Perinatal Stroke: Understanding Brain Reorganization

• Sponsor: University of Minnesota (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02743728
• Collaborator: Cerebral Palsy Alliance (Other), American Academy of Cerebral Palsy and Developmental Medicine (Other), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 20
• Location: 1
• Anticipated Duration (Months): 75
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The incidence of perinatal stroke is relatively common, as high as 1 in 2,300 births, but little is known about the resulting changes in the brain that eventually manifest as cerebral palsy (CP). Motor signs that indicate the infant is beginning to develop CP often do not become evident for several months after the diagnosis of perinatal stroke which delays therapy. The main purpose of this study is to examine early brain reorganization in infants 3-12 months of age corrected for prematurity with perinatal stroke using magnetic resonance imaging (MRI) and non-invasive transcranial magnetic stimulation (TMS). In addition, the association between the brain reorganization and motor outcomes of these infant participants will be identified.

In this study, the MRI scans will include diffusion tensor imaging (DTI) - an established method used to investigate the integrity of pathways in the brain that control limb movement. Infants will be scanned during nature sleeping after feeding. The real scanning time will be less than 38 minutes. TMS is a painless, non-surgical brain stimulation device which uses principles of electromagnetic induction to excite cortical tissue from outside the skull. Using TMS as a device to modulate and examine cortical excitability in children with hemiparetic CP and in adults has been conducted previously.

In this infant study, we will assess cortical excitability from the motor cortex of both the ipsilesional and contralesional hemispheres under the guidance of a frameless stereotactic neuronavigation system. Additionally, the investigators will assess infants' movement quality using an age-appropriate standardized movement assessment. This will allow the investigators to examine the relationship between measures of motor pathway integrity and early signs of potential motor impairment. We will longitudinally follow enrolled infants, and complete repeat assessments at 12- and 24-months corrected age to assess how infants develop over time after perinatal stroke. The remote follow-up will occur at 5 years or less.

Condition or Disease	Intervention/Treatment	Phase
Stroke; Hemiparesis	Device: Magnetic Resonance Imaging; Device: Transcranial Magnetic Stimulation; Behavioral: General Movement Assessment

Detailed Description

Understanding the early brain reorganization before the brain has not yet largely reorganized is critical for developing efficacious early intervention. As a unique aspect of investigation, this study will combine Magnetic Resonance Imaging (MRI)/ Diffusion Tensor Imaging (DTI) and TMS to provide an additional opportunity to assess both the cortical excitability and corticospinal tract (CST) integrity in infants with perinatal stroke.

Identifying the association between laboratory assessment results and developmental outcomes is also critical. This study is to use MRI/DTI and TMS to comprehensively examine both the CST integrity and cortical excitability in infants following perinatal stroke, and to identify association with motor outcome as evaluated by movement assessment.

Study Design

• Study Type: Observational
• Actual Enrollment: 20 participants
• Observational Model: Other
• Time Perspective: Cross-Sectional
• Official Title: Perinatal Stroke: Understanding Brain Reorganization Through Infant Neuroimaging and Neuromodulation
• Actual Study Start Date: May 1, 2016
• Actual Primary Completion Date: Jul 31, 2021
• Anticipated Study Completion Date: Jul 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
All Infants Each infant will receive an Magnetic Resonance Imaging, then Transcranial Magnetic Stimulation Cortical Excitability testing, and General Movement Assessment. These 3 different components of the one arm in which all infants are involved will be collectively assessed.	Device: Magnetic Resonance Imaging; Anatomical and Diffusion Tensor Imaging Analysis.; Device: Transcranial Magnetic Stimulation; Assessment of brain (cortical) excitability; Behavioral: General Movement Assessment; Spontaneous movement assessment of infant while lying in unperturbed state.

Outcome Measures

Primary Outcome Measures

1. Cortical Excitability MEP Amplitude (µV) [2 hours]

   Cortical excitability of ipsilesional and contralesional hemispheres assessed by transcranial magnetic stimulation (TMS) in infants with perinatal stroke. TMS will be used to assess cortical excitability through electromagnetic depolarization of targeted cortical neurons through painless pulses delivered over the scalp. The estimated time of TMS assessment is around 2 hours during Visit 2. Outcome is reported as MEP amplitude in units of microvolts (µV).

