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Available online at www.sciencedirect.com
www.elsevier.com/locate/semperi
Plasticity following early-life brain injury: Insights from quantitative MRI Simona Fiori, MDa, and Andrea Guzzetta, MD, PhDa,b,n a
SMILE, Department of Developmental Neuroscience, Stella Maris Scientific Institute, Via dei Giacinti 2, 56018 Calambrone, Pisa, Italy b Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
article info
abstra ct
Keywords:
Over the last decade, the application of novel advanced neuroimaging techniques to study
Neuroplasticity
congenital brain damage has provided invaluable insights into the mechanisms underlying
Diffusion imaging
early neuroplasticity. The concept that is clearly emerging, both from human and nun-
fMRI
human studies, is that functional reorganization in the immature brain is substantially
Children
different from that of the more mature, developed brain. This applies to the reorganization
Infants
of language, the sensorimotor system, and the visual system. The rapid implementation
Cerebral palsy
and development of higher order imaging methods will offer increased, currently unavailable knowledge about the specific mechanisms of cerebral plasticity in infancy, which is essential to support the development of early therapeutic interventions aimed at supporting and enhancing functional reorganization during a time of greatest potential brain plasticity. & 2015 Published by Elsevier Inc.
Introduction Neuroplasticity reflects the capability of the brain to modify throughout life by adapting, at different levels, to environmental exposition.1 It underlies the processes of learning and memorizing and the damage-induced processes of brain recovery and reorganization. Neuroplastic mechanisms appear to be greatest during infancy, the so-called critical period, at a time when brain maturation has a faster pace.2,3 Children have, for instance, an enhanced ability to become proficient in speaking a new language or playing a musical instrument, if adequately trained. This enhanced neuroplasticity plays an essential role in functional reorganization following early brain damage.4–8 Congenital brain lesions provide an interesting model for studying cerebral reorganization, as they naturally encompass the different combinations of distribution (focal and
diffuse) and timing (early gestation, late gestation, and term) of damage.9 Several factors influence the efficacy of compensatory mechanisms of brain functions, in particular, the distribution of the lesion and the timing of the insult. According to the timing of the insult, the brain can be affected (i) during periods of neuronal proliferation, migration, and cortical organization, resulting in brain malformations (first or second trimester of pregnancy) or (ii) during periods of selective vulnerability of white or gray matter and result in periventricular or cortical and deep gray matter gliotic or cystic lesions (third trimester).10 The stage of cerebral development at the moment of the insult is key for the type of reorganizational response; however, the specificities of the young brain's neuroplastic mechanisms expose it to the risk of dysfunctional processes of reorganization (the so-called maladaptive plasticity).5 A full understanding of the
n Corresponding author at: SMILE, Department of Developmental Neuroscience, Stella Maris Scientific Institute, Via dei Giacinti 2, 56128 Calambrone, Pisa, Italy. E-mail address: [email protected] (A. Guzzetta).
http://dx.doi.org/10.1053/j.semperi.2015.01.007 0146-0005/& 2015 Published by Elsevier Inc.
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mechanisms underlying the reorganization of brain functions after early damage is therefore essential in order to target the rehabilitative intervention in terms of intensity, quality, and duration, maximizing the processes of adaptive plasticity and limiting the maladaptive ones.11 An essential contribution for the understanding of brain abnormalities associated with maldevelopments or lesions is provided by non-invasive neuroimaging techniques and in particular by magnetic resonance imaging (MRI). Structural MRI has been increasingly applied in children, allowing for a detailed study of pathophysiology and timing of cerebral lesions and a strict monitoring of their evolution, thus providing critical insights into the relation between lesion and function.12 Conventional structural MRI can be complemented by advanced MR techniques such as functional MRI (fMRI) or diffusion MRI (dMRI). These techniques allow the study of brain functional reorganization beyond structural imaging (i.e., fMRI) or the in vivo study of microstructure of white matter and brain connectivity (i.e., dMRI) (Fig. 1). The complex and heterogeneous functional correlates observed in children with congenital brain lesions are the result of different degrees of involvement of the various systems and of their supra-modal compensatory processes. Only for the sake of clarity, the principal systems will be considered independently, focusing on the aspects of cerebral plasticity explored by the different brain MRI techniques.
