Maturation of the human brain and epilepsy

Handbook of Clinical Neurology, Vol. 107 (3rd series) Epilepsy, Part I H. Stefan and W.H. Theodore, Editors # 2012 Elsevier B.V. All rights reserved

Chapter 7

Maturation of the human brain and epilepsy GREGORY L. HOLMES 1*, M.D. MATHIEU MILH 2, AND OLIVIER DULAC 3 1 Department of Neurology, Dartmouth Medical School, Lebanon, NH, USA 2

Department of Pediatric Neurology, APHM La Timone, INMED, Marseilles, France

3

Department of Pediatric Neurology, APHP Necker-Enfants Malades, UMR663, Paris, France

INTRODUCTION Age plays a major role in virtually all aspects of epilepsy (Hauser, 1992). Children are at substantially higher risk for epilepsy than young and middle-aged adults (Hauser, 1994, 1995; Forsgren et al., 2005). In addition to the higher incidence of epilepsy in children than in adults, precipitating factors such as fever are far more likely to induce a seizure in a young child than in an adult (Hauser, 1992; Fetveit, 2008). Age is critical in the clinical and electroencephalographic (EEG) features of seizures. Disorders such as infantile spasms and Landau–Kleffner syndrome always begin in early childhood. EEG features such as hypsarrhythmia and electrical status epilepticus of sleep (ESES) are confined to childhood. Age is also a determinant for prognosis. Intellectual impairment (Huttenlocher and Hapke, 1990; Glosser et al., 1997; Bulteau et al., 2000; Bjornaes et al., 2001; Hermann et al., 2002; Cormack et al., 2007), learning disabilities (Sillanpaa, 2004; Soria et al., 2007; Fastenau et al., 2008), social outcome (Lindsay et al., 1979; Sillanpaa, 1983), and medical refractoriness (Berg et al., 1996; Casetta et al., 1999; Camfield and Camfield, 2007) all appear to be influenced by age of onset. The reason age is such an important factor in pediatric epilepsy is that it serves as a surrogate marker for brain development. Enormous developmental changes occur in the brain. In fact, from birth to adulthood the human brain expands by a factor of 3.3. The adult brain has approximately 10 billion neurons, which on average are connected to other neurons through roughly 10 000 synapses. Infants start off with only about 10% of the synapses found in the adult brain. Hundreds of new g-aminobutyric acid (GABA)ergic and glutamatergic synapses are established every day on a pyramidal

neuron during the last third of gestation and first months of life. Along with the massive increase in connectivity and cell growth, myelination occurs throughout childhood and early adulthood. In addition to growth, the developing brain also is continuously redesigning itself through apoptosis and pruning of connections. Understanding the morphological and physiological developmental changes provides insight into the unique features of childhood epilepsy. In this chapter, key features of brain development, as it relates to pediatric epilepsy, will be reviewed. As many key features of ontogeny are similar in the rat and human brain, this chapter will incorporate information from both animals and humans.

DEVELOPMENTAL CHANGES IN BRAIN MORPHOLOGY Brain weight reaches adult values (about 1.45 kg) between 10 and 12 years of age. The fastest growth occurs during the first 3 years of life so that by the age of 5 years the infant’s brain weighs about 90% of the adult value (Dekaban, 1978). Although the brain continues to change throughout life, changes in brain morphology during childhood and adolescence are more subtle than those in the first 4 years of life. Synapse number peaks during infancy and then declines (Huttenlocher et al., 1982a; Huttenlocher, 1984, 1990). Huttenlocher (1979) used the phosphotungstic acid method to study the density of synaptic profiles in layer 3 of middle frontal gyrus in 21 normal human brains ranging from newborn to age 90 years. Synaptic density increased during infancy, reaching a maximum

*Correspondence to: Gregory L. Holmes, M.D., Dartmouth Medical School, One Medical Center Drive, Lebanon, New Hampshire 03756, USA. Tel: +1-603-650-7610, Fax: +1-603-650-7617, E-mail: [email protected]

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at age 1–2 years, which was about 50% above the adult mean. The decline in synaptic density observed between ages 2 and 16 years was accompanied by a slight decrease in neuronal density. Synaptic density was constant throughout adult life (ages 16–72 years) with a mean of 11.05
108 synapses/mm3. Similar time profiles have been found in the visual cortex (Huttenlocher et al., 1982b) and striatum (Huttenlocher and de Courten, 1987). In addition to development of synapses, there is a progressive increase in arborization of the dendrites and an increase in dendritic spines with age. The phenomenal growth of the dendritic tree and formation of synapses occurs at a time when cortical networks are developing. There is increasing evidence that neuronal network development is driven by external or endogenous stimuli such as light (Desai et al., 2002) and muscle twitches (Khazipov et al., 2004b). In addition, as will be described below, seizures can also dramatically alter brain development. Paralleling morphological brain maturation are biochemical changes characterized by an increase in N-acetylaspartate (NAA) and creatine, and a concomitant decrease in choline, myoinositol, and lipids (Kreis et al., 1993). The choline peak includes free choline, glycerophosphorylcholine, and phosphorylcholine. It represents the high levels of substrate needed for the formation of cell membranes, with gradual reduction as soon as incorporation of lipids has taken place. NAA is considered as a neuronal marker and is also expressed in immature and mature oligodendrocytes. Therefore, NAA also reflects oligodendrocyte proliferation and differentiation (Bhakoo and Pearce, 2000). As neuronal cell density in cortex decreases with dendritic maturation, the increase in NAA with age reflects a contribution from non-neuronal origins. Regional variations are pronounced at all ages between gray and white matter, and also within different areas of gray and white matter. Highest choline, creatine, and NAA peak intensities occur in the thalamus, followed by basal ganglia, and then other regions in preterm and term infants (Barkovich et al., 2001). This probably reflects the high cellular density in these areas and the more mature status of deep brain structures compared with white matter. Concentration of NAA is higher in gray matter than in white matter, probably because NAA is expressed in mitochondria located in the cellular soma and not in axons or oligodendrocytes. Creatine concentration is also higher in gray matter than in white matter, whereas choline levels are slightly lower in gray matter than in white matter.

