Perinatal Stroke: Understanding Brain Reorganization

Recruiting

Phase N/A Results N/A

Trial Description

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). More importantly, no therapy has been devised to mitigate these specific maladaptive changes leading to hemiplegic CP. However, 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. This delays therapy. We view the first several months after perinatal stroke as a "window of opportunity" because it is known to be a critical period of development. During this period, a well-designed intervention could minimize maladaptive changes in the brain. To design such a science-based rehabilitation protocol for young infants during this window of opportunity, we must first develop efficient and reliable assessments to detect and measure maladaptive cortical reorganization in the brain.
Therefore, the main purpose of this study is to examine early brain reorganization in 3-5 months old infants with unilateral 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' spontaneous movement quality using the General Movement Assessment (GMA) procedure. This will allow the investigators to examine the relationship between measures of motor pathway integrity and early signs of potential motor impairment.

Detailed Description

Background and Significance
Perinatal stroke affects more than1 in 2,300 live births. Perinatal stroke is the most common cause of hemiparetic cerebral palsy (CP). Even with prompt behavioral therapy, ongoing significant residual motor impairments are common in these children. In this case, innovative interventions that take advantage of the early critical window for optimizing outcomes are urgently needed—in infancy. Thus, understanding the early brain reorganization before the brain has not yet largely reorganized is critical for developing efficacious early intervention.
Current pediatric studies have employed non-invasive brain stimulation, and most commonly use the single or paired-pulses of Transcranial Magnetic Stimulation (TMS) to evaluate brain plasticity by assessing cortical excitability. To date, there is only one infant study using TMS to assess cortical excitability with perinatal stroke. 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. The General Movements Assessment (GMA) is a quick and non-invasive way to evaluate motor performance and to predict CP in high-risk infants before 20 weeks of age (corrected age for preterm infants). Thus, the purpose of 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 GMA.
Specific Aims/Study Objectives
Aim 1: Use TMS to index maladaptive cortical reorganization by assessing the relative excitability of corticospinal projections from each hemisphere to upper extremity musculature in 3 to 5 month old infants who have a confirmed diagnosis of perinatal stroke.
Hypothesis: The ipsilesional hemisphere will have a smaller "map volume" (lower cortical excitability) than the contralesional hemisphere (larger map volume).
Aim 2: Index maladaptive cortical reorganization by evaluating the organizational integrity of the CSTs bilaterally via fractional anisotropy (FA), a standardized metric derived from DTI, in infants with perinatal stroke.
Hypothesis 1: Ipsilesional CST will have a lower value of FA than the contralesional CST.
Hypothesis 2: Smaller cortical excitability volumes will be associated with lower values of FA.
Aim 3: For infants with perinatal stroke, examine the relationship between movement quality derived from the GMA and cortical excitability and with CST integrity.
Hypothesis: Atypical GMA outcome scores will be associated with a lower FA value and lower ipsilesional CST excitability.
Aim 4: Record any feasibility issues that arise, and monitor for adverse events during TMS cortical mapping and MRI scanning of infants with perinatal stroke.
Hypothesis 1: TMS and MRI assessments of infants with perinatal stroke are feasible.
Hypothesis 2: No seizure or other serious adverse event related to TMS or MRI/DTI will occur in this study.
Research Design and Methods
Study design and sample size:
This study will be a cross-sectional, two-visit pilot study with MRI scanning on Visit 1, and TMS and GMA testing on the Visit 2. Ten term or preterm infants with the diagnosis of perinatal stroke will be enrolled.
Subjects Recruitment Plan:
Stage 1: For families who contact the investigators with interest in this study after seeing the recruitment letter or flyer, initial screening process will be completed. This includes review of medical records obtained by signatures on an authorization form to list the clinics to be contacted for medical records.
Stage 2: Once the investigators have determined eligibility for study criteria for the infant, they will mail the family the consent and HIPAA for review, follow-up with a phone call to discuss any questions and then schedule a consent meeting to discuss and obtain signatures. If the family deems appropriate, this can occur on the same day as Visit 1.
Procedures
Visit 1 (MRI/DTI)
Preparatory Activity:
One week prior to Visit 1, the study team will educate caregivers as to how to prepare the infant for the optimal MRI experience. Caregivers will receive a digital file with a recording of the MRI operation sound. The caregivers will be asked to play these sounds while the infant sleeps so they become familiarized with these noises.
Day of Visit:
Infants will be fed, by their caregiver in a separate calming room, and then allowed to fall asleep for MRI scanning. A memory foam mattress for infants will be used to support them firmly and comfortably on the scanner table. Both silicone infant ear plugs and ear protector will both be used to diminish the noises during scanning. One researcher will stay with the infants throughout the scanning session to ensure and monitor infants' responses and safety. Subjects will be scanned on a Siemens 3Tesla (magnet strength) system at the Center for Magnetic Resonance Research (CMRR).