The language system Language processing has been estimated to involve mostly the left hemisphere of the human brain in healthy adult subjects. This inborn predisposition of the left hemisphere for language processing is sustained by anatomical studies on structural asymmetries between the two hemispheres in perisylvian regions13 and in sulcal patterns,14 which become more evident during childhood as a proof of a regional specialization in the acquisition of language.
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In spite of this innate predisposition, converging evidence from fMRI and MEG suggests that a bilateral early developmental involvement for language representation is a fundamental prerequisite for language neuroplasticity. Indeed, long before the advent of neuroimaging, it has been demonstrated that focal lesions acquired during fetal life or infancy can be compensated for much more effectively compared to similar lesions acquired later in life. An injury that occurs early in the dominant hemisphere can be compensated for by a contralateral organization of language networks.15 During this process, the intact right hemisphere develops and strengthens a language network that mostly mirrors the typical left-hemispheric topography of healthy individuals.15,16 This neuroplastic potential was shown for different etiopathogenic patterns, including periventricular parenchymal damage,15 arterial stroke,16 cortico-subcortical lesions of perinatal origin,17 or hemispherectomy.18 The timing of the insult or the distribution of the lesion might affect plastic mechanisms of re-mapping. For example, in periventricular damage, the severity of the lesion as assessed by structural MRI metrics, such as the distance between the lateral outline of the ventricle and the midline in specific coronal projections, was shown to reliably predict the type of language organization.15 In slightly later damage, the arterial stroke of the term infant, the involvement of Broca's area, or the presence of a thalamic lesion are strong predictors of a contralateral organization of language networks16 (Fig. 2). Subtle differences in language outcome in right versus left congenital lesions are observed and reinforce the idea of a specialization of the two hemispheres, in spite of their plastic potential. Convincing data support the hypothesis that a price for language function plasticity has to be paid by right hemispheric functions, the so-called crowding effect. For example, it has been demonstrated by fMRI that children with left-lesion-induced right-hemispheric language organization show deficits in visuospatial abilities, and the degree of visuospatial dysfunction is proportional to the degree of right language representation.19
Fig. 1 – Whole-brain diffusion tractography in a subject with right arterial stroke. A general reduction of tracts stemming from the right hemisphere is shown.
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Fig. 2 – Reorganization of language function following perinatal stroke. fMRI activations following a covert rhyme generation task in two adolescents with perinatal stroke. In both the subjects, fMRI results supported language reorganization within the right hemisphere. In one case (left column), damage was limited to the basal ganglia and thalamus (lesion is indicated by the black arrowhead), and in the other case (right column), damage involved the left Broca's area.
Fig. 3 – Reorganization of primary motor function following congenital brain damage. fMRI activations following an active hand motor task in two children with congenital malformation. In one subject (left column), fMRI results supported an ipsilesional reorganization of primary motor function in a more anterior area of the frontal lobe, confirmed by the results of TMS of the affected hemisphere. In the other subject (right column), fMRI results supported a contralesional reorganization of primary motor function, confirmed by the results of TMS of the unaffected hemisphere. It is of note how the apparent extension of damage to the primary motor cortex, more obvious in the patient on the left, would have misled the prediction of the type of reorganization.
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Primary motor and sensory functions Neuroplastic mechanisms allow the potential recovery of voluntary movements after a congenital brain lesion involving the motor system by restoring the cortical impulse to the spinal motor neurons and inter-neurons. Two major mechanisms have been described for the corticospinal system to recover its connection to the spinal level after congenital brain insult. The first one implicates the motor cortex ipsilateral to brain damage to re-organize its functions either within primary or within adjacent non-primary motor areas. The second mechanism, specific to perinatal lesions, is based on the persistence of fast-conducting corticospinal connections between each motor cortex and the ipsilateral body side5,6,20,21 (Fig. 3). This latter mechanism is made possible by the existence, during the first weeks of life, of bilateral motor projections originating from the primary motor areas.6 Physiologically, the great majority of these fibers withdraw during development, but they can persist in case of unilateral cerebral damage, giving rise to a contralesional reorganization of motor function. This type of reorganization is specific for unilateral perinatal brain lesions, as it requires, at the time when damage occurs, the presence of a bilateral innervation of motoneuronal pools and a developmental increase in the number of both fast-conducting ipsilateral and contralateral corticospinal axons from the intact hemisphere. A significant hypertrophy of the corticospinal tract arising from the noninfarcted hemisphere can be found indirectly from MRI measurements and more directly from post-mortem analysis,