DEVELOPMENTAL CHANGES IN MYELINATION Myelination is an important developmental process that begins during the fifth fetal month with myelination of the cranial nerves, and continues throughout life.

The major changes in myelination occur from 3 weeks to 1 year for all brain regions. Myelination appears to occur earliest in the posterior fossa, with the middle cerebellar peduncle identifiable by age 3 months. By the age of 1 year, all major white matter tracts including the corpus callosum, subcortical white matter, and the internal capsule are well defined. In contrast to the high rate of myelination in the first year, the changes between 1 and 2 years are more subtle, although changes in radial diffusivity on diffusion tensor imaging suggest a pruning process. The development of white matter begins from the center to the periphery and from the occipital to the frontal lobes (Gao et al., 2009). During the first year of life, the magnetic resonance imaging (MRI) white matter signal on T2 changes from hyperintense to hypointense, and vice versa on T1 (Barkovich, 2000). Like other membranes, myelin is composed of a bilayer of lipids with several large proteins, most of which span the bilayer (including myelin basic protein and proteolipid protein). The outer lipid layers are composed mainly of cholesterol and glycolipids, whereas the inner portion of the lipid bilayer is composed mainly of phospholipids. It is thought that the high signal intensity seen on T1-weighted images with the maturation of white matter results from T1 shortening caused by the cholesterol, glycolipids, and possibly the proteins in the outer lipid layers of the membrane, whereas it is thought that the diminishing signal intensity seen on the T2-weighted images with maturation results from a decreased number of water molecules caused by development of the hydrophobic phospholipid inner layer (Svennerholm and Vanier, 1978; Svennerholm et al., 1978; Holland et al., 1986; Barkovich et al., 1988). The changes in signal intensity in myelin with age may make interpretation of MRI scans in children with epilepsy difficult. Distinguishing leukoencephalopathies from normal age-dependent changes in myelination can be challenging. In addition, how well cortical dysplasias are seen on the MRI may be related to the degree of myelination. In some cortical dysplasias the lesion may be seen better on MRI before extensive myelination occurs (Eltze et al., 2005). However, in some cases cortical dysplasias may be more evident with increased myelination (Yoshida et al., 2008). In addition to myelination affecting the clinical and EEG features of seizures, epilepsy and its causes may alter myelination. For example, delays in myelination have been seen in children with infantile spasms (Muroi et al., 1996; Natsume et al., 1996; Takano et al., 2007). Children with prenatally or perinatally acquired brain lesions appear to have more severe delays of myelination (Schropp et al., 1994). The mechanism by which seizures alter the rate of myelination is not known.

MATURATION OF THE HUMAN BRAIN AND EPILEPSY The myelination pattern may also have a significant role in when infantile spasms begin. Koo et al. (1993) reviewed 93 cases of infantile spasms with focal cerebral lesions confined to frontal, centrotemporoparietal, or occipital regions. The mean age of onset of infantile spasms was around 3 months in patients with occipital lesions, versus 6 months in those with centrotemporoparietal lesions, and 10 months in those with frontal lesions. It is therefore of considerable interest that myelination occurs in the occipital lobe and moves forward into the temporal, parietal, and frontal lobes. The age distribution pattern of spasm onset according to localization of cortical lesion was therefore closely correlated with that of the normal sequence of brain maturation, suggesting that myelination may be necessary for the seizures to occur. With greater myelination of the frontal lobes there is a greater likelihood of seeing spike–wave discharges arising frontally. Lennox–Gastaut syndrome, with frontal predominantly slow spike–wave discharges, typically does not begin in the first year of life but may evolve from West syndrome as the brain myelinates more fully. Likewise, the development of epilepsy with myoclonic– astatic seizures is an age-related phenomenon, occurring in toddlers but not in infants (Doose, 1992).