2. Cortical Excitability Percentage of Maximum [2 hours]

   Cortical excitability of ipsilesional and contralesional hemispheres assessed by transcranial magnetic stimulation (TMS) in infants with perinatal stroke. TMS will be used to assess cortical excitability through electromagnetic depolarization of targeted cortical neurons through painless pulses delivered over the scalp. The estimated time of TMS assessment is around 2 hours during Visit 2. The outcome of motor threshold will be reported as the percentage of maximum stimulator output.

Secondary Outcome Measures

1. General Movement Assessment [15 minutes]

   Movement quality will be assessed by general movement assessment (GMA). GMA requires 5-10 minutes videotaping when infants are placed in spine position for scoring. Infants are scores categorically as typical (present fidgety movements) or atypical (absent, sporadic, or abnormal fidgety movements). Outcome is reported as the number of typical infants and number of atypical infants.

2. Adverse Events [2 days]

   Recording of adverse events will take place during TMS cortical mapping and MRI scanning of infants with perinatal stroke. Assessment of vital signs changes and pain/stress responses during both MRI and TMS assessment during visit 1 and visit 2. Outcome is reported as the number of adverse events recorded.

3. Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) [15 minutes]

   The PEDI-CAT uses Item Response Theory statistical models to estimate a child's ability from a minimal number of items. Three functional domains will be assessed. The PEDI-CAT software provides normative standard scores presented as T scores and age percentile ranges to assess daily activities, mobility, and social/cognitive function. Outcome is reported as the mean score generated by the PEDI-CAT software. Scores are based on t-test values and do not have a unit of measure or a defined range. Higher scores indicate greater deviation from the standardized mean score.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Months to 5 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria for Pilot Study:

• Birth diagnosis of unilateral perinatal stroke by cranial ultrasound, computer tomography (CT) or magnetic resonance imaging (MRI)

• Corrected gestational age between 3 and 24 months of age for both infants with stroke and typically developing infants

Exclusion Criteria for Pilot Study :

• Metabolic Disorders

• Neoplasm

• Disorders of Cellular Migration and Proliferation

• Acquired Traumatic Brain Injury

• Received surgeries that may constraint current spontaneous movements

• Indwelling metal or incompatible medical devices

• Received surgeries that may constraint current spontaneous movements

• Other neurologic disorders unrelated to stroke

• Small for gestational age (SGA): Infants are smaller in size than normal for the gestational age

• Apneic episodes and syncope (known heart defects) for the safety of participants in the stud.

• Genetic disorders

• Uncontrolled seizures

Additional Inclusion Criteria for Follow-up Study:

• Previous participation in pilot study

Additional Exclusion Criteria for Follow-up Study:

• Lack of wireless internet access or computer to participate in virtual Zoom call

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Minnesota	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• University of Minnesota
• Cerebral Palsy Alliance
• American Academy of Cerebral Palsy and Developmental Medicine
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Bernadette T Gillick, PhD, MSPT, PT, University of Minnesota

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 21, 2021
• Informed Consent Form - Mar 26, 2021