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by which a significantly increased number of corticospinal axons projecting from the non-affected hemisphere can be detected.6 The application of functional MRI can provide relevant information on the type of sensorimotor reorganization, as it generally shows, during active motor tasks, a clear contralateral activation in ipsilesional reorganizations and a bilateral activation in the contralesional ones.5 This latter pattern is likely due to the usual persistence of the primary somatosensory function within the affected hemisphere, which gives rise to a sensory contralateral activation from the moving hand. It is important to underline that information from fMRI can never be considered exhaustive. Reorganization of primary motor function needs investigation by transcranial magnetic stimulation (TMS), a technique that provides the necessary temporal resolution to unequivocally map the corticospinal tract.22 Reorganization of primary somatosensory function similarly requires high-temporalresolution techniques such as electroencephalography (EEG) or magnetoencephalography (MEG). In contrast to primary motor function, the intrahemispheric (ipsilesional) reorganization of primary sensory function is the principal compensatory mechanism following damage to the sensory system, even when it occurs during the very early stages of development.5 This is probably due to the lack of anatomical substrates for contralesional reorganization, even in the early stages of development. Additionally, it was also shown that, at least for some types of perinatal lesions, the thalamo-cortical fibers are still developing when the insult occurs and are thus able to bypass the lesion and reconnect with the sensory cortex within the damaged
Fig. 4 – Graphic representation of a possible mechanism correlating severity of brain damage and type of long-term reorganization of primary motor function. According to this model, in subjects with mild or severe damage to the corticospinal tract, the type of reorganization is pre-determined by the lesion. In subjects with damage of moderate severity, the type of reorganization is potentially influenced by the environment (e.g., intervention).
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hemisphere.23 This evidence comes from the combined use of structural imaging methods, such as diffusion-MRI-based tractography,24 which identify the likely trajectories of thalamo-cortical white matter bundles, and functional imaging methods, such as MEG, which are capable of reliably mapping the cortical location of primary sensory processing.25 Data obtained from these particular mechanisms of early neuroplasticity in primary sensory and motor systems generate distinctive patterns of reorganization that need to be accurately characterized at the single subject level. This complexity is further enhanced by the crucial role of the environment in driving neuroplasticity. Indeed, the pattern of sensorimotor reorganization is by no means a mere consequence of the size and site of the lesion but is strongly influenced by the experience following damage (actiondependent reorganization). Figure 4 illustrates the complex interaction between residual motor output from the affected hemisphere and somatosensory feedback from the affected limb. Not surprising, the early structural asymmetries of the corticospinal tract are not always able to predict the presence and, most of all, the severity of later hemiplegia.26 This concept is further supported by diffusion studies performed during the chronic phases of the disorder, i.e., in adolescents and young adults with unilateral cerebral palsy, which show that the asymmetry of the corticospinal tract is less correlated with sensory and motor function than the asymmetry of other projections such as the thalamo-cortical ones. These data suggest an essential role of higher-order compensatory mechanisms in shaping the long-term functional outcome.24 A growing body of evidence supports the hypothesis that the reorganization of motor function does not only take place within the sensorimotor cortex but also heavily involves subcortical structures such as the thalamus, brainstem or spinal cord, and cerebellum.27 The complex interplay between early brain plasticity of the sensorymotor system and its relation to functional outcome remains poorly understood and the subject of future ongoing studies.
The visual system Visual impairment is very common after congenital brain injury, given that a substantial part of the brain is directly or indirectly involved in vision. However, visual deficits can vary in terms of the characteristics and severity of the disorder, depending on the site, extension, and timing of brain injury.28,29 The correlation between damage to the optic radiations or the occipital cortex and deficits to the corresponding visual field is far less consistent with early lesions as compared to later ones. This finding may be related to the more powerful cerebral plasticity mechanisms in young children, which have at least in part similar neurophysiological bases to what we have described for the somatosensory system and, in particular, the possibility that thalamocortical fibers develop after the lesion, bypassing it.30 The exact characteristics and limits of this specific type of plasticity involving thalamo-cortical networks are not fully understood. It is of interest, however, that even when a visual field deficit is present, the subject with early damage seems
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to show fewer difficulties in environmental navigation and exploration. This finding is directly in line with animal model experiments, which clearly show how the ablation of the whole primary visual cortex in newborn animals does not affect their visual orientation performances, which are massively impaired after a similar lesion in adult animals.31 This phenomenon is linked to a reorganization of the pathways connecting subcortical visual structures directly to the extrastriatal visual cortex. Moreover, this occurrence appears to take place in humans as well, as shown, for example, by the increase in activation of extra-striatal structures on fMRI after the stimulation of the affected hemi-field. Taken together, available data in humans support the presence of a more effective reorganization of visual function after early brain damage, which may consist of either a “reconnection” with the targeted structures or secondary to an enhanced use of compensating circuitries.28 Even if these circuitries are not able to restore complete vision on the contralesional hemisphere, they can allow for good compensation in spatial orienting and localization.
