Calmer Brains in Very Preterm Infants

Very preterm infants (< 32 weeks gestational age \[GA\]) experience developmentally unexpected, repeated stress as part of lifesaving care in the NICU during a period of considerable brain maturation and growth. Exposure to early-life stress alters brain maturation resulting in long-term changes in neurodevelopment. Parental skin-to-skin care (SSC) can mitigate stress; however, parents are not always available. Calmer, a patented, therapeutic medical device, was invented to simulate aspects of SSC (skin-like surface, breathing motion, heartbeat sounds) with rates of the latter two individualized for each infant. In a randomized trial, Calmer has been shown to stabilize brain blood flow during a single, routine blood test. Most recently, we found that very preterm infants who received Calmer treatment for 3 continuous weeks had 25% greater head growth compared to controls. However, we do not know if/how Calmer treatment affects brain development in very preterm infants.

Objectives: We will gather pilot data for a larger trial to examine differences in brain structural and functional development in very preterm infants who receive Calmer treatment for 2-3 consecutive weeks compared to controls.

Methods: 22 infants born 26-30 weeks GA admitted to BC Women's Hospital NICU will be randomized to either control (n=11) or treatment groups (n=11; Calmer for 2-3 continuous weeks, 3 hours/day minimum treatment). Infants from both groups will undergo feed and bundle MRI scans at term-equivalent age using high resolution volumetric, diffusion and resting-state functional MRI to explore group differences in whole-brain volumes and structural and functional connectivity. Images will be processed using existing quantitative neonatal imaging analysis pipelines in the Selvanathan and Weber labs at BC Children's Hospital Research Institute. Analyses will include: measures of trial feasibility and description of brain differences between groups.

Significance: Ultimately, Calmer may support healthy brain maturation optimizing the neurodevelopment of vulnerable infants in Canada and beyond.

• Calmer (Device): Calmer, a unique, patented, therapeutic bed that mimics key aspects of SSC that reduce stress in preterm infants. Calmer fits into NICU incubators and cribs, and delivers 3 key SSC stimuli: touch, breathing motion, and heartbeat sounds; the rates of the latter 2 stimuli are individualized to each infant based on their parents' breathing and heart rates. Calmer is designed to provide complementary care only when parents are not able to give SSC. It is not meant nor designed to replace human SSC, so will never be tested as such a replacement. Instead, Calmer was invented to enhance and optimize brain development in preterm infants by reducing stress during the NICU stay, when parents/caregivers are not available for SSC. Our ultimate goal is to enable use of Calmer from an infant's admission to discharge, only during those times when caregivers are not available.

Primary outcomes

• Brain Volumes [When each participant reaches 40 weeks post-conceptual age and return for their MRI scan]: Anatomical analysis: Anatomical images (T2w) will be manually inspected for quality control. Images with very poor tissue contrast or motion artefacts will be rejected. T2w images will be bias-field corrected using ANTs N4ITK. The images will then be skull-stripped and segmented using the dHCP anatomical pipeline to calculate total and sub-regional brain volumes.
• Brain Functional Connectivity [When each participant reaches 40 weeks post-conceptual age]: Resting state fMRI analysis: Fieldmaps will be generated using the dual-echo EPI and magnitude scan. The dHCP functional pipeline will be implemented to achieve distortion-correction and motion-correction, register the functional image to the corresponding T2w structural image, generate a transform matrix from functional space to the 40-week T2w template; and we will perform temporal high-pass filtering (150 s high-pass cutoff) and independent component analysis (ICA) denoising using ICA FIX. Scans with a mean FD > 1 mm will be excluded. The dHCP functional pipeline will then be run on all subjects using the study-specific training file. Spatial smoothing of 5 mm will be applied using FSL's SUSAN and grand mean intensity normalization will be computed. Functional connectivity measures will be computed using the CONN toolbox.
• Brain Fractional Anisotropy [When participants reach term-equivalent age]: Diffusion tensor imaging analysis: The dHCP neonatal dMRI data processing pipeline will be used to pre-process the diffusion weighted images. Briefly, opposite phase b0 images are used to estimate the off-resonance field that is then used in the simultaneous correction of motion artefacts, susceptibility-induced and eddy current distortions. Data will then be super-resolved and, after pre-processing is complete, local diffusion and microstructural models are fitted in every voxel and averaged to calculate mean fractional anisotropy.

Secondary outcomes

• Clinical weight measures [From the start of study treatment (or enrolment if Control group) to 2-3 weeks later, at the end of intervention exposure.]: Weight: infant weight in kilograms captured when enrolled in the study (i.e. baseline T1) and end of experimental phase (2-3 weeks later; T2) We will use the weight measure to determine changes between baseline and the end of treatment.
• Head growth measures [From the start of study treatment (or enrolment if Control group) to 2-3 weeks later, at the end of intervention exposure.]: Head circumference: infant head circumference in centimetres (occipito-frontal circumference) captured when enrolled in the study (i.e. baseline T1) and end of experimental phase (2-3 weeks later; T2). We will use the head circumference measures to determine changes between baseline and the end of treatment.

Other outcomes

• Trial feasibility [2 years from the start of the study]: Consent rate: overall average consent rate of infants/month
• Trial feasibility [2 years from the start of the study]: Protocol delivery: % of on/off protocol infants
• Trial feasibility [2 years from the start of the study]: Outcome measures: % of infants with complete primary outcome data
• Trial feasibility [2 years from the start of the study]: Rate/nature of safety issues

Sex: All, ages: 26 Weeks to 30 Weeks

Inclusion Criteria:

* Very preterm infants admitted to the NICU at the BC Women's Hospital

Exclusion Criteria: Infants who have

* Congenital anomalies;
* Born small for GA (per medical admission history);
* History of birthing parent substance use in pregnancy;
* Ongoing infection at the time of enrollment;
* Pre-existing cardiovascular instability defined by shock/hypotension/need for cardiovascular drugs;
* Receiving paralytic drugs;
* Major neurological injury (e.g. hypoxic ischemic encephalopathy, hemorrhage/stroke; VP shunt);
* Beyond the 30th completed week GA (30 weeks + 6 days) at enrollment.

• Results publication: Holsti L, MacLean K, Oberlander T, Synnes A, Brant R. Calmer: a robot for managing acute pain effectively in preterm infants in the neonatal intensive care unit. Pain Rep. 2019 Mar 14;4(2):e727. doi: 10.1097/PR9.0000000000000727. eCollection 2019 Mar-Apr. PMID 31041426
• Results publication: Ranger M, Albert A, MacLean K, Holsti L. Cerebral hemodynamic response to a therapeutic bed for procedural pain management in preterm infants in the NICU: a randomized controlled trial. Pain Rep. 2021 Jan 12;6(1):e890. doi: 10.1097/PR9.0000000000000890. eCollection 2021 Jan-Feb. PMID 33490850

• Manon Ranger, PhD, Principal investigator, University of British Columbia
• Liisa Holsti, PhD, Principal investigator, University of British Columbia