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From Bryan Kolb, Richelle Mychasiuk, Arif Muhammad, Robbin Gibb, Brain
Plasticity in the Developing Brain. In Michael M. Merzenich, Mor Nahum, Thomas
M. Van Vleet editors: Progress in Brain Research, Vol. 207,
Burlington: Academic Press, 2013, pp. 35-64.
ISBN: 978-0-444-63327-9
© Copyright 2013 Elsevier B.V.
Academic Press
Author's personal copy
CHAPTER
Brain Plasticity in the

Developing Brain
Bryan Kolb1, Richelle Mychasiuk, Arif Muhammad, Robbin Gibb

2
Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, AB, Canada
1
Corresponding author: Tel.: þ1-403-329-2405; Fax: þ1-403-329-2775,
e-mail address: kolb@uleth.ca
Abstract
The developing normal brain shows a remarkable capacity for plastic change in response to a
wide range of experiences including sensory and motor experience, psychoactive drugs,
parent–child relationships, peer relationships, stress, gonadal hormones, intestinal flora, diet,
and injury. The effects of injury vary with the precise age-at-injury, with the general result
being that injury during cell migration and neuronal maturation has a poor functional outcome,
whereas similar injury during synaptogenesis has a far better outcome. A variety of factors
influence functional outcome including the nature of the behavior in question and the age
at behavioral assessment as well as pre- and postinjury experiences. Here, we review the
phases of brain development, how factors influence brain, and behavioral development in both
the normal and perturbed brain, and propose mechanisms that may underlie these effects.
Keywords
brain development, prefrontal cortex, recovery of function, types of plasticity
1 INTRODUCTION
The development of the brain and behavior is guided not only by a basic genetic blue-
print but also by a wide range of experiences that shape the emerging brain. Brains
exposed to different environmental events such as sensory stimuli, stress, injury,
diet, drugs, and social relationships show a unique developmental trajectory. The
explosion of epigenetic studies in the past few years has also demonstrated that pre-
natal, and even preconceptual, experiences modify the organization of neural
networks. The goal of this review is to consider the manner in which the developing
brain can be modified by a range of prenatal and postnatal factors that can influence
how the brain responds to other experiences later in life. Our focus will be on the
Progress in Brain Research, Volume 207, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63327-9.00005-9
© 2013 Elsevier B.V. All rights reserved.
35
36 CHAPTER 2 Brain Plasticity in the Developing Brain
neocortex of the rat because the majority of our knowledge regarding the modulation
of brain development is based on studies of neocortical development. We begin with
a brief review of the stages of brain development followed by a consideration of how
factors influence brain development and behavior.
2 STAGES OF BRAIN DEVELOPMENT

The Roman philosopher Seneca concluded that an embryo is an adult in miniature
and the purpose of development was to grow bigger. By the twentieth century, it be-
came clear that this was not the case. Today, development can broadly be divided
into two phases. In mammals, the first phase is in utero and reflects a genetically
determined sequence of events that can be modulated by the maternal environment.
The principal developmental stages here are neural generation and migration. The
second phase, which is largely postnatal in species such as the rat, but both pre-
and postnatal in species such as humans where brain development is more prolonged.
The second phase of development is a period in which the emerging connectivity of
the brain is very sensitive to both environmental stimuli but also to the patterns of
brain activity produced by previous experiences.
Table 1 summarizes seven general stages of brain development characteristic of
all mammals. The generation of neurons in rats begins on embryonic (E) day 10.5–11
when the neural tube is formed with the generative zone, called the subventricular
zone, as the primary “nursery” (for reviews, see Bayer and Altman, 1991; Semple
et al., 2013). The cerebral cortex is mainly generating cells from E15–21. Once
generated in the subventricular zone, the putative neurons migrate to their appropri-
ate locations in the developing cortical plate. The migratory process can take
2–5 days, depending upon the final location (see Fig. 1) (Bayer and Altman;,
1991; Hicks and D’Amato, 1968). There are two types of migration. Pyramidal cells
migrate from the ventricular zone along radial glia to their respective cortical layers
(Rakic, 1972). Interneurons take a tangential trajectory in what Bayer and Altman
call the lateral migratory stream as illustrated in Fig. 1. These cells are generated
more laterally in the ventricular zone in a region known as the ganglionic eminence
(Cuzon et al., 2006; Jimenz et al., 2002). Errors in the migration process, including
abnormal cell proliferation, abnormal timing or migration, or abnormal cortical
Table 1 Stages of brain development