Conclusions Brain mapping techniques and, in particular, fMRI have offered important insights to many critical questions that had been pending for decades, as it relates to how the immature brain responds to early-life brain injury. The concept that is clearly emerging, both from human and nun-human studies, is that functional reorganization in the immature brain is complex and substantially different from that of a mature brain that has already completed critical stages of development. Although a complete understanding of the underlying mechanisms of cerebral plasticity in early infancy is still far from understood, a fundamental understanding of the neurobiological and neurophysiological principles underlying repair after injury will be essential for more targeted prescription and tuning of therapeutic intervention programs. The successful application and refinement of advanced MRI techniques to the developing brain (e.g., ultra-high field MR) will undoubtedly provide important, currently unavailable insights to these intriguing questions.
refere nces
1. Chen R, Cohen LG, Hallett M. Nervous system reorganization following injury. Neuroscience. 2002;111(4):761–773. 2. Lewis TL, Maurer D. Multiple sensitive periods in human visual development: evidence from visually deprived children. Dev Psychobiol. 2005;46(3):163–183. 3. Berardi N, Pizzorusso T, Maffei L. Critical periods during sensory development. Curr Opin Neurobiol. 2000;10(1):138–145. 4. Bates E, Reilly J, Wulfeck B, et al. Differential effects of unilateral lesions on language production in children and adults. Brain Lang. 2001;79(2):223–265. 5. Staudt M, Gerloff C, Grodd W, Holthausen H, Niemann G, Krägeloh-Mann I. Reorganization in congenital hemiparesis acquired at different gestational ages. Ann Neurol. 2004;56 (6):854–863.
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6. Eyre JA, Smith M, Dabydeen L, et al. Is hemiplegic cerebral palsy equivalent to amblyopia of the corticospinal system? Ann Neurol. 2007;62(5):493–503. 7. Lidzba K, Staudt M. Development and (re)organization of language after early brain lesions: capacities and limitation of early brain plasticity. Brain Lang. 2008;106(3):165–166. 8. Lidzba K, Wilke M, Staudt M, Krägeloh-Mann I. Early plasticity versus early vulnerability: the problem of heterogeneous lesion types. Brain. 2009;132(Pt 10):e128. 9. Anderson V, Spencer-Smith M, Leventer R, et al. Childhood brain insult: can age at insult help us predict outcome? Brain. 2010;133(Pt 6):1855 [Brain. 2010 Aug;133(Pt 8):2505]. 10. Krägeloh-Mann I, Horber V. The role of magnetic resonance imaging in elucidating the pathogenesis of cerebral palsy: a systematic review. Dev Med Child Neurol. 2007;49(2):144–151 [review]. 11. Cioni G, D'Acunto G, Guzzetta A. Perinatal brain damage in children: neuroplasticity, early intervention, and molecular mechanisms of recovery. Prog Brain Res. 2011;189:139–154. 12. Arnfield E, Guzzetta A, Boyd R. Relationship between brain structure on magnetic resonance imaging and motor outcomes in children with cerebral palsy: a systematic review. Res Dev Disabil. 2013;34(7):2234–2250. 13. Geschwind N, Levitsky W. Human brain: left–right asymmetries in temporal speech region. Science. 1968;161(3837): 186–187. 14. Sowell ER, Trauner DA, Gamst A, Jernigan TL. Development of cortical and subcortical brain structures in childhood and adolescence: a structural MRI study. Dev Med Child Neurol. 2002;44(1):4–16. 15. Staudt M, Lidzba K, Grodd W, Wildgruber D, Erb M, KrägelohMann I. Right-hemispheric organization of language following early left-sided brain lesions: functional MRI topography. Neuroimage. 2002;16(4):954–967. 16. Guzzetta A, Pecini C, Biagi L, et al. Language organisation in left perinatal stroke. Neuropediatrics. 2008;39(3):157–163. 17. Tillema JM, Byars AW, Jacola LM, et al. Cortical reorganization of language functioning following perinatal left MCA stroke. Brain Lang. 2008;105(2):99–111. 18. Liégeois F, Connelly A, Baldeweg T, Vargha-Khadem F. Speaking with a single cerebral hemisphere: fMRI language organization after hemispherectomy in childhood. Brain Lang. 2008;106(3):195–203. 19. Lidzba K, Staudt M, Wilke M, Krägeloh-Mann I. Visuospatial deficits in patients with early left-hemispheric lesions and