BEHAVIORAL AND ELECTROENCEPHALOGRAPHIC CORRELATES OF BRAIN DEVELOPMENT As described above, the most robust changes involve cell growth, connectivity, and myelination. These changes in brain growth are reflected in the EEG and behavioral manifestations of seizures. In very preterm infants (< 30 weeks estimated conceptional age; ECA), the EEG is discontinuous with long periods of inactivity with intermittent bursts of higher voltage slow activity. From around 30 weeks ECA, the EEG exhibits no interhemispheric synchronization and consists of poorly organized waveforms. The asymmetry and discontinuous nature of the record likely relates to the poor myelination in the cerebral hemispheres as well as the lack of developed neuronal networks. With increasing age and increasing connectivity and myelination, the EEG becomes more continuous with better interhemispheric synchronization of activity. This occurs simultaneously with development of thalamocortical connections (Minlebaev et al., 2009). Electrographic ictal discharges in neonates are focal and may be limited to a small cortical area due to lack of myelin in the forebrain combined with limited connectivity between cortical regions. If seizures propagate, they do so very slowly. Behaviorally, the most common seizure type in infants is focal or multifocal seizures.

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Generalized seizures, either electrographically or behaviorally, are quite unusual in newborns. As connectivity and myelination occur during the first year of life, thalamocortical and intrahemispheric and interhemispheric networks are organized and features such as sleep spindles and rhythmic delta and theta background patterns emerge. During the first year of life generalized seizures (partial with secondary generalization) begin to occur. Infantile spasms with generalized hypsarrhythmia rarely occur before 3 months of age, but start to occur when the cerebral hemispheres begin to myelinate.

DEVELOPMENTAL CHANGES IN THE BRAIN PHYSIOLOGY Children during the first months of life are at particularly high risk for seizures, with the largest number of new-onset seizure disorders occurring during this time (Hauser, 1995). There is considerable evidence that the immature brain is more susceptible to seizures than the mature brain. The propensity for seizures in the immature brain has been demonstrated in a number of experimental models, including kainic acid (Tremblay et al., 1984; Khalilov et al., 2003), electrical stimulation (Moshe, 1981), hypoxia (Jensen et al., 1991), penicillin (Swann and Brady, 1984), picrotoxin (Gomez-Di Cesare et al., 1997), GABAB receptor antagonists (McLean et al., 1996), and increased extracellular potassium (Dzhala and Staley, 2003; Khazipov et al., 2004a). The enhanced excitability of the immature brain compared with the mature brain is related to the sequential development and expression of essential signaling pathways. In the adult brain, glutamate is the primary excitatory neurotransmitter and GABA is the principal inhibitory transmitter. Synaptic transmission is mediated by glutamate, which is released from the pyramidal neurons and depolarizes and excites the target neurons via ionotropic receptors: N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA), and kainic acid (KA). Fast inhibition is through GABA activation of GABA receptors. Although all of the glutamate subreceptors respond to glutamate, they have individual characteristics. NMDA receptors are heteromeric with an obligate NR1 subunit. In the immature brain, the predominant NR2 subunit is the NR2B subunit (Chang et al., 2009). The NMDA receptor has characteristics of both a ligand-mediated and voltage-gated channel. The ion Mg2 þ lies in the pore of the channel, preventing permeability of Naþ and Ca2 þ ions. When Mg2 þ is released from the pore by membrane depolarization, the flow of Naþ and Ca2 þ ions can occur. Compared with the NR2A subunit, which is highly expressed on mature

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neurons, NR2B subunits have reduced Mg2 þ sensitivity, resulting in increased excitability (Hollmann and Heinemann, 1994). Other developmentally regulated subunits (NR2C, NR2D, and NR3A) also are increased in the first two postnatal weeks (Monyer et al., 1994). The AMPA receptor is responsible for fast excitatory neurotransmission. AMPA receptors are heteromeric and made up of four subunits, including combinations of the glutamate receptor (GluR) 1, GluR2, GluR3, or GlurR4 subunits (Hollmann and Heinemann, 1994). In the immature rodent and human brain, AMPA receptors are Ca2 þ permeable because they lack the GluR2 subunit (Hollmann et al., 1991; Sanchez et al., 2001; Kumar et al., 2002). The enhanced Ca2 þ permeability would result in greater excitability and increase the likelihood of seizures in the immature brain. The development of GABAergic and glutamatergic synapses follows distinct timelines. During fetal development, GABAergic synapses develop before glutamatergic synapses (Khazipov et al., 2001). During the first few weeks of life there is enhanced excitation due to an overabundance of NMDA and AMPA receptors (McDonald et al., 1990; Miller et al., 1990). With maturation, axonal collaterals and attendant synapses regress (Swann et al., 1991). In addition to changes in the receptors, structures that anchor the synapses to the membrane also change with age. The postsynaptic density (PSD) is a cytoskeleton specialization at neuronal synapses that comprises glutamate receptors, their molecular scaffolding molecules, cell adhesion molecules, and a diverse set of other signaling proteins. The PSD has been proposed to concentrate and organize neurotransmitter receptors to respond rapidly to neurotransmitter in the synaptic cleft. The ontogeny of PSD parallels the ontogeny of NMDA receptors, with substantial decreases in NR2B and increases in NR2A and PSD during development (Sans et al., 2000). There are also developmental changes in the neurophysiology of the receptors. The NMDA excitatory postsynaptic currents (EPSCs) show a maturational decrease in rise time but no change in decay time, whereas AMPA EPSCs show neither rise nor decay time changes with development (Ye et al., 2005). AMPA receptors possess mature kinetics and become the dominant glutamatergic current during early brain development. The AMPA receptor responds rapidly to glutamate with opening of the channel to allow Naþ to enter the cell and depolarize the membrane. This influx of Naþ is sufficient to allow the displacement of Mg2 þ from the NMDA channel, and to permit Naþ and Ca2 þ ions to enter the cell through the NMDA receptor. The rise in intracellular Ca2 þ is an essential signal for memory processes; hence the NMDA receptor plays an important role in learning and plasticity.