More Information

Publications

• Chen CY, Tafone S, Lo W, Heathcock JC. Perinatal stroke causes abnormal trajectory and laterality in reaching during early infancy. Res Dev Disabil. 2015 Mar;38:301-8. doi: 10.1016/j.ridd.2014.11.014. Epub 2015 Jan 9.
• Einspieler C, Prechtl HF. Prechtl's assessment of general movements: a diagnostic tool for the functional assessment of the young nervous system. Ment Retard Dev Disabil Res Rev. 2005;11(1):61-7. Review.
• Eyre JA, Miller S, Clowry GJ, Conway EA, Watts C. Functional corticospinal projections are established prenatally in the human foetus permitting involvement in the development of spinal motor centres. Brain. 2000 Jan;123 ( Pt 1):51-64.
• Eyre JA, Smith M, Dabydeen L, Clowry GJ, Petacchi E, Battini R, Guzzetta A, Cioni G. Is hemiplegic cerebral palsy equivalent to amblyopia of the corticospinal system? Ann Neurol. 2007 Nov;62(5):493-503.
• Eyre JA, Taylor JP, Villagra F, Smith M, Miller S. Evidence of activity-dependent withdrawal of corticospinal projections during human development. Neurology. 2001 Nov 13;57(9):1543-54.
• Gillick BT, 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. Arch Phys Med Rehabil. 2015 Apr;96(4 Suppl):S104-13. doi: 10.1016/j.apmr.2014.09.012. Epub 2014 Oct 2.
• Gillick BT, Krach LE, Feyma T, Rich TL, Moberg K, Thomas W, Cassidy JM, Menk J, Carey JR. Primed low-frequency repetitive transcranial magnetic stimulation and constraint-induced movement therapy in pediatric hemiparesis: a randomized controlled trial. Dev Med Child Neurol. 2014 Jan;56(1):44-52. doi: 10.1111/dmcn.12243. Epub 2013 Aug 21.
• Kirton A, Chen R, Friefeld S, Gunraj C, Pontigon AM, Deveber G. Contralesional repetitive transcranial magnetic stimulation for chronic hemiparesis in subcortical paediatric stroke: a randomised trial. Lancet Neurol. 2008 Jun;7(6):507-13. doi: 10.1016/S1474-4422(08)70096-6. Epub 2008 May 1.
• Lehman LL, Rivkin MJ. Perinatal arterial ischemic stroke: presentation, risk factors, evaluation, and outcome. Pediatr Neurol. 2014 Dec;51(6):760-8. doi: 10.1016/j.pediatrneurol.2014.07.031. Epub 2014 Aug 14. Review.
• Narayana S, Rezaie R, McAfee SS, Choudhri AF, Babajani-Feremi A, Fulton S, Boop FA, Wheless JW, Papanicolaou AC. Assessing motor function in young children with transcranial magnetic stimulation. Pediatr Neurol. 2015 Jan;52(1):94-103. doi: 10.1016/j.pediatrneurol.2014.08.031. Epub 2014 Sep 18.
• Thelen E, Corbetta D, Spencer JP. Development of reaching during the first year: role of movement speed. J Exp Psychol Hum Percept Perform. 1996 Oct;22(5):1059-76.
• van de Ruit M, Perenboom MJ, Grey MJ. TMS brain mapping in less than two minutes. Brain Stimul. 2015 Mar-Apr;8(2):231-9. doi: 10.1016/j.brs.2014.10.020. Epub 2014 Nov 8.

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT02743728
• Other Study ID Numbers: PT-2015-23643
• First Posted: Apr 19, 2016
• Last Update Posted: Apr 14, 2022
• Last Verified: Apr 1, 2022

• Keywords provided by University of Minnesota: perinatal stroke; transcranial magnetic stimulation; magnetic resonance imaging; diffusion tensor imaging; non-invasive brain stimulation; infant
• Additional relevant MeSH terms: Stroke; Paresis

Study Results

Participant Flow

Arm/Group Title	All Infants
Arm/Group Description	Each infant will receive an Magnetic Resonance Imaging, then Transcranial Magnetic Stimulation Cortical Excitability testing, and General Movement Assessment. These 3 different components of the one arm in which all infants are involved will be collectively assessed. Magnetic Resonance Imaging: Anatomical and Diffusion Tensor Imaging Analysis. Transcranial Magnetic Stimulation: Assessment of brain (cortical) excitability General Movement Assessment: Spontaneous movement assessment of infant while lying in unperturbed state.
Period Title: Overall Study
STARTED	20
COMPLETED	20
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	All Infants
Arm/Group Description	Each infant will receive an Magnetic Resonance Imaging, then Transcranial Magnetic Stimulation Cortical Excitability testing, and General Movement Assessment. These 3 different components of the one arm in which all infants are involved will be collectively assessed. Magnetic Resonance Imaging: Anatomical and Diffusion Tensor Imaging Analysis. Transcranial Magnetic Stimulation: Assessment of brain (cortical) excitability General Movement Assessment: Spontaneous movement assessment of infant while lying in unperturbed state.
Overall Participants	20
Age (Count of Participants)
<=18 years	20 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	6 30%
Male	14 70%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
United States	20 100%