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functional reorganization of language: consequence of lesion or reorganization? Neuropsychologia. 2006;44(7):1088–1094. Guzzetta A, Bonanni P, Biagi L, et al. Reorganization of the somatosensory system after early brain damage. Clin Neurophysiol. 2007;118(5):1110–1121. Thickbroom GW, Byrnes ML, Archer SA, et al. Differences in sensory and motor cortical organization following brain injury early in life. Ann Neurol. 2001;49(3):320–327. Zsoter A, Pieper T, Kudernatsch M, Staudt M. Predicting hand function after hemispherotomy: TMS versus fMRI in hemispheric polymicrogyria. Epilepsia. 2012;53(6):e98–e101. Papadelis C, Leonardelli E, Staudt M, Braun C. Can magnetoencephalography track the afferent information flow along white matter thalamo-cortical fibers? Neuroimage. 2012;60(2): 1092–1105. Rose S, Guzzetta A, Pannek K, Boyd R. MRI structural connectivity, disruption of primary sensorimotor pathways, and hand function in cerebral palsy. Brain Connect. 2011;1(4): 309–316. Staudt M, Braun C, Gerloff C, Erb M, Grodd W, Krägeloh-Mann I. Developing somatosensory projections bypass periventricular brain lesions. Neurology. 2006;67(3):522–525. Guzzetta A, Pizzardi A, Belmonti V, et al. Hand movements at 3 months predict later hemiplegia in term infants with neonatal cerebral infarction. Dev Med Child Neurol. 2010;52(8): 767–772. Dinomais M, Groeschel S, Staudt M, Krägeloh-Mann I, Wilke M. Relationship between functional connectivity and sensory impairment: red flag or red herring? Hum Brain Mapp. 2012;33(3):628–638. Guzzetta A, D'Acunto G, Rose S, Tinelli F, Boyd R, Cioni G. Plasticity of the visual system after early brain damage. Dev Med Child Neurol. 2010;52(10):891–900. Ramenghi LA, Ricci D, Mercuri E, et al. Visual performance and brain structures in the developing brain of pre-term infants. Early Hum Dev. 2010;86(suppl 1):73–75. Guzzetta A, Fiori S, Scelfo D, Conti E, Bancale A. Reorganization of visual fields after periventricular haemorrhagic infarction: potentials and limitations. Dev Med Child Neurol. 2013;55 (suppl 4):23–26. Fagiolini M, Pizzorusso T, Berardi N, Domenici L, Maffei L. Functional postnatal development of the rat primary visual cortex and the role of visual experience: dark rearing and monocular deprivation. Vision Res. 1994;34(6): 709–720.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/semperi
Plasticity following early-life brain injury: Insights from quantitative MRI Simona Fiori, MDa, and Andrea Guzzetta, MD, PhDa,b,n a
SMILE, Department of Developmental Neuroscience, Stella Maris Scientific Institute, Via dei Giacinti 2, 56018 Calambrone, Pisa, Italy b Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
article info
abstra ct
Keywords:
Over the last decade, the application of novel advanced neuroimaging techniques to study
Neuroplasticity
congenital brain damage has provided invaluable insights into the mechanisms underlying
Diffusion imaging
early neuroplasticity. The concept that is clearly emerging, both from human and nun-
fMRI
human studies, is that functional reorganization in the immature brain is substantially
Children
different from that of the more mature, developed brain. This applies to the reorganization
Infants
of language, the sensorimotor system, and the visual system. The rapid implementation
Cerebral palsy
and development of higher order imaging methods will offer increased, currently unavailable knowledge about the specific mechanisms of cerebral plasticity in infancy, which is essential to support the development of early therapeutic interventions aimed at supporting and enhancing functional reorganization during a time of greatest potential brain plasticity. & 2015 Published by Elsevier Inc.