During the early postnatal period, at a time when the immature brain is highly susceptible to seizures (Jensen and Baram, 2000; Khazipov et al., 2004a), GABA, which in the adult brain is the primary inhibitory neurotransmitter, exerts paradoxical excitatory action (Dzhala and Staley, 2003; Khazipov et al., 2004a). GABA is excitatory in the immature brain because of a larger intracellular concentration of chloride in immature neurons than mature ones (Ben-Ari et al., 1989; Ben-Ari, 2002; Ben-Ari and Holmes, 2005). The shift from a depolarizing to a hyperpolarizing chloride current occurs over an extended period depending on the age and developmental stage of the structure (Glykys et al., 2009). The shift is mediated by an active Naþ–Kþ–2Cl cotransporter (NKCC1) that facilitates the accumulation of chloride in neurons, and a delayed expression of a Kþ–Cl cotransporter (KCC2) that extrudes Cl to establish adult concentrations of intracellular Cl (Dzhala et al., 2005). The depolarization by GABA of immature neurons is sufficient to generate Naþ action potentials and to remove the voltage-dependent Mg2 þ blockade of NMDA channels and activate voltage-dependent Ca2 þ channels, leading to a large influx of Ca2 þ that in turn triggers long-term changes of synaptic efficacy. The synergistic action of GABA with NMDA and Ca2 þ channels is unique to the developing brain and has many consequences on the impact of GABAergic synapses on the network. In addition, agents that interfere with the transport of Cl exert an antiepileptogenic action (Dzhala et al., 2005). With maturation there is increasing function of KCC2 and decreasing function of NKCC1, a transporter that brings Cl into the cell resulting in an inhibitory effect of GABA. Figure 7.1 shows in cartoon form the developmental changes in the chloride content of pyramidal cells. The lack of an efficient time-locked inhibition, the delayed maturation of postsynaptic GABAB-mediated currents, and the high input resistance of immature neurons will facilitate the generation of action potentials and synchronized activities (Gaiarsa et al., 1995; McLean et al., 1996). The imbalance of excitation over inhibition may help to explain some of the early-life epileptic syndromes. For example, encephalopathy with suppression bursts may have its onset even before birth (Ohtahara et al., 1987). The EEG shows bilateral bursts of polyspikes contrasting with very little slow-wave activity (Aicardi and Goutie`res, 1978). The premature activation of NMDA neurotransmission, before GABA has become inhibitory, likely plays a major role in this very hyperexcitable EEG picture (Milh et al., 2007). In summary, the immature brain’s high susceptibility for seizures can be explained by the morphological and physiological events occurring during early life. The overabundance of synaptic connections, the increased

MATURATION OF THE HUMAN BRAIN AND EPILEPSY

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GABAergic interneuron

GABAergic interneuron

ClCl-

-

Cl K+

K+

Cl-

KCC2

KCC2

GABAA

GABAA

[Cl-]i +

Na -

2Cl

Na+,K+

GLU-R

NK CC 1

Na+,K+

NK CC 1

[Cl-]i

2Cl-

+

Na

GLU-R

Epileptiform discharges No epileptiform discharges

A

B

Fig. 7.1. Cartoons of (A) immature and (B) mature neurons. The immature neuron (A) is in a more excitable state than the mature neuron (B). Because the Naþ–Kþ–2Cl cotransporter (NKCC1) develops and functions sooner than the Kþ–Cl cotransporter (KCC2) there is an increase of chloride within immature neurons compared with that in mature neurons (A). The increase in intracellular chloride results in a depolarized chloride equilibrium potential. When the g-aminobutyric acid (GABA) channel is activated by GABA, there is a flow of chloride from inside the cell to outside the cell. As chloride carries a negative charge, the exodus of chloride served to depolarize the cell, making it more likely to discharge when sodium enters the cell. In the mature neuron (B), KCC2 is functional and balances the increase of chloride through NKCC1 with an outward flow of chloride. Because of lower intracellular chloride levels when the GABA receptor is activated, chloride enters the cell carrying a negative charge, thus resulting in hyperpolarization. GLU-R, glutamate receptor.

intracellular Cl resulting in a depolarizing effect of GABA, and the overexpression of AMPA and NMDA receptors with a composition that enhances excitability of neuronal networks, and the lack of developed inhibitory networks, leads to a situation were the immature brain is at high risk for seizures.

ALTERATIONS IN BRAIN DEVELOPMENT AS A CONSEQUENCE OF SEIZURES As described above, the construction of cortical networks is associated with a sequential shift from an ensemble of immature cells with little or no organized communication devices to an active network composed of neurons endowed with thousands of active synapses. This shift is mediated by a series of processes that include intrinsic programs and extrinsic factors. It is known that seizures, like other insults, will modify these developmental processes leading to persistent deleterious sequels.

