Spectroscopic biomarkers of motor cortex developmental plasticity in hemiparetic children after perinatal stroke

Abstract

Perinatal stroke causes hemiparetic cerebral palsy and lifelong motor disability. Bilateral motor cortices are key hubs within the motor network and their neurophysiology determines clinical function. Establishing biomarkers of motor cortex function is imperative for developing and evaluating restorative interventional strategies. Proton magnetic resonance spectroscopy (MRS) quantifies metabolite concentrations indicative of underlying neuronal health and metabolism in vivo. We used functional magnetic resonance imaging (MRI)-guided MRS to investigate motor cortex metabolism in children with perinatal stroke. Children aged 6-18 years with MRI-confirmed perinatal stroke and hemiparetic cerebral palsy were recruited from a population-based cohort. Metabolite concentrations were assessed using a PRESS sequence (3T, TE = 30 ms, voxel = 4 cc). Voxel location was guided by functional MRI activations during finger tapping tasks. Spectra were analysed using LCModel. Metabolites were quantified, cerebral spinal fluid corrected and compared between groups (ANCOVA) controlling for age. Associations with clinical motor performance (Assisting Hand, Melbourne, Box-and-Blocks) were assessed. Fifty-two participants were studied (19 arterial, 14 venous, 19 control). Stroke participants demonstrated differences between lesioned and nonlesioned motor cortex N-acetyl-aspartate [NAA mean concentration = 10.8 ± 1.9 vs. 12.0 ± 1.2, P < 0.01], creatine [Cre 8.0 ± 0.9 vs. 7.4 ± 0.9, P < 0.05] and myo-Inositol [Ins 6.5 ± 0.84 vs. 5.8 ± 1.1, P < 0.01]. Lesioned motor cortex NAA and creatine were strongly correlated with motor performance in children with arterial but not venous strokes. Interrogation of motor cortex by fMRI-guided MRS is feasible in children with perinatal stroke. Metabolite differences between hemispheres, stroke types and correlations with motor performance support functional relevance. MRS may be valuable in understanding the neurophysiology of developmental neuroplasticity in cerebral palsy. Hum Brain Mapp 38:1574-1587, 2017. © 2016 Wiley Periodicals, Inc.

Keywords: cerebral palsy; hemiparesis; magnetic resonance imaging; magnetic resonance spectroscopy; neuroimaging; pediatric; spectroscopy.

Figure 1

Function‐guided MRS voxel placement. MRS voxel placement viewed on axial, coronal and sagittal slices approximates the hand‐knob in the precentral gyrus in a representative (A) Arterial, (B) PVI and (C) TD participant. Voxels were placed corresponding to task fMRI activations measured during a finger tapping task. Lesioned hemispheres have all been reoriented to the right side.

Figure 2

Sample spectra from the lesioned/nondominant hemisphere of (A) arterial, (B) PVI and (C) TD participants. LCM fit in red overlaid on raw data in black as well as baseline. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 3

MRS voxel placement by patient group. Dispersion maps illustrating voxel placement by patient group (overlaid on a standard template image). Each marker represents the centre of mass of each voxel for (A) arterial, (B) PVI and (C) TD participants on coronal and axial slices. Lesioned hemisphere markers have been reoriented to the right side. Note that some markers are not visible on the currently selected slice. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 4

Boxplots illustrating CSF‐corrected metabolite concentrations (i.u.) using a water reference by patient group and hemisphere. A. N‐acetyl‐aspartate (NAA), B. Creatine compounds (Cre), C. myo‐Inositol (Ins) D. Choline compounds (Cho), E. Glutamate + glutamine (Glx). Median (solid line) and mean (dotted line) concentrations as well as quartile ranges and outliers (filled circles) are displayed. ** P < 0.01, * P < 0.05. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 5

A–D. Boxplots illustrating metabolite concentrations (using creatine concentration ratios) by patient group and hemisphere. A. N‐acetyl‐aspartate (NAA/Cre), B. myo‐Inositol (Ins/Cre) C. Choline compounds (Cho/Cre), D. Glutamate + glutamine (Glx/Cre). Median (solid line) and mean (dotted line) concentrations as well as quartile ranges and outliers (filled circles) are displayed. ** P < 0.01, * P < 0.05. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 6

Relationship between motor function and metabolite concentrations in the lesioned hemispheres of arterial stroke participants. Shown are corrected concentrations (i.u.) of N‐acetyl‐aspartate (NAA) and creatine‐containing compounds (Cre) in relation to four motor function tasks: (A) MA, Melbourne Assessment of Unilateral Upper Limb Function, (B) AHA, Assisting Hand Assessment, (C) BBT, Box and Block Test for affected and (D) unaffected hands. [Color figure can be viewed at http://wileyonlinelibrary.com]