
TE D
49
55
List of Abbreviations:
56
repetitive transcranial magnetic stimulation (rTMS)
57
modified constraint-induced movement therapy (mCIMT)
58
primary motor area (M1)
3
ACCEPTED MANUSCRIPT
resting motor threshold (RMT)
60
active motor threshold (AMT)
61
Consolidated Standards of Reporting Trials (CONSORT)
62
extensor digitorum (ED)
63
Gross Motor Function Classification Scale (GMFCS)
64
Functional magnetic imaging (fMRI)
65
TOKEN test for children (TTFC)
66
analysis of covariance (ANCOVA)
67
Manual Ability Classification System (MACS)
68
Data Safety Monitoring Board (DSMB)
69
Minor adverse events (MAE)
72
73
M AN U
TE D
EP
71
AC C
70
SC
59
RI PT
Safety rTMS mCIMT
74
75
4
ACCEPTED MANUSCRIPT Safety rTMS mCIMT 76
The “doubly-disabled” adult brain after unilateral stroke is affected not only by the lesion itself,
78
but also by exaggerated interhemispheric inhibition from the contralesional primary motor area
79
(M1) acting on ipsilesional M1.1 In the child with congenital hemiparesis, a similar inhibition
80
may occur through “developmental disuse,” in which a child predominantly uses the less
81
affected extremities, masking potential function in the affected extremity.2 Low-frequency
82
(inhibitory) contralesional repetitive transcranial magnetic stimulation (rTMS) has shown
83
promising cortical effects by inhibiting the contralesional M1, thereby disinhibiting surviving
84
neurons in ipsilesional M1.3-5 More studies are investigating the use of rTMS as an intervention
85
to restore higher excitability in ipsilesional M1.
M AN U
SC
RI PT
77
86
Iyer et al (2003) found that the effects of 1 Hz low-frequency stimulation can be enhanced
88
through preceding the low-frequency session with a “priming” 6-Hz high-frequency session.6
89
The use of 6-Hz priming of low-frequency rTMS to the contralesional hemisphere in children
90
with stroke may work by creating greater disruption of the exaggerated interhemispheric effects
91
of the contralesional hemisphere upon the ipsilesional hemisphere. In an effort to achieve
92
improved outcomes, 6-Hz priming rTMS employed immediately prior to the low-frequency
93
rTMS can be used to capitalize on principles of homeostatic plasticity.7 Homeostatic plasticity
94
encompasses several mechanisms aimed at stabilizing neuronal activity to maintain synaptic
95
specificity and prevent unconstrained synaptic plasticity from predominating in the system.8
96
Importantly, homeoplastic plasticity depends on the previous history of synaptic activity. 9
97
Thus, excitatory priming stimulation biases the neural network to seek return to its baseline
98
activity level. In combination then, low-frequency rTMS applied in the facilitated state yields a
AC C
EP
TE D
87
5
ACCEPTED MANUSCRIPT Safety rTMS mCIMT 99 100
more pronounced inhibition compared to low-frequency rTMS that is not preceded by highfrequency rTMS.6
101
Distinct from rTMS, motor learning with use of constraint is an additional intervention with
103
potent effects on brain reorganization.10-12 Modified constraint-induced movement therapy
104
(mCIMT) is defined as
S0003-9993(14)01118-6
DOI:
10.1016/j.apmr.2014.09.012
Reference:
YAPMR 55977
To appear in:
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
Received Date: 20 May 2014 Revised Date:
8 September 2014
Accepted Date: 9 September 2014
Please cite this article as: Gillick B, Krach LE, Feyma T, Rich TL, Moberg K, Menk J, Cassidy J, Kimberley T, Carey JR, Safety of primed repetitive transcranial magnetic stimulation and modified constraint-induced movement therapy in a randomized controlled trial in pediatric hemiparesis, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2014), doi: 10.1016/ j.apmr.2014.09.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Safety rTMS mCIMT
Title: Safety of primed repetitive transcranial magnetic stimulation and modified constraintinduced movement therapy in a randomized controlled trial in pediatric hemiparesis
SC
RI PT
Authors: Bernadette Gillick, PhD, MSPT, PT1 Linda E Krach, MD1,2 Tim Feyma, MD2 Tonya L Rich, OTL/R2 Kelli Moberg, OTL/R2 Jeremiah Menk, MS1 Jessica Cassidy, DPT1 Teresa Kimberley, PhD, PT1 James R Carey, PhD, PT1
M AN U
Location of Work: 1)University of Minnesota, Medical School, Department of Physical Medicine and Rehabilitation, Minneapolis, MN 2)Gillette Children’s Specialty Healthcare, St. Paul, MN Presentation of Work: Gillick BT, Krach LE, Moberg K, Rich T, Carey JR. Pediatric Hemiparesis: Repetitive Transcranial Magnetic Stimulation and Constraint-Induced Therapy. AACPDM Annual Conference, September 13, 2012, Toronto, Canada.
