Background
Paediatric arterial ischaemic stroke (AIS) has an incidence of at least 2.1:100,000 children per year [
1]. It is a rare but devastating event that impacts the lives of affected children, their families, and individuals in their social environment [
2]. Paediatric AIS has an estimated mortality of up to 20% [
3] and is a considerable cause of childhood morbidity [
4,
5]. Two-thirds of patients who experience AIS suffer from lifelong cognitive or neurological handicaps [
2,
6]. It is important to have solid models to enable prediction of recovery after paediatric AIS, not only to provide useful information for parents and children, but also to develop and choose potentially beneficial interventions.
Recovery after AIS largely depends on plastic properties of the brain. The term neuroplasticity refers to the ability of the central nervous system to adapt to changes in the external and internal milieu [
7] and is associated with structural and functional modifications in the brain which can be detected via neuroimaging and neurophysiological methods. To improve the functional outcome of children after a brain injury, a deeper understanding of processes driving neuroplastic changes is crucial [
8].
There is an ongoing debate on whether or not young age is advantageous with regard to brain plasticity. “Young age plasticity privilege” or the “Kennard-effect” derive from studies describing superior recovery of cognitive and motor skills after brain lesions in infant animals and humans compared to adults [
9-
11], attributed to superior plasticity in the immature brain. Other studies support an “early vulnerability” concept, in which young brains are especially vulnerable to strokes [
12-
15]. A third, more recent perspective merges both extremes and considers outcome after brain lesions to be influenced by different factors such as age at injury and sociodemographic factors, oscillating on a “recovery continuum” between plasticity and vulnerability [
16].
Recent developments suggest that functional recovery after brain injury is strongly dependent on changes in widely distributed neuronal networks controlling brain functions [
17]. This network perspective suggests that effects of a brain injury are best assessed by examining entire networks rather than single sites of structural damages or adjacent regions [
18]. Cerebral network maturation is a long lasting process [
19], and functional connections between different regions change with age [
20]. During childhood, functional connections to distant regions become stronger with advancing maturation [
21]. Furthermore, certain networks, such as the default mode network [
20], are only slightly functionally connected in childhood but increase in connection strength over time until they are fully developed by adulthood [
20]. Thus, an early childhood stroke that affects immature connections might have a wider impact on functional reorganisation than a stroke affecting more mature networks.
For visualisation of paediatric brain networks and their changes during development or after injury, resting state functional magnetic resonance imaging (rsfMRI) is one of the most appropriate techniques. Resting state fMRI measures the temporal correlation of the blood oxygen level dependent (BOLD) signal between different brain regions at rest. It is particularly suited to examine lesion effects on proximal and distal brain areas by displaying different networks across the whole brain [
22] and also reduces scanning time if multiple networks are being investigated [
23]. Therefore, it provides information about lesion effects in a short time period (<10 minutes) and requires no active participation, both of which are useful for research with handicapped and/or young children [
22,
23].
Findings of rsfMRI studies in adult patients after AIS suggest that the functional connectivity between the ipsilesional and the contralesional hemisphere in a resting state situation is predictive for motor and cognitive outcome [
24-
26]. For example, He et al. (2007) showed that functional connectivity between the left and right hemispheric posterior intraparietal sulcus was reduced in acute stroke patients but fully recovered at the chronic stage. This corresponded with improved behavioural performance from acute to chronic stage [
24]. Concerning motor recovery, rsfMRI data revealed greater functional connectivity with ipsilesional structures, and decreased functional connectivity with the contralesional motor cortex [
25]. Motor recovery 6 months post-stroke was positively correlated with functional connectivity of the ipsilesional motor cortex with the contralesional thalamus, supplementary motor area, and middle frontal gyrus at time of acute stroke [
25].
To our knowledge, only Dinomais et al. (2012) have published results of rsfMRI in paediatric AIS patients [
27]. The authors applied rsfMRI to a relatively small sample of children after neonatal stroke and analysed the relationship between functional connectivity and sensory impairment. Children who had lesions in the middle cerebral artery displayed significantly less functional connectivity in the somatosensory cortex than children who had periventricular lesions. However, this difference disappeared after correction for the loss of cortical grey-matter volume. The authors concluded that rsfMRI is a valid approach to investigate functional networks after brain lesions in children, noting especially the advantage of independence from compliance and level of performance [
27].