Introduction Neuroplasticity reflects the capability of the brain to modify throughout life by adapting, at different levels, to environmental exposition.1 It underlies the processes of learning and memorizing and the damage-induced processes of brain recovery and reorganization. Neuroplastic mechanisms appear to be greatest during infancy, the so-called critical period, at a time when brain maturation has a faster pace.2,3 Children have, for instance, an enhanced ability to become proficient in speaking a new language or playing a musical instrument, if adequately trained. This enhanced neuroplasticity plays an essential role in functional reorganization following early brain damage.4–8 Congenital brain lesions provide an interesting model for studying cerebral reorganization, as they naturally encompass the different combinations of distribution (focal and
diffuse) and timing (early gestation, late gestation, and term) of damage.9 Several factors influence the efficacy of compensatory mechanisms of brain functions, in particular, the distribution of the lesion and the timing of the insult. According to the timing of the insult, the brain can be affected (i) during periods of neuronal proliferation, migration, and cortical organization, resulting in brain malformations (first or second trimester of pregnancy) or (ii) during periods of selective vulnerability of white or gray matter and result in periventricular or cortical and deep gray matter gliotic or cystic lesions (third trimester).10 The stage of cerebral development at the moment of the insult is key for the type of reorganizational response; however, the specificities of the young brain's neuroplastic mechanisms expose it to the risk of dysfunctional processes of reorganization (the so-called maladaptive plasticity).5 A full understanding of the
n Corresponding author at: SMILE, Department of Developmental Neuroscience, Stella Maris Scientific Institute, Via dei Giacinti 2, 56128 Calambrone, Pisa, Italy. E-mail address: [email protected] (A. Guzzetta).
http://dx.doi.org/10.1053/j.semperi.2015.01.007 0146-0005/& 2015 Published by Elsevier Inc.
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mechanisms underlying the reorganization of brain functions after early damage is therefore essential in order to target the rehabilitative intervention in terms of intensity, quality, and duration, maximizing the processes of adaptive plasticity and limiting the maladaptive ones.11 An essential contribution for the understanding of brain abnormalities associated with maldevelopments or lesions is provided by non-invasive neuroimaging techniques and in particular by magnetic resonance imaging (MRI). Structural MRI has been increasingly applied in children, allowing for a detailed study of pathophysiology and timing of cerebral lesions and a strict monitoring of their evolution, thus providing critical insights into the relation between lesion and function.12 Conventional structural MRI can be complemented by advanced MR techniques such as functional MRI (fMRI) or diffusion MRI (dMRI). These techniques allow the study of brain functional reorganization beyond structural imaging (i.e., fMRI) or the in vivo study of microstructure of white matter and brain connectivity (i.e., dMRI) (Fig. 1). The complex and heterogeneous functional correlates observed in children with congenital brain lesions are the result of different degrees of involvement of the various systems and of their supra-modal compensatory processes. Only for the sake of clarity, the principal systems will be considered independently, focusing on the aspects of cerebral plasticity explored by the different brain MRI techniques.
The language system Language processing has been estimated to involve mostly the left hemisphere of the human brain in healthy adult subjects. This inborn predisposition of the left hemisphere for language processing is sustained by anatomical studies on structural asymmetries between the two hemispheres in perisylvian regions13 and in sulcal patterns,14 which become more evident during childhood as a proof of a regional specialization in the acquisition of language.
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In spite of this innate predisposition, converging evidence from fMRI and MEG suggests that a bilateral early developmental involvement for language representation is a fundamental prerequisite for language neuroplasticity. Indeed, long before the advent of neuroimaging, it has been demonstrated that focal lesions acquired during fetal life or infancy can be compensated for much more effectively compared to similar lesions acquired later in life. An injury that occurs early in the dominant hemisphere can be compensated for by a contralateral organization of language networks.15 During this process, the intact right hemisphere develops and strengthens a language network that mostly mirrors the typical left-hemispheric topography of healthy individuals.15,16 This neuroplastic potential was shown for different etiopathogenic patterns, including periventricular parenchymal damage,15 arterial stroke,16 cortico-subcortical lesions of perinatal origin,17 or hemispherectomy.18 The timing of the insult or the distribution of the lesion might affect plastic mechanisms of re-mapping. For example, in periventricular damage, the severity of the lesion as assessed by structural MRI metrics, such as the distance between the lateral outline of the ventricle and the midline in specific coronal projections, was shown to reliably predict the type of language organization.15 In slightly later damage, the arterial stroke of the term infant, the involvement of Broca's area, or the presence of a thalamic lesion are strong predictors of a contralateral organization of language networks16 (Fig. 2). Subtle differences in language outcome in right versus left congenital lesions are observed and reinforce the idea of a specialization of the two hemispheres, in spite of their plastic potential. Convincing data support the hypothesis that a price for language function plasticity has to be paid by right hemispheric functions, the so-called crowding effect. For example, it has been demonstrated by fMRI that children with left-lesion-induced right-hemispheric language organization show deficits in visuospatial abilities, and the degree of visuospatial dysfunction is proportional to the degree of right language representation.19
Fig. 1 – Whole-brain diffusion tractography in a subject with right arterial stroke. A general reduction of tracts stemming from the right hemisphere is shown.