TE D
Gillick BT, Ellsworth ST, Elmajri L, Henneman ES, Carey JR.Pediatric Hemiparesis: Synergistic Treatment Using Repetitive Transcranial Magnetic Stimulation and Constraint-Induced Therapy. APTA Combined Sections, 2012, Chicago, IL , Student co-authors: Ellsworth, Elmajri, Henneman.
AC C
EP
Acknowledgment of financial support: This study was funded by NIH grant #1 RC1HD06383801. This publication [or project] was also supported by Grant Number 1UL1RR033183-01from the National Center for Research Resources (NCRR) and by Grant Number 8 UL1 TR000114-02 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) to the University of Minnesota Clinical and Translational Science Institute (CTSI). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the CTSI or the NIH. The University of Minnesota CTSI is part of a national Clinical and Translational Science Award (CTSA) consortium created to accelerate laboratory discoveries into treatments for patients. University of Minnesota Center for Magnetic Resonance Research funding supported the imaging work #P41 EB015894. Dr. Gillick was supported by the Foundation for Physical Therapy Promotion of Doctoral Studies during this thesis work. No author has a conflict of interest.
ACCEPTED MANUSCRIPT Safety rTMS mCIMT
RI PT
Author for Correspondence and Reprints: Name: Bernadette T. Gillick, PhD, MSPT, PT Address: University of Minnesota- Medical School- Program in Physical Therapy 420 Delaware Street SE, MMC 388 Minneapolis, MN 55455 Telephone: 612.626.3121 Email: [email protected]
AC C
EP
TE D
M AN U
SC
The study is registered on clinicaltrials.gov (# NCT01104064) of the United States National Institutes of Health.
ACCEPTED MANUSCRIPT Safety rTMS mCIMT 1
Title: Safety of primed repetitive transcranial magnetic stimulation and modified constraint-
2
induced movement therapy in a randomized controlled trial in pediatric hemiparesis
3
RI PT
4 5 6
SC
7 8
M AN U
9 10 11 12
16 17 18 19
20
EP
15
AC C
14
TE D
13
21
22
1
ACCEPTED MANUSCRIPT Safety rTMS mCIMT
ABSTRACT
24
Objective. To investigate the safety of combining 6-Hz primed low-frequency repetitive
25
transcranial magnetic stimulation (rTMS) intervention in the contralesional hemisphere with a
26
modified constraint-induced movement therapy (mCIMT) program in children with congenital
27
hemiparesis.
RI PT
23
Design. Phase 1 randomized, double-blinded, placebo-controlled pretest/posttest trial.
M AN U
29
SC
28
30
31
Setting. University academic facility and a pediatric specialty hospital.
32
Participants. Nineteen subjects aged 8 to 17 years with congenital hemiparesis due to ischemic
34
stroke or periventricular leukomalacia. No subject withdrew due to adverse events. All subjects
35
included completed the study.
EP AC C
36
TE D
33
37
Interventions. Subjects were randomized to one of two groups: either rTMSreal with mCIMT (n =
38
10) or rTMSsham with mCIMT (n = 9).
39
2
ACCEPTED MANUSCRIPT Safety rTMS mCIMT
Main Outcome Measures. Adverse events, physician assessment, ipsilateral hand function,
41
stereognosis, cognitive function, subject report of symptoms assessment and subject
42
questionnaire.