The scan protocol will include both an anatomical T1-weighted structural MPRAGE scan with spatial resolution 1x1x1mm3 that will be used to guide the TMS testing in Aim 2 and DTI which will allow investigation of the variation in connectivity of the CST in these infants with perinatal stroke. High angular resolution diffusion imaging (HARDI) with whole-brain coverage using the 'Human Connectome Project' (HCP) DTI sequence and spatial resolution 1.8x1.8x1.8mm3, b-value=1500 s/mm2, 128 gradient directions and 15 additional nondiffusion weighted images will be obtained. HCP tractographic methods will be applied to the HARDI data to define the two CST's and compute the integrity metrics of track volume and mean fractional anisotropy (FA). The complete MRI dataset will be obtained in less than 38 minutes.
Visit 2 (GMA and TMS):
Visit 2 will be scheduled within 7 days after Visit 1 to avoid nonsynchronous results of MRI/DTI and TMS due to natural developmental changes of central nervous system.
GMA:
For GMA scoring, infants will be placed in supine position wearing only a diaper to allow for clear observation of trunk and limbs spontaneous movements. Infants will be observed and videotaped for 5-10 minutes in an awake but calm state without interacting with people around them or while playing with a toy. The classifications of "typical" and "atypical" of different movement categories of GMA will be determined to define the ranks of motor outcomes in each infant.
TMS:
Single-pulse TMS (Bistim2, Magstim, UK) with a 50mm figure-of-eight coil (P/N4186-00,Magstim, UK) will be used to assess cortical excitability from the M1 region of both the ipsilesional and contralesional hemispheres under the guidance of a frameless stereotactic neuronavigation system (Brainsight, Rogue Research, Montreal, Quebec, Canada). Each infant's MRI will be projected onto the neuronavigation system to assist with localization of the motor cortex (T1 MPRage).
Mapping (10 minutes): A 5-by-5 cortical grid of target (25 targets in total) with the interval 1 cm (4X4 cm2) will be generated over the motor cortex area in the Neuronavigation System. A response map based on the peak-to-peak amplitude of MEP will be created in real time by a customized program (LabVIEW, v2012, National Instruments, Austin, TX) program.
Hotspot determination and motor threshold determination (15 minutes): The target with the greatest motor evoke potential (MEP) peak-to-peak amplitude will be defined as the hotspot which is the most responsive location on the motor cortex. After determining the hotspot, the motor threshold (MT) will be assessed over the hotspot. We define the resting MT as the minimal TMS output necessary to produce MEPs with a peak-to-peak amplitude >50 microvolts in at least 3 out of 5 consecutive trials. EMG signal will be recorded using surface electromyography (EMG) electrodes attached over bilateral biceps based. All data will be collected by a custom EMG amplifier and data acquisition system and stored by LabVIEW program (National Instruments, Austin, TX) for offline analysis.
Anticipated Risks/Risk Mitigation:
MRI-Dislodging of indwelling metals and disruption of medical devices: Exclude if metal/medical devices are incompatible.
MRI-Metal projectiles inadvertently presented during MRI: Conduct on-site screen and removal of potential projectiles (coins, keys, etc).
MRI-Temporary mild hearing loss due to noise level of equipment: Subjects will wear earplugs (~20 decibel reduction) and headphones (~35 dB reduction) during MRI to protect against excessive noise MRI-Discomfort due to positioning: Investigator to be present in MRI room throughout the scan with visual and tactile monitoring MRI-Wake up and move during the MRI scanning: One investigator will stay with the infants throughout the scanning process to monitor infants' arousal state and secure the infants if the infants are fully awake TMS-Stimulation over a tumor which may alter metabolic activity: Screen appropriately for exclusion criteria of neoplasm.
TMS-Threshold altering pharmacologic agent: Physician review of each medical record for determination of appropriateness for study inclusion.
TMS-Pain: Age-appropriate Vital signs (HR, RR and BP), skin integrity, distress responses will be continuously monitored for determination of pausing or stopping.
TMS-Fatigue, Sleepiness: Infant arousal state will be monitored and recorded each minute during the TMS test TMS-Temporary mild hearing loss due to noise level of equipment: Silicon infant-appropriate ear plugs will be inserted before TMS and continuously checked for placement.
TMS-Safe practices will be further ensured by establishing the location for testing within the University of Minnesota's Clinical and Translational Science Institute (CTSI), where the equipment and personnel to manage a seizure or other complications are present if an adverse event occurs, the protocol will be following and the infant will be assessed and the study reviewed for safety.
TMS-No serious adverse events have been reported from the few published studies investigating TMS in infants. As the innovation of this study is to investigate comprehensively both the safety and feasibility of TMS and neuroimaging in infant, we have devised complete individual and entire study stopping rules.
GMA-Concern for facial recognition and loss of anonymity: The recording will be destroyed after it is coded, up to 5 years after the completion of the study. This recording will not be used for any purposes outside of the research study.
Although this study does not incorporate a formal long-term assessment, the investigators will incorporate a follow-up phone call 1-month after participation to continue the assessment of safety. Questions pertaining to change in medical status, including any onset of seizures will be asked.