1. Cell birth (neurogenesis, gliogenesis)
2. Cell migration
3. Cell differentiation
4. Cell maturation (dendrite and axon growth)
5. Synaptogenesis (formation of synapses)
6. Cell death and synaptic pruning
7. Myelogenesis (formation of myelin)
2 Stages of Brain Development 37
Dorsomedial
neocor tex
2 days
D eo
n
or co
so r t
lat ex
er
3 days
al
Ventricular
LA
zone TE
Head
RA
LC
Ventrolateral
neocor tex
OR
TIC
Striatum
AL
STR
EAM
4 days
Reservoir
Pirifo
5 days
rm
co
Basal ?
r te
telencephalon
x
FIGURE 1
A summary figure showing cell migration in the anterior and middle parts of the developing
neocortex. Neurons generated in the ventricular zone (striped layer) migrate radially to
the dorsal cortical plate in 2 days, migrate laterally to the lateral cortical plate in 3 days and
to the ventrolateral cortical plate in 4 days. Some cells generated in the ventricular zone
migrate in the lateral cortical stream for up to 4 days and accumulate in the reservoir.
Some migrate into the pyriform cortex, whereas others migrate to as yet unidentified areas in
the basal telencephalon.
From Bayer and Altman (1991), with permission.
organization, have been implicated in disorders such as epilepsy, autism, and schizo-
phrenia among others (e.g., Mochida and Walsh, 2004). Furthermore, prenatal expo-
sure to drugs, such as diazepam (a GABA agonist), can alter migration patterns
(Cuzon et al., 2006).
Once the cells reach their appropriate locations, there is a rapid differentiation
into cell types and growth of dendrites and axons, a process that peaks at 7–10 days
postnatal (P). Synapse production begins once neurons mature with a rapid increase
beginning around P10. Micheva and Ceaulieu (1996) counted the number of GABA
and non-GABA cells and found that the cell volume peaks at about P30 in
somatosensory cortex. There was no further change in synapse number at P60, which
was the oldest age that the authors examined. It is well documented that in primates
there is an overproduction and later elimination of synapses (e.g., Huttenlocher,
1984; Petanjek et al., 2011), which in humans continues well into the third decade
of life. However, the possible overproduction and pruning of synapses is not well
studied in the rat. Although Micheva and Beaulieu did not see any change up to
P60 in somatosensory cortex, it is likely that at least some regions are shedding syn-
apses after P60. Van Eden et al. (1990) showed a decline in cortical thickness in pre-
frontal cortex from P60 to P90 and Vinish et al. (2013) showed a decrease in spine
density over a similar time period in medial prefrontal cortex (mPFC). These results
imply that a more systematic analysis of synaptic formation beyond weaning is re-
quired in the rat. The need for neuronal and synaptic pruning is likely related to the
uncertainty in the number of neurons that will reach their appropriate destinations
and the appropriateness of the connections that they form.
Three features of brain development are especially important in the current con-
text. First, the cells lining the subventricular zone include stem cells that remain ac-
tive throughout life. These stem cells can produce neural or glial progenitor cells that
are able to migrate into the cerebral white or gray matter in adulthood. The role of
these cells is poorly understood as they appear to remain quiescent for extended pe-
riods but can be activated to produce neurons or glia, especially after injury
(e.g., Kolb et al., 2007). Second, cells in the dentate gyrus of the hippocampus
are generated there throughout life, although this production declines with aging.
These cells appear to play a role in functions such as memory (e.g., Spanswick
and Sutherland, 2010). Third, dendrites and spines show remarkable plasticity in re-
sponse to experience and can form synapses within hours and possibly even minutes
after some experiences (e.g., Greenough and Chang, 1989). We discuss this in the
following section.
3 GENERAL TYPES OF BRAIN PLASTICITY