RI PT
40
43
Results. No major adverse events occurred. Minor adverse events were found in both groups.
45
The most common were headaches (real: 50%, sham: 89%, p=0.14) and cast irritation (real:
46
30%, sham: 44%, p = 0.65). No differences between groups in secondary cognitive and
47
unaffected hand motor measures were found.
M AN U
SC
44
48
Conclusions. Primed rTMS can be used safely with mCIMT in congenital hemiparesis. We
50
provide new information on the use of rTMS in combination with mCIMT in children. These
51
findings could be useful in research and future clinical applications in advancing function in
52
congenital hemiparesis.
53
Key Words Hemiparesis, Transcranial Magnetic Stimulation, stroke, safety, pediatrics
EP AC C
54
TE D
49
55
List of Abbreviations:
56
repetitive transcranial magnetic stimulation (rTMS)
57
modified constraint-induced movement therapy (mCIMT)
58
primary motor area (M1)
3
ACCEPTED MANUSCRIPT
resting motor threshold (RMT)
60
active motor threshold (AMT)
61
Consolidated Standards of Reporting Trials (CONSORT)
62
extensor digitorum (ED)
63
Gross Motor Function Classification Scale (GMFCS)
64
Functional magnetic imaging (fMRI)
65
TOKEN test for children (TTFC)
66
analysis of covariance (ANCOVA)
67
Manual Ability Classification System (MACS)
68
Data Safety Monitoring Board (DSMB)
69
Minor adverse events (MAE)
72
73
M AN U
TE D
EP
71
AC C
70
SC
59
RI PT
Safety rTMS mCIMT
74
75
4
ACCEPTED MANUSCRIPT Safety rTMS mCIMT 76
The “doubly-disabled” adult brain after unilateral stroke is affected not only by the lesion itself,
78
but also by exaggerated interhemispheric inhibition from the contralesional primary motor area
79
(M1) acting on ipsilesional M1.1 In the child with congenital hemiparesis, a similar inhibition
80
may occur through “developmental disuse,” in which a child predominantly uses the less
81
affected extremities, masking potential function in the affected extremity.2 Low-frequency
82
(inhibitory) contralesional repetitive transcranial magnetic stimulation (rTMS) has shown
83
promising cortical effects by inhibiting the contralesional M1, thereby disinhibiting surviving
84
neurons in ipsilesional M1.3-5 More studies are investigating the use of rTMS as an intervention
85
to restore higher excitability in ipsilesional M1.
M AN U
SC
RI PT
77
86
Iyer et al (2003) found that the effects of 1 Hz low-frequency stimulation can be enhanced
88
through preceding the low-frequency session with a “priming” 6-Hz high-frequency session.6
89
The use of 6-Hz priming of low-frequency rTMS to the contralesional hemisphere in children
90
with stroke may work by creating greater disruption of the exaggerated interhemispheric effects
91
of the contralesional hemisphere upon the ipsilesional hemisphere. In an effort to achieve
92
improved outcomes, 6-Hz priming rTMS employed immediately prior to the low-frequency
93
rTMS can be used to capitalize on principles of homeostatic plasticity.7 Homeostatic plasticity
94
encompasses several mechanisms aimed at stabilizing neuronal activity to maintain synaptic
95
specificity and prevent unconstrained synaptic plasticity from predominating in the system.8
96
Importantly, homeoplastic plasticity depends on the previous history of synaptic activity. 9
97
Thus, excitatory priming stimulation biases the neural network to seek return to its baseline
98
activity level. In combination then, low-frequency rTMS applied in the facilitated state yields a
AC C
EP
TE D
87
5
ACCEPTED MANUSCRIPT Safety rTMS mCIMT 99 100
more pronounced inhibition compared to low-frequency rTMS that is not preceded by highfrequency rTMS.6
101
Distinct from rTMS, motor learning with use of constraint is an additional intervention with
103
potent effects on brain reorganization.10-12 Modified constraint-induced movement therapy
104
(mCIMT) is defined as