Outcome Measures

1. Primary Outcome

Title	Cortical Excitability MEP Amplitude (µV)
Description	Cortical excitability of ipsilesional and contralesional hemispheres assessed by transcranial magnetic stimulation (TMS) in infants with perinatal stroke. TMS will be used to assess cortical excitability through electromagnetic depolarization of targeted cortical neurons through painless pulses delivered over the scalp. The estimated time of TMS assessment is around 2 hours during Visit 2. Outcome is reported as MEP amplitude in units of microvolts (µV).
Time Frame	2 hours

Outcome Measure Data

Analysis Population Description

Of the 20 enrolled infants, 11 infants participated in TMS. 3 of the 11 infants participated in TMS sessions at two different timepoints; therefore, 14 datasets for TMS outcome measures (MEP amplitude (Outcome 1), Resting Motor Threshold (Outcome 2) were analyzed.

Arm/Group Title	All Infants
Arm/Group Description	Each infant will receive an Magnetic Resonance Imaging, then Transcranial Magnetic Stimulation Cortical Excitability testing, and General Movement Assessment. These 3 different components of the one arm in which all infants are involved will be collectively assessed. Magnetic Resonance Imaging: Anatomical and Diffusion Tensor Imaging Analysis. Transcranial Magnetic Stimulation: Assessment of brain (cortical) excitability General Movement Assessment: Spontaneous movement assessment of infant while lying in unperturbed state.
Measure Participants	14
Median (Full Range) [µV]	325

2. Primary Outcome

Title	Cortical Excitability Percentage of Maximum
Description	Cortical excitability of ipsilesional and contralesional hemispheres assessed by transcranial magnetic stimulation (TMS) in infants with perinatal stroke. TMS will be used to assess cortical excitability through electromagnetic depolarization of targeted cortical neurons through painless pulses delivered over the scalp. The estimated time of TMS assessment is around 2 hours during Visit 2. The outcome of motor threshold will be reported as the percentage of maximum stimulator output.
Time Frame	2 hours

Outcome Measure Data

Analysis Population Description

Of the 20 enrolled infants, 11 infants participated in TMS. 3 of the 11 infants participated in TMS sessions at two different timepoints; therefore, 14 datasets for TMS outcome measures (MEP amplitude (Outcome 1), Resting Motor Threshold (Outcome 2) were analyzed.

Arm/Group Title	All Infants
Arm/Group Description	Each infant will receive an Magnetic Resonance Imaging, then Transcranial Magnetic Stimulation Cortical Excitability testing, and General Movement Assessment. These 3 different components of the one arm in which all infants are involved will be collectively assessed. Magnetic Resonance Imaging: Anatomical and Diffusion Tensor Imaging Analysis. Transcranial Magnetic Stimulation: Assessment of brain (cortical) excitability General Movement Assessment: Spontaneous movement assessment of infant while lying in unperturbed state.
Measure Participants	14
Median (Full Range) [%MSO]	70

3. Secondary Outcome

Title	General Movement Assessment
Description	Movement quality will be assessed by general movement assessment (GMA). GMA requires 5-10 minutes videotaping when infants are placed in spine position for scoring. Infants are scores categorically as typical (present fidgety movements) or atypical (absent, sporadic, or abnormal fidgety movements). Outcome is reported as the number of typical infants and number of atypical infants.
Time Frame	15 minutes

Outcome Measure Data

Analysis Population Description

Of the 20 enrolled infants, 12 were able to complete the General Movements Assessment (GMA). The GMA was only completed if infants were between 3-5 months of age at the time of enrollment.