In the adult animals, prolonged or frequent seizures cause neuronal loss in hippocampal fields CA1, CA3, and the dentate hilus (Nadler, 1981; Cavazos and Sutula, 1990; Cavazos et al., 1991; Ben-Ari, 2001). Although the threshold for seizure generation is lower in immature brains than in adult brains, developing neurons are less vulnerable, in terms of neuronal damage and cell loss, than adult neurons to a wide variety of pathological insults. Compared with adult animals, young animals have far less cell loss in the hippocampus following a prolonged seizure (Albala et al., 1984; Berger et al., 1984; Holmes and Thompson, 1988; Sankar et al., 1998; Sankar et al., 2000). Although cell loss does not occur in the young brain, early-life seizures can result in spine loss in CA3 pyramidal cells (Jiang et al., 1998) and synaptic reorganization of the axons and terminals of the mossy fibers of the dentate granule cells (Holmes et al., 1998; Huang et al., 1999, 2002; Sogawa et al., 2001). The mossy fiber sprouting differs significantly from the sprouting seen after status epilepticus in adult rats, occurring primarily

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in the CA3 pyramidal cell layer (de Rogalski Landrot et al., 2001) rather than the supragranular region. Recurrent seizures in developing rats can also adversely affect neurogenesis. McCabe and colleagues (2001) studied the extent of neurogenesis in the granule cell layer of the dentate gyrus over multiple time points following a series of 25 flurothyl-induced seizures administered during the first 5 days of life. Rats with neonatal seizures had a significant reduction in the number of newly formed neurons in the dentate gyrus and hilus compared with controls, with reductions in new cell formation continuing for 6 days after the final seizure. In addition to sprouting and impaired neurogenesis, recurrent early-life seizures have been shown to result in immunohistological alterations of glutamate (Sogawa et al., 2001; Bo et al., 2004) and GABA subunit expression (Ni et al., 2004). Neonatal seizures have been associated with a decrease in GluR2 mRNA expression and protein levels (Zhang et al., 2004b), and selective reduction in the membrane pool of GluR subunits and decrease in the total amount of NMDA receptor 2A (Cornejo et al., 2007). In addition, excitatory amino acid carrier 1 (EAAC1) was reduced in rats with neonatal seizures compared with controls (Zhang et al., 2004b). Animals with alterations in glutamate receptors have been shown to have deficits in hippocampal-dependent radial arm water maze (Cornejo et al., 2007), demonstrating the relationship between neonatal seizures and memory deficits with specific alterations in glutamatergic synaptic function. Significant alterations in GABAergic function have also been reported following neonatal seizures. Rats subjected to lithium–pilocarpine-induced seizures at postnatal day 10 show long-term GABAA receptor changes, including a 2-fold increase in a1-subunit expression (compared with lithium-injected controls) and enhanced type I benzodiazepine augmentation, the opposite to those seen after status epilepticus in adult rats (Zhang et al., 2004a). Persistent decreases in GABA amplitude in the hippocampus in rats also occur following neonatal seizures (Isaeva et al., 2006).

SUMMARY All features of childhood epilepsy are intimately related to brain development. The clinical EEG features of seizures are closely related to developmental changes in cell growth, synapse formation, and myelination. The immature brain is highly excitable due to the depolarizing effects of GABA, overexpression of glutamatergic receptors, and lack of efficient inhibitory control. Seizures have an age-specific effect on brain development. Whereas early life seizures rarely result in cell loss, they can induce changes in synapse organization and receptor physiology.

ACKNOWLEDGMENTS Supported by grants from the National Institutes of Health (NINDS): NS0415951 and NS056170.

REFERENCES Aicardi J, Goutie`res F (1978). Ence´phalopathie myoclonique ne´onatale. Rev Electroencephalogr Neurophysiol Clin 8: 99–101. Albala BJ, Moshe´ SL, Okada R (1984). Kainic-acid-induced seizures: a developmental study. Dev Brain Res 13: 139–148. Barkovich AJ (2000). Concepts of myelin and myelination in neuroradiology. AJNR Am J Neuroradiol 21: 1099–1109. Barkovich AJ, Kjos BO, Jackson DE, Jr et al. (1988). Normal maturation of the neonatal and infant brain: MR imaging at 1.5 T. Radiology 166: 173–180. Barkovich AJ, Westmark KD, Bedi HS et al. (2001). Proton spectroscopy and diffusion imaging on the first day of life after perinatal asphyxia: preliminary report. AJNR Am J Neuroradiol 22: 1786–1794. Ben-Ari Y (2001). Cell death and synaptic reorganizations produced by seizures. Epilepsia 42: 5–7. Ben-Ari Y (2002). Excitatory actions of GABA during development: the nature of the nurture. Nat Rev Neurosci 3: 728–739. Ben-Ari Y, Holmes GL (2005). The multiple facets of gammaaminobutyric acid dysfunction in epilepsy. Curr Opin Neurol 18: 141–145. Ben-Ari Y, Cherubini E, Corradetti R et al. (1989). Giant synaptic potentials in immature rat CA3 hippocampal neurones. J Physiol 416: 303–325. Berg AT, Levy SR, Novotny EJ et al. (1996). Predictors of intractable epilepsy in childhood: a case–control study. Epilepsia 37: 24–30. Berger ML, Tremblay E, Nitecka L et al. (1984). Maturation of kainic acid seizure–brain damage syndrome in the rat. III. Postnatal development of kainic acid binding sites in the limbic system. Neuroscience 13: 1095–1104. Bhakoo KK, Pearce D (2000). In vitro expression of N-acetyl aspartate by oligodendrocytes: implications for proton magnetic resonance spectroscopy signal in vivo. J Neurochem 74: 254–262. Bjornaes H, Stabell K, Henriksen O et al. (2001). The effects of refractory epilepsy on intellectual functioning in children and adults. A longitudinal study. Seizure 10: 250–259. Bo T, Jiang Y, Cao H et al. (2004). Long-term effects of seizures in neonatal rats on spatial learning ability and Nmethyl-D-aspartate receptor expression in the brain. Brain Res Dev Brain Res 152: 137–142. Bulteau C, Jambaque I, Viguier D et al. (2000). Epileptic syndromes, cognitive assessment and school placement: a study of 251 children. Dev Med Child Neurol 42: 319–327. Camfield P, Camfield C (2007). Long-term prognosis for symptomatic (secondarily) generalized epilepsies: a population-based study. Epilepsia 48: 1128–1132. Casetta I, Granieri E, Monetti VC et al. (1999). Early predictors of intractability in childhood epilepsy: a community-based

