Changes in spectroscopic biomarkers after transcranial direct current stimulation in children with perinatal stroke
Introduction
Perinatal stroke causes lifelong motor disability, typically hemiparetic cerebral palsy, affecting independence and quality of life [1]. Perinatal strokes are common, focal, vascular brain injuries occurring between 20 weeks gestation and 28 days of life [2], [3]. There are no prevention strategies, resulting in a large, ongoing burden. As an isolated, unilateral injury of defined timing, perinatal stroke represents an ideal human model of developmental plasticity [4]. Modern neuroimaging has defined specific perinatal stroke disease states [5]. Periventricular venous infarctions (PVI) are small subcortical strokes affecting periventricular white matter occurring in utero prior to 32–34 weeks [5]. In contrast, arterial ischemic strokes (AIS) of the middle cerebral artery typically occur near term and damage large cortical and subcortical structures [6]. Such arterial strokes can present acutely at birth (neonatal arterial ischemic stroke, NAIS) or later in infancy (arterial presumed perinatal ischemic stroke, APPIS). Both AIS and PVI typically injure one or more components of the motor system, resulting in contralateral hemiparetic cerebral palsy. Emerging animal [7] and human [4], [8], [9] models are defining how the motor system develops following such early injury. Integrity of both the lesioned and contralesional motor cortices, and the balance between them, are essential determinants of function. These models have identified potential cortical targets for therapeutic neuromodulation [10].
Non-invasive neuromodulation technologies such as transcranial direct current stimulation (tDCS) combined with intensive motor therapy have shown promise in chronic hemiparesis after adult stroke [11], [12]. During tDCS, a weak electrical current is applied to the scalp, altering cortical plasticity. Trends include relative increases in excitability with anodal stimulation and decreased excitability with cathodal stimulation [13], [14] though exceptions are increasingly recognized [15], [16], [17]. When paired with task learning or rehabilitation, lasting changes in performance have been demonstrated [12], [18]. tDCS also lends itself to blinded clinical trials with effective sham techniques [19]. Anodal tDCS over damaged primary motor cortex (paired with intensive motor therapy) may improve motor function by increasing perilesional cortical excitability [20]. Conversely, cathodal tDCS over the intact hemisphere may have effects by altering transcallosal inhibition [12]. Both the lesioned and contralesional M1 are the main targets of such neuromodulation but molecular mechanisms are almost entirely unknown.
Emerging evidence suggests similar potential of non-invasive neuromodulation in children with perinatal stroke and hemiparesis. Two controlled trials of repetitive transcranial magnetic stimulation (rTMS) have suggested efficacy and safety [21], [22]. That tDCS can safely produce marked enhancement of motor learning in healthy school-aged children has also now been established [18]. A recent phase 1/2 controlled clinical trial of contralesional M1 tDCS combined with 2 weeks of intensive motor therapy suggested potential efficacy for children with hemiparesis after perinatal stroke [23].
The mechanisms of non-invasive neuromodulation are poorly understood but amenable to investigation with pre- and post-interventional neuroimaging [24], [25]. Most studies to date have focused on changes in functional connectivity, task-based functional MRI activation patterns or white matter structure rather than neurochemistry. Measuring cortical metabolite concentrations with proton magnetic resonance spectroscopy (MRS) can provide information on neuronal health (N-acetyl-aspartate [NAA]), cell membrane health (choline compounds [Cho]), energy metabolism (creatine compounds [Cre]), health of glial cells (myo-Inositol [Ins]), metabolic activity and excitatory neurotransmitter concentrations (glutamate [Glu]) among others [26], [27]. Limited evidence supports specific neurochemical changes after tDCS in adults. Increased glutamate and glutamine (Glx) under the stimulating anode with smaller changes in contralateral homologous regions may occur and correlate with changes in motor behaviour [28]. Metabolite increases after anodal tDCS have also been demonstrated for total NAA [28] and myo-inositol [29] whereas decreases may occur in γ-Aminobutyric acid (GABA) [30]. During cathodal tDCS, decreases in both Glx and GABA have been reported [30]. Using fMRI-guided MRS, we recently demonstrated specific neurochemical alterations in bilateral M1 in children with perinatal stroke that correlated with degree of hemiparesis [31].
Therefore, MRS represents a novel means by which mechanisms of therapy and modulation-induced changes in cortical function might be explored in disabled children. Our aim here was to examine intervention-induced metabolic changes in the motor cortex in children with perinatal stroke and hemiparesis within a tDCS neuromodulation clinical trial [23]. We hypothesized that Glx concentration would decrease under cathodal stimulation in the non-lesioned M1 with the degree of change correlating with change in clinical function.
Section snippets
Population
Participants with perinatal stroke were recruited via the Alberta Perinatal Stroke Project (APSP), a population-based research cohort [32]. Inclusion criteria were: (1) unilateral, MRI-confirmed perinatal stroke syndrome according to previously validated criteria [5] including neonatal arterial ischemic stroke (NAIS), arterial presumed perinatal ischemic stroke (APPIS), or periventricular venous infarction (PVI), (2) current age 6–19 years and term birth (>36 weeks), and (3) symptomatic
Population
Of the 23 stroke children enrolled in the clinical trial, a subset of 15 (mean age (SD) [range] = 12.1 (3.0) [6.6–18.3] years, 27% female) had complete neuroimaging and clinical data. The remaining eight participants successfully completed the trial but were excluded from the MRS imaging portion due to MRI contraindications (braces, significant anxiety about MRI) or excessive head motion. A group of 19 TDC were included for comparison [mean age (SD)[range] = 12.72(3.7)[6.0–19.0] years, 47%
Discussion
We have previously demonstrated that intensive motor learning therapy combined with tDCS may increase motor function in perinatal stroke patients [23]. The current study in a subset of these patients demonstrated decreases in Glx and Cre concentrations corresponding to the site of active cathodal tDCS compared to sham. Metabolite concentrations in the lesioned hemisphere were highly correlated with pre-intervention motor function and these correlations consistently strengthened after
Conflicts of interest
None of the authors has any conflicts of interest to declare.
Acknowledgements
The authors would like to thank the Heart and Stroke Foundation of Canada and the Alberta Children's Hospital Foundation for financial support of this project.
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