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Fig. 2 – Reorganization of language function following perinatal stroke. fMRI activations following a covert rhyme generation task in two adolescents with perinatal stroke. In both the subjects, fMRI results supported language reorganization within the right hemisphere. In one case (left column), damage was limited to the basal ganglia and thalamus (lesion is indicated by the black arrowhead), and in the other case (right column), damage involved the left Broca's area.
Fig. 3 – Reorganization of primary motor function following congenital brain damage. fMRI activations following an active hand motor task in two children with congenital malformation. In one subject (left column), fMRI results supported an ipsilesional reorganization of primary motor function in a more anterior area of the frontal lobe, confirmed by the results of TMS of the affected hemisphere. In the other subject (right column), fMRI results supported a contralesional reorganization of primary motor function, confirmed by the results of TMS of the unaffected hemisphere. It is of note how the apparent extension of damage to the primary motor cortex, more obvious in the patient on the left, would have misled the prediction of the type of reorganization.
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Primary motor and sensory functions Neuroplastic mechanisms allow the potential recovery of voluntary movements after a congenital brain lesion involving the motor system by restoring the cortical impulse to the spinal motor neurons and inter-neurons. Two major mechanisms have been described for the corticospinal system to recover its connection to the spinal level after congenital brain insult. The first one implicates the motor cortex ipsilateral to brain damage to re-organize its functions either within primary or within adjacent non-primary motor areas. The second mechanism, specific to perinatal lesions, is based on the persistence of fast-conducting corticospinal connections between each motor cortex and the ipsilateral body side5,6,20,21 (Fig. 3). This latter mechanism is made possible by the existence, during the first weeks of life, of bilateral motor projections originating from the primary motor areas.6 Physiologically, the great majority of these fibers withdraw during development, but they can persist in case of unilateral cerebral damage, giving rise to a contralesional reorganization of motor function. This type of reorganization is specific for unilateral perinatal brain lesions, as it requires, at the time when damage occurs, the presence of a bilateral innervation of motoneuronal pools and a developmental increase in the number of both fast-conducting ipsilateral and contralateral corticospinal axons from the intact hemisphere. A significant hypertrophy of the corticospinal tract arising from the noninfarcted hemisphere can be found indirectly from MRI measurements and more directly from post-mortem analysis,
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by which a significantly increased number of corticospinal axons projecting from the non-affected hemisphere can be detected.6 The application of functional MRI can provide relevant information on the type of sensorimotor reorganization, as it generally shows, during active motor tasks, a clear contralateral activation in ipsilesional reorganizations and a bilateral activation in the contralesional ones.5 This latter pattern is likely due to the usual persistence of the primary somatosensory function within the affected hemisphere, which gives rise to a sensory contralateral activation from the moving hand. It is important to underline that information from fMRI can never be considered exhaustive. Reorganization of primary motor function needs investigation by transcranial magnetic stimulation (TMS), a technique that provides the necessary temporal resolution to unequivocally map the corticospinal tract.22 Reorganization of primary somatosensory function similarly requires high-temporalresolution techniques such as electroencephalography (EEG) or magnetoencephalography (MEG). In contrast to primary motor function, the intrahemispheric (ipsilesional) reorganization of primary sensory function is the principal compensatory mechanism following damage to the sensory system, even when it occurs during the very early stages of development.5 This is probably due to the lack of anatomical substrates for contralesional reorganization, even in the early stages of development. Additionally, it was also shown that, at least for some types of perinatal lesions, the thalamo-cortical fibers are still developing when the insult occurs and are thus able to bypass the lesion and reconnect with the sensory cortex within the damaged
Fig. 4 – Graphic representation of a possible mechanism correlating severity of brain damage and type of long-term reorganization of primary motor function. According to this model, in subjects with mild or severe damage to the corticospinal tract, the type of reorganization is pre-determined by the lesion. In subjects with damage of moderate severity, the type of reorganization is potentially influenced by the environment (e.g., intervention).