Arm/Group Title	All Infants
Arm/Group Description	Each infant will receive an Magnetic Resonance Imaging, then Transcranial Magnetic Stimulation Cortical Excitability testing, and General Movement Assessment. These 3 different components of the one arm in which all infants are involved will be collectively assessed. Magnetic Resonance Imaging: Anatomical and Diffusion Tensor Imaging Analysis. Transcranial Magnetic Stimulation: Assessment of brain (cortical) excitability General Movement Assessment: Spontaneous movement assessment of infant while lying in unperturbed state.
Measure Participants	12
Typical	8 40%
Atypical	4 20%

4. Secondary Outcome

Title	Adverse Events
Description	Recording of adverse events will take place during TMS cortical mapping and MRI scanning of infants with perinatal stroke. Assessment of vital signs changes and pain/stress responses during both MRI and TMS assessment during visit 1 and visit 2. Outcome is reported as the number of adverse events recorded.
Time Frame	2 days

Outcome Measure Data

Analysis Population Description

Of the 20 enrolled infants, 13 infants participated in either MRI or TMS (during which adverse events were recorded).

Arm/Group Title	All Infants
Arm/Group Description	Each infant will receive an Magnetic Resonance Imaging, then Transcranial Magnetic Stimulation Cortical Excitability testing, and General Movement Assessment. These 3 different components of the one arm in which all infants are involved will be collectively assessed. Magnetic Resonance Imaging: Anatomical and Diffusion Tensor Imaging Analysis. Transcranial Magnetic Stimulation: Assessment of brain (cortical) excitability General Movement Assessment: Spontaneous movement assessment of infant while lying in unperturbed state.
Measure Participants	13
Number [# Adverse Events]	0

5. Secondary Outcome

Title	Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT)
Description	The PEDI-CAT uses Item Response Theory statistical models to estimate a child's ability from a minimal number of items. Three functional domains will be assessed. The PEDI-CAT software provides normative standard scores presented as T scores and age percentile ranges to assess daily activities, mobility, and social/cognitive function. Outcome is reported as the mean score generated by the PEDI-CAT software. Scores are based on t-test values and do not have a unit of measure or a defined range. Higher scores indicate greater deviation from the standardized mean score.
Time Frame	15 minutes

Outcome Measure Data

Analysis Population Description

Of the 20 enrolled infants, 6 infants participated in remote follow-up and were assessed with the PEDI-CAT.

Arm/Group Title	All Infants
Arm/Group Description	Each infant will receive an Magnetic Resonance Imaging, then Transcranial Magnetic Stimulation Cortical Excitability testing, and General Movement Assessment. These 3 different components of the one arm in which all infants are involved will be collectively assessed. Magnetic Resonance Imaging: Anatomical and Diffusion Tensor Imaging Analysis. Transcranial Magnetic Stimulation: Assessment of brain (cortical) excitability General Movement Assessment: Spontaneous movement assessment of infant while lying in unperturbed state.
Measure Participants	6
Daily Activities	46
Mobility	42
Social/Cognitive	38

Adverse Events

Time Frame	Recording of adverse events will take place during TMS cortical mapping and MRI scanning of infants with perinatal stroke. Assessment of vital signs changes and pain/stress responses during both MRI and TMS assessment during visit 1 and visit 2.
Arm/Group Title	All Infants
Arm/Group Description	Each infant will receive an Magnetic Resonance Imaging, then Transcranial Magnetic Stimulation Cortical Excitability testing, and General Movement Assessment. These 3 different components of the one arm in which all infants are involved will be collectively assessed. Magnetic Resonance Imaging: Anatomical and Diffusion Tensor Imaging Analysis. Transcranial Magnetic Stimulation: Assessment of brain (cortical) excitability General Movement Assessment: Spontaneous movement assessment of infant while lying in unperturbed state.
All Cause Mortality
	All Infants
	Affected / at Risk (%)	# Events
Total	0/13 (0%)
Serious Adverse Events
	All Infants
	Affected / at Risk (%)	# Events
Total	0/13 (0%)
Other (Not Including Serious) Adverse Events
	All Infants
	Affected / at Risk (%)	# Events
Total	0/13 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.