Changes in the brain can be shown at many levels of analysis (see Table 2) ranging
from behavior to molecules. There is no correct level of analysis, but rather the mea-
sure of plasticity must be suited to the research question being asked. Noninvasive
Table 2 Levels of analysis of plasticity

Behavior
Functional organization (e.g., maps)
Cell structure (e.g., dendritic organization)
Synaptic structure
Mitotic activity (e.g., neurogenesis)
Molecular structure (e.g., proteins)
Gene expression
3 General Types of Brain Plasticity 39
imaging is appropriate to study experience-dependent changes in humans but is far

more difficult to use in laboratory animals. An advantage of using laboratory ani-
mals, however, is that it is possible to measure anatomical and molecular changes
in postmortem tissue of animals with different experiences. Our bias in the current
review is to emphasize the correlation between synaptic change, using Golgi-type
stains, and epigenetic analyses, looking for changes in gene methylation and/or gene
expression.
Three types of plasticity can be distinguished in the normal brain: experience-
independent, experience-expectant, and experience-dependent (Greenough et al.,
1987; Shatz, 1992). Experience-independent plasticity is largely a prenatal develop-
mental process. It is impractical for the genome to specify the connectivity of every
connection in neuron development. Instead, the brain produces a rough structure in
which there is an overproduction of neurons, and later, connections, that are sculpted
in response to internal and external events. A good example of experience-
independent plasticity is the development of the eye-specific layers of the lateral ge-
niculate nucleus (LGN) of the cat (Campbell and Shatz, 1992). Axons arriving from
the retina eventually terminate in separate layers in the LGN, but retinal cells initially
also send axonal branches to the layer for the other eye. In order to segregate the
layers correctly, the retinal ganglion cells spontaneously fire so as to correlate their
firing with nearby cells but independent of those in the other eye. Cells that fire to-
gether increase their connections, whereas those out of synch weaken their connec-
tions and eventually die out. This type of plasticity, which is independent of external
sensory input, allows the nervous system more precise in connectivity without re-
quiring overwhelmingly complex genetic instructions.
Experience-expectant plasticity largely occurs during development. A good ex-
ample is the development of ocular dominance columns found in the primary visual
cortex. These alternating columns provide a mechanism for the inputs from the right
and left eyes to be combined to produce binocular vision. Wiesel and Hubel (1963)
showed in kittens that if one eye is kept closed after birth, the open eye expands its
territory, leading to shrinkage of the column related to the closed eye. When the
closed eye is eventually opened, its vision is compromised.
Finally, experience-dependent plasticity refers to a process of changing neuro-
nal ensembles that are already present. This can be seen in situations such as when
animals learn problems (e.g., Greenough and Chang, 1989), when topographic
maps expand or shrink in response to experience (e.g., Blake et al., 2002), when
animals receive intense environmental manipulations (e.g., Greenough and
Chang, 1989), injury (e.g., Kolb, 1995), or in response to abnormal experiences
such as psychoactive drugs (e.g., Robinson and Kolb, 2004). These types of expe-
riences both increase and decrease synapse numbers, often in the same animals, but
in different brain regions (see below). The key point is that the synaptic changes
reflect modifications of a basic phenotype formed in development. It is important
to note that although it is often assumed that experience-dependent plasticity
largely reflects the addition of synapses, it may be seen both in the addition
and/or pruning of synapses.
Table 3 Summary of the effects of frontal cortical injury at different ages

Age at
injury Result Basic reference
E18 Cortex develops with odd structure Kolb, Cioe, and Muirhead (1998)
Functional recovery
P1–6 Small brain, dendritic atrophy Kolb and Gibb (1993)
Poor functional outcome
P7–12 Dendrite and spine hypertrophy Kolb and Gibb (1993)
Cortical regrowth Kolb et al. (1998a,b)
Functional recovery
P25–35 Small brain Kolb and Whishaw (1981)
Partial recovery Nemati and Kolb (2012)
Dendritic hypertrophy
P55 No recovery Nemati and Kolb (2012)
4 FACTORS INFLUENCING BRAIN DEVELOPMENT IN THE