MATURATION OF THE HUMAN BRAIN AND EPILEPSY case–control study in Copparo, Italy. Acta Neurol Scand 99: 329–333. Cavazos JE, Sutula TP (1990). Progressive neuronal loss induced by kindling: a possible mechanism for mossy fiber synaptic reorganization and hippocampal sclerosis. Brain Res 527: 1–6. Cavazos JE, Golarai G, Sutula TP (1991). Mossy fiber synaptic reorganization induced by kindling: time course of development, progression, and permanence. J Neurosci 11: 2795–2803. Chang LR, Liu JP, Zhang N et al. (2009). Different expression of NR2B and PSD-95 in rat hippocampal subregions during postnatal development. Microsc Res Tech 72: 517–524. Cormack F, Helen CJ, Isaacs E et al. (2007). The development of intellectual abilities in pediatric temporal lobe epilepsy. Epilepsia 48: 201–204. Cornejo BJ, Mesches MH, Coultrap S et al. (2007). A single episode of neonatal seizures permanently alters glutamatergic synapses. Ann Neurol 61: 411–426. de Rogalski Landrot I, Minokoshi M, Silveira DC et al. (2001). Recurrent neonatal seizures: relationship of pathology to the electroencephalogram and cognition. Brain Res Dev Brain Res 129: 27–38. Dekaban AS (1978). Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights. Ann Neurol 4: 345–356. Desai NS, Cudmore RH, Nelson SB et al. (2002). Critical periods for experience-dependent synaptic scaling in visual cortex. Nat Neurosci 5: 783–789. Doose H (1992). Myoclonic–astatic epilepsy. Epilepsy Res Suppl 6: 163–168. Dzhala VI, Staley KJ (2003). Transition from interictal to ictal activity in limbic networks in vitro. J Neurosci 23: 7873–7880. Dzhala VI, Talos DM, Sdrulla DA et al. (2005). NKCC1 transporter facilitates seizures in the developing brain. Nat Med 11: 1205–1213. Eltze CM, Chong WK, Bhate S et al. (2005). Taylor-type focal cortical dysplasia in infants: some MRI lesions almost disappear with maturation of myelination. Epilepsia 46: 1988–1992. Fastenau PS, Jianzhao S, Dunn DW et al. (2008). Academic underachievement among children with epilepsy: proportion exceeding psychometric criteria for learning disability and associated risk factors. J Learn Disabil 41: 195–207. Fetveit A (2008). Assessment of febrile seizures in children. Eur J Pediatr 167: 17–27. Forsgren L, Beghi E, Oun A et al. (2005). The epidemiology of epilepsy in Europe – a systematic review. Eur J Neurol 12: 245–253. Gaiarsa JL, Tseeb V, Ben-Ari Y (1995). Postnatal development of pre- and postsynaptic GABAB-mediated inhibitions in the CA3 hippocampal region of the rat. J Neurophysiol 73: 246–255. Gao W, Lin W, Chen Y et al. (2009). Temporal and spatial development of axonal maturation and myelination of white matter in the developing brain. AJNR Am J Neuroradiol 30: 290–296.