Conditions

Interventions

  • Transcranial Magnetic Stimulation Device
    Other Names: TMS
    Intervention Desc: Assessment of brain (cortical) excitability
    ARM 1: Kind: Experimental
    Label: All Infants
    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 Procedure
    Other Names: Magnetic Resonance Imaging Scan; MRI
    Intervention Desc: Anatomical and Diffusion Tensor Imaging Analysis.
    ARM 1: Kind: Experimental
    Label: All Infants
    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.
  • General Movement Assessment Behavioral
    Intervention Desc: Spontaneous movement assessment of infant while lying in unperturbed state.
    ARM 1: Kind: Experimental
    Label: All Infants
    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.

Trial Design

  • Masking: Open Label
  • Purpose: Diagnostic
  • Endpoint: Safety Study
  • Intervention: Single Group Assignment

Outcomes

Type Measure Time Frame Safety Issue
Primary Cortical excitability (map volume) of ipsilesional and contralesional hemispheres assessed by transcranial magnetic stimulation (TMS) in infants with perinatal stroke Day 2, 2 hour assessment performed once in the entire study No
Secondary Bilateral corticospinal tract integrity (fractional anisotropy) derived from diffusion tensor imaging Day 1, 2 hour Imaging Session performed once in the entire study No
Secondary The association of movement quality (atypical vs. typical movement) with ipsilesional cortical excitability and relative tract integrity between hemispheres (ratio of FA values) Day 2, 15 minute assessment performed once in the entire study No
Secondary Recording adverse events during TMS cortical mapping and MRI scanning of infants with perinatal stroke Day 1 during 2 hour session, and Day 2 during 2 hour 15 minute sessions once during the entire study No

Sponsors