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hemisphere.23 This evidence comes from the combined use of structural imaging methods, such as diffusion-MRI-based tractography,24 which identify the likely trajectories of thalamo-cortical white matter bundles, and functional imaging methods, such as MEG, which are capable of reliably mapping the cortical location of primary sensory processing.25 Data obtained from these particular mechanisms of early neuroplasticity in primary sensory and motor systems generate distinctive patterns of reorganization that need to be accurately characterized at the single subject level. This complexity is further enhanced by the crucial role of the environment in driving neuroplasticity. Indeed, the pattern of sensorimotor reorganization is by no means a mere consequence of the size and site of the lesion but is strongly influenced by the experience following damage (actiondependent reorganization). Figure 4 illustrates the complex interaction between residual motor output from the affected hemisphere and somatosensory feedback from the affected limb. Not surprising, the early structural asymmetries of the corticospinal tract are not always able to predict the presence and, most of all, the severity of later hemiplegia.26 This concept is further supported by diffusion studies performed during the chronic phases of the disorder, i.e., in adolescents and young adults with unilateral cerebral palsy, which show that the asymmetry of the corticospinal tract is less correlated with sensory and motor function than the asymmetry of other projections such as the thalamo-cortical ones. These data suggest an essential role of higher-order compensatory mechanisms in shaping the long-term functional outcome.24 A growing body of evidence supports the hypothesis that the reorganization of motor function does not only take place within the sensorimotor cortex but also heavily involves subcortical structures such as the thalamus, brainstem or spinal cord, and cerebellum.27 The complex interplay between early brain plasticity of the sensorymotor system and its relation to functional outcome remains poorly understood and the subject of future ongoing studies.
The visual system Visual impairment is very common after congenital brain injury, given that a substantial part of the brain is directly or indirectly involved in vision. However, visual deficits can vary in terms of the characteristics and severity of the disorder, depending on the site, extension, and timing of brain injury.28,29 The correlation between damage to the optic radiations or the occipital cortex and deficits to the corresponding visual field is far less consistent with early lesions as compared to later ones. This finding may be related to the more powerful cerebral plasticity mechanisms in young children, which have at least in part similar neurophysiological bases to what we have described for the somatosensory system and, in particular, the possibility that thalamocortical fibers develop after the lesion, bypassing it.30 The exact characteristics and limits of this specific type of plasticity involving thalamo-cortical networks are not fully understood. It is of interest, however, that even when a visual field deficit is present, the subject with early damage seems
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to show fewer difficulties in environmental navigation and exploration. This finding is directly in line with animal model experiments, which clearly show how the ablation of the whole primary visual cortex in newborn animals does not affect their visual orientation performances, which are massively impaired after a similar lesion in adult animals.31 This phenomenon is linked to a reorganization of the pathways connecting subcortical visual structures directly to the extrastriatal visual cortex. Moreover, this occurrence appears to take place in humans as well, as shown, for example, by the increase in activation of extra-striatal structures on fMRI after the stimulation of the affected hemi-field. Taken together, available data in humans support the presence of a more effective reorganization of visual function after early brain damage, which may consist of either a “reconnection” with the targeted structures or secondary to an enhanced use of compensating circuitries.28 Even if these circuitries are not able to restore complete vision on the contralesional hemisphere, they can allow for good compensation in spatial orienting and localization.
Conclusions Brain mapping techniques and, in particular, fMRI have offered important insights to many critical questions that had been pending for decades, as it relates to how the immature brain responds to early-life brain injury. The concept that is clearly emerging, both from human and nun-human studies, is that functional reorganization in the immature brain is complex and substantially different from that of a mature brain that has already completed critical stages of development. Although a complete understanding of the underlying mechanisms of cerebral plasticity in early infancy is still far from understood, a fundamental understanding of the neurobiological and neurophysiological principles underlying repair after injury will be essential for more targeted prescription and tuning of therapeutic intervention programs. The successful application and refinement of advanced MRI techniques to the developing brain (e.g., ultra-high field MR) will undoubtedly provide important, currently unavailable insights to these intriguing questions.
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