141

Glosser G, Cole LC, French JA et al. (1997). Predictors of intellectual performance in adults with intractable temporal lobe epilepsy. J Int Neuropsychol Soc 3: 252–259. Glykys J, Dzhala VI, Kuchibhotla KV et al. (2009). Differences in cortical versus subcortical GABAergic signaling: a candidate mechanism of electroclinical uncoupling of neonatal seizures. Neuron 63: 657–672. Gomez-Di Cesare CM, Smith KL, Rice FL et al. (1997). Axonal remodeling during postnatal maturation of CA3 hippocampal pyramidal neurons. J Comp Neurol 384: 165–180. Hauser WA (1992). Seizure disorders: the changes with age. Epilepsia 33: S6–S14. Hauser WA (1994). The prevalence and incidence of convulsive disorders in children. Epilepsia 35: S1–S6. Hauser WA (1995). Epidemiology of epilepsy in children. Neurosurg Clin N Am 6: 419–429. Hermann BP, Seidenberg M, Bell B (2002). The neurodevelopmental impact of childhood onset temporal lobe epilepsy on brain structure and function and the risk of progressive cognitive effects. Prog Brain Res 135: 429–438. Holland BA, Haas DK, Norman D et al. (1986). MRI of normal brain maturation. AJNR Am J Neuroradiol 7: 201–208. Hollmann M, Heinemann S (1994). Cloned glutamate receptors. Annu Rev Neurosci 17: 31–108. Hollmann M, Hartley M, Heinemann S (1991). Ca2 þ permeability of KA-AMPA-gated glutamate receptor channels depends on subunit composition. Science 252: 851–853. Holmes GL, Thompson JL (1988). Effects of kainic acid on seizure susceptibility in the developing brain. Brain Res 467: 51–59. Holmes GL, Gairsa JL, Chevassus-Au-Louis N et al. (1998). Consequences of neonatal seizures in the rat: morphological and behavioral effects. Ann Neurol 44: 845–857. Huang L, Cilio MR, Silveira DC et al. (1999). Long-term effects of neonatal seizures: a behavioral, electrophysiological, and histological study. Brain Res Dev Brain Res 118: 99–107. Huang LT, Yang SN, Liou CW et al. (2002). Pentylenetetrazolinduced recurrent seizures in rat pups: time course on spatial learning and long-term effects. Epilepsia 43: 567–573. Huttenlocher PR (1979). Synaptic density in human frontal cortex – developmental changes and effects of aging. Brain Res 163: 195–205. Huttenlocher PR (1984). Synapse elimination and plasticity in developing human cerebral cortex. Am J Ment Defic 88: 488–496. Huttenlocher PR (1990). Morphometric study of human cerebral cortex development. Neuropsychologia 28: 517–527. Huttenlocher PR, de Courten C (1987). The development of synapses in striate cortex of man. Hum Neurobiol 6: 1–9. Huttenlocher PR, Hapke RJ (1990). A follow-up study of intractable seizures in childhood. Ann Neurol 28: 699–705. Huttenlocher PR, de Courten C, Garey LJ et al. (1982a). Synaptic development in human cerebral cortex. Int J Neurol 16–17: 144–154. Huttenlocher PR, de Courten C, Garey LJ et al. (1982b). Synaptogenesis in human visual cortex – evidence for

142

G.L. HOLMES ET AL.

synapse elimination during normal development. Neurosci Lett 33: 247–252. Isaeva E, Isaev D, Khazipov R et al. (2006). Selective impairment of GABAergic synaptic transmission in the flurothyl model of neonatal seizures. Eur J Neurosci 23: 1559–1566. Jensen FE, Baram TZ (2000). Developmental seizures induced by common early-life insults: short- and long-term effects on seizure susceptibility. Ment Retard Dev Disabil Res Rev 6: 253–257. Jensen FE, Applegate CD, Holtzman D et al. (1991). Epileptogenic effect of hypoxia in the immature rodent brain. Ann Neurol 29: 629–637. Jiang M, Lee CL, Smith KL et al. (1998). Spine loss and other persistent alterations of hippocampal pyramidal cell dendrites in a model of early-onset epilepsy. J Neurosci 18: 8356–8368. Khalilov I, Holmes GL, Ben-Ari Y (2003). In vitro formation of a secondary epileptogenic mirror focus by interhippocampal propagation of seizures. Nat Neurosci 6: 1079–1085. Khazipov R, Esclapez M, Caillard O et al. (2001). Early development of neuronal activity in the primate hippocampus in utero. J Neurosci 21: 9770–9781. Khazipov R, Khalilov I, Tyzio R et al. (2004a). Developmental changes in GABAergic actions and seizure susceptibility in the rat hippocampus. Eur J Neurosci 19: 590–600. Khazipov R, Sirota A, Leinekugel X et al. (2004b). Early motor activity drives spindle bursts in the developing somatosensory cortex. Nature 432: 758–761. Koo B, Hwang PA, Logan WJ (1993). Infantile spasms: outcome and prognostic factors of cryptogenic and symptomatic group. Neurology 43: 2322–2327. Kreis R, Ernst T, Ross BD (1993). Development of the human brain: in vivo quantification of metabolite and water content with proton magnetic resonance spectroscopy. Magn Reson Med 30: 424–437. Kumar SS, Bacci A, Kharazia V et al. (2002). A developmental switch of AMPA receptor subunits in neocortical pyramidal neurons. J Neurosci 22: 3005–3015. Lindsay J, Ounsted C, Richards P (1979). Long-term outcome in children with temporal lobe seizures. I: Social outcome and childhood factors. Dev Med Child Neurol 21: 285–298. McCabe BK, Silveira DC, Cilio MR et al. (2001). Reduced neurogenesis after neonatal seizures. J Neurosci 21: 2094–2103. McDonald JW, Johnston MV, Young AB (1990). Differential ontogenic development of three receptors comprising the NMDA receptor/channel complex in the rat hippocampus. Exp Neurol 110: 237–247. McLean HA, Caillard O, Khazipov R et al. (1996). Spontaneous release of GABA activates GABAB receptors and controls network activity in the neonatal rat hippocampus. J Neurophysiol 76: 1036–1046. Milh M, Becq H, Villeneuve N et al. (2007). Inhibition of glutamate transporters results in a “suppression-burst” pattern and partial seizures in the newborn rat. Epilepsia 1: 169–174. Miller LP, Johnson AE, Gelhard RE et al. (1990). The ontogeny of excitatory amino acid receptors in the rat forebrain – II. Kainic acid receptors. Neuroscience 35: 45–51.