Besides neuroimaging techniques, neurophysiological technologies such as transcranial magnetic stimulation (TMS) have contributed to the understanding of functional reorganisation after AIS [
28-
34]. TMS is a safe, non-invasive technique that uses direct stimulation of the brain for diagnostic and therapeutic purposes in neurologically impaired adults [
35] and children [
36]. Among other applications, TMS has been used to examine the existence of descending ipsilesional and/or contralesional corticospinal projections in hemiparetic patients [
37] and also to analyse the central motor facilitatory and inhibitory processes, which allows study of interhemispheric inhibition (IHI), a physiological process in which one hemisphere inhibits its contralateral homologous counterpart [
28,
38]. After AIS, adult patients show increased IHI [
28]. Despite the small number of studies, some evidence supports the presence of this phenomenon in children after AIS [
34]. Enhanced IHI after AIS correlates with adverse motor outcome [
28,
38-
40].
Whereas rsfMRI provides a detailed topographical analysis about the location and extent of cerebral networks, it does not provide information about the activity of these networks. In contrast, no particular information about spatial properties of neural networks is available from TMS, but it is especially suited to assess activational remapping of the sensorimotor cortex after a lesion. In order to gather information about both the extent and the activity of cerebral networks, parallel use of rsfMRI and TMS are optimal complementary measures.
To date, neither a cross-sectional nor a longitudinal study has assessed the process of cortical reorganisation using a combination of TMS and neuroimaging technologies in children recovering from AIS. Therefore, the aim of the proposed study is to investigate post-stroke plasticity characteristics over time, with comparison to healthy controls, using an approach that covers both mapping and outcome of network changes. We generally assume that changes in networks over time compared to healthy controls will be correlated with changes in neuropsychological domains and in motor functions. Furthermore, the findings will provide new insights into paediatric brain development. The study could substantially contribute to the broad discussion of “young age plasticity”.
Discussion
Understanding more about functional reorganisation and recovery after stroke might enable better prediction and prevention of post-stroke deficits. Because AIS produces mostly focal, unilateral lesions, it can be used to investigate reorganizational patterns and thus to display how cerebral reorganisation and functional improvement are interrelated. The resulting information could also provide insight into unknown dysfunctional plastic mechanisms, as plastic changes may be maladaptive and do not necessarily lead to functional improvements [
11]. Through the additional knowledge about the reorganizational capabilities of a child’s brain, the present study will improve treatment of children with stroke, not only by better adapting specialised education and counselling for patients and parents, but also by providing new insights into specific plasticity-related characteristics, which could help to improve individualized therapeutic rehabilitation procedures.
The human brain has remarkable plasticity throughout the life span. Structural and functional flexibility enables the developing brain to counteract adverse events such as stroke. Compared with adults, who often show long lasting cognitive and motor impairment, children with AIS often show surprisingly good functional outcomes. For these reasons children present a unique study population to learn more about mechanisms of neuroplasticity, particularly because the functional specificity of maturing brains is incomplete [
16]. This study has the potential to answer the decades-old question of whether young brains recover and adapt more quickly after injury as compared to older brains.
A major strength of this study is the combination of rsfMRI and TMS. On the one hand, rsfMRI enables visualisation of different neuronal brain networks in the form of functional network maps for injured and healthy children. Subsequent comparisons might reveal direct consequences of stroke lesions on the connectivity between certain brain regions. These visual findings must be correlated with neuropsychological and neurological features, which allow further insight into how network disruptions impact functional outcome. On the other hand, TMS can detect possible imbalances in the interhemispheric motor system after a brain lesion, and the resulting activity can also be correlated with network changes, thereby providing information about the motor outcome after certain network disruptions. Taken together, this study offers a differentiated, non-invasive approach to identify mechanisms of functional recovery in a child’s brain over time.
Research in patients with stroke is not only relevant to unravelling the neuroplastic processes of recovery, but may also provide information about general developmental properties of the normal human brain. This study may also expand our knowledge of the development of neuropsychological and motor functions in the healthy brain. Thus, data regarding functional patterns in the healthy developing brain will be an added benefit of the present study, allowing for definition of normative standards and an improved identification of pathological patterns.
In conclusion, the present study allows the collection of data on a rare but serious clinical condition. It therefore contributes to the overall understanding of the maturing brain, of how it deals with a focal injury, of the role and functioning of underlying reorganisation processes, and eventually of the connection between these processes and the functional outcome.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
MS, SG and RE designed the study, obtained funding and are responsible for the collection, analysis and interpretation of the data. SK wrote this study protocol. JD provided annotations and important corrections. SK and JD are doctoral students involved in data collection, analysis and interpretation of the data. RW, CW and PM are the experts in charge of the organization of the rsfMRI, AK is the expert in charge of the organization of TMS. RW, CW, PM and AK contributed much to this study protocol by providing important knowledge and consistent corrections about rsfMRI and TMS respectively. AK provides proprietary software for the TMS part of the study. All authors read and approved the final manuscript.