Minlebaev M, Ben-Ari Y, Khazipov R (2009). NMDA receptors pattern early activity in the developing barrel cortex in vivo. Cereb Cortex 19: 688–696. Monyer H, Burnashev N, Laurie DJ et al. (1994). Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12: 529–540. Moshe SL (1981). The effects of age on the kindling phenomenon. Dev Psychobiol 14: 75–81. Muroi J, Okuno T, Kuno C et al. (1996). An MRI study of the myelination pattern in West syndrome. Brain Dev 18: 179–184. Nadler JV (1981). Kainic acid as a tool for the study of temporal lobe epilepsy. Life Sci 29: 2031–2042. Natsume J, Watanabe K, Maeda N et al. (1996). Cortical hypometabolism and delayed myelination in West syndrome. Epilepsia 37: 1180–1184. Ni H, Jiang YW, Bo T et al. (2004). Long-term effects of neonatal seizures on subsequent N-methyl-D-aspartate receptor-1 and gamma-aminobutyric acid receptor A-alpha1 receptor expression in hippocampus of the Wistar rat. Neurosci Lett 368: 254–257. Ohtahara S, Ohtuska Y, Yamatogi Y et al. (1987). The earlyinfantile-epileptic encephalopathy with suppression-burst: developmental aspects. Brain Dev 9: 371–376. Sanchez RM, Koh S, Rio C et al. (2001). Decreased glutamate receptor 2 expression and enhanced epileptogenesis in immature rat hippocampus after perinatal hypoxia-induced seizures. J Neurosci 21: 8154–8163. Sankar R, Shin DH, Liu H et al. (1998). Patterns of status epilepticus-induced neuronal injury during development and long-term consequences. J Neurosci 18: 8382–8393. Sankar R, Shin D, Mazarati AM et al. (2000). Epileptogenesis after status epilepticus reflects age- and model-dependent plasticity. Ann Neurol 48: 580–589. Sans N, Petralia RS, Wang YX et al. (2000). A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J Neurosci 20: 1260–1271. Schropp C, Staudt M, Staudt F et al. (1994). Delayed myelination in children with West syndrome: an MRI-study. Neuropediatrics 25: 116–120. Sillanpaa M (1983). Social functioning and seizure status of young adults with onset of epilepsy in childhood. An epidemiological 20-year follow-up study. Acta Neurol Scand Suppl 96: 1–81. Sillanpaa M (2004). Learning disability: occurrence and longterm consequences in childhood-onset epilepsy. Epilepsy Behav 5: 937–944. Sogawa Y, Monokoshi M, Silveira DC et al. (2001). Timing of cognitive deficits following neonatal seizures: relationship to histological changes in the hippocampus. Brain Res Dev Brain Res 131: 73–83. Soria C, El Sabbagh S, Escolano S et al. (2007). Quality of life in children with epilepsy and cognitive impairment: a review and a pilot study. Dev Neurorehabil 10: 213–221. Svennerholm L, Vanier MT (1978). Lipid and fatty acid composition of human cerebral myelin during development. Adv Exp Med Biol 100: 27–41.

MATURATION OF THE HUMAN BRAIN AND EPILEPSY Svennerholm L, Vanier MT, Jungbjer B (1978). Changes in fatty acid composition of human brain myelin lipids during maturation. J Neurochem 30: 1383–1390. Swann JW, Brady RJ (1984). Penicillin-induced epileptogenesis in immature rats CA3 hippocampal pyramidal cells. Dev Brain Res 12: 243–254. Swann JW, Smith KL, Brady RJ (1991). Age-dependent alterations in the operations of hippocampal neural networks. Ann N Y Acad Sci 627: 264–276. Takano T, Hayashi A, Sokoda T et al. (2007). Delayed myelination at the onset of cryptogenic West syndrome. Pediatr Neurol 37: 417–420. Tremblay E, Nitecka L, Berger ML et al. (1984). Maturation of kainic acid seizure-brain damage syndrome in the rat. I. Clinical, electrographic and metabolic observations. Neuroscience 13: 1051–1072.

143

Ye GL, Yi S, Gamkrelidze G et al. (2005). AMPA and NMDA receptor-mediated currents in developing dentate gyrus granule cells. Brain Res Dev Brain Res 155: 26–32. Yoshida F, Morioka T, Hashiguchi K et al. (2008). Appearance of focal cortical dysplasia on serial MRI after maturation of myelination. Childs Nerv Syst 24: 269–273. Zhang G, Raol YH, Hsu FC et al. (2004a). Effects of status epilepticus on hippocampal GABAA receptors are agedependent. Neuroscience 125: 299–303. Zhang G, Raol YS, Hsu FC et al. (2004b). Long-term alterations in glutamate receptor and transporter expression following early-life seizures are associated with increased seizure susceptibility. J Neurochem 88: 91–101.