NORMAL BRAIN
When researchers began to study experience-dependent changes in the brain, there
was a belief that changes would be most dramatic in severely impoverished condi-
tions, such as being raised in the dark (e.g., Reisen, 1961). Such extreme experiences
did profoundly alter brain development, but it soon became clear that a wide range of
experiences, and even fairly innocuous-looking experiences, could also produce
large changes in the brain (see Table 3).
4.1 Complex housing

The simplest and most dramatic way to manipulate experience is to compare the
brain structure in animals placed in complex environments (sometimes called
enriched environments) versus that of animals housed in standard laboratory caging.
The original studies by the group at Berkley (e.g., Rozenweig et al., 1967) found
changes in cortical thickness and neurochemistry; however, it is now known that
there are changes in brain size, cortical thickness, neuron size, dendritic branching,
spine density, synapses per neuron, glial numbers and complexity, expression of neu-
rotransmitters and growth factors, and vascular arborization (e.g., Greenough and
Chang, 1989; Sirevaag and Greenough, 1988). Such changes are correlated with a
wide range of enhanced cognitive and motor abilities.
It has only been more recently that the effect of complex housing on brain devel-
opment has been investigated, especially examining the effects on the visual system
(see review by Baroncelli et al., 2010). Complex housing from birth accelerates the
maturation of visual acuity, which is associated with electrophysiological changes.
4 Factors Influencing Brain Development in the Normal Brain 41
Interestingly, complex housing can promote the development of the visual system
even in the absence of visual stimulation in animals housed in the dark (Bartoletti
et al., 2004). In fact, the latter study showed that the nonvisual effects of complex
housing could reverse the effects of raising animals in the dark. Although the mech-
anism of this effect is not known, one possibility is that pups raised in complex en-
vironments receive more maternal care (Sale et al., 2004), which is known to be a
strong factor in changing brain development (see below).
There are few studies of other cortical regions but one particular study showed
enhanced auditory functioning in rats raised in complex environments (Cai et al.,
2009). Early complex housing also alters the development of the parietal cortex.
Kolb et al. (2003a) placed weanling rats in complex environments and compared
the cortical changes to animals placed in the same environments as adults. Whereas
adult rats showed increased dendritic length and spine density after 90 days, juvenile
rats showed a similar increase in dendritic length but a decrease in spine density.
That is, the young animals showed a qualitatively different change in the distribution
of synapses on pyramidal neurons compared to the older animals. This result was
surprising, so the researchers wondered what earlier experience might do. In a
follow-up experiment, pregnant dams were placed in complex environments for
8 h a day beginning a week prior to their pregnancy and then throughout the 3-week
gestation. The brains of their offspring were examined in adulthood and showed a
decrease in dendritic length and an increase in spine density in parietal cortex
76
* * * *
74
Percent global methylation
72
Maternal enrichment
Paternal enrichment
70
Control
68
66
Hippocampus Frontal cortex
FIGURE 2
Average global DNA methylation levels in the hippocampus and frontal cortex of offspring
of males who were housed in complex environments for 28 days prior to mating with a
control female and females who were housed in complex environments for 7 days prior to
conception and for the duration of the pregnancy.
After Mychasiuk et al. (2012).
(Gibb, 2004). Thus, complex housing has qualitatively different effects at different
developmental ages. In a parallel study, Pena et al. (2009) found enduring effects of
complex housing from weaning until adulthood on pituitary–adrenal function, social
behavior, and cognitive behavior in adulthood.
Early complex housing has also been shown to attenuate the effects of exposure to
both methylphenidate and amphetamine later in life. Alvers et al. (2012) found a re-
duction in the self-administration of low, but not high, doses of methylphenidate,
whereas Li, Robinson, and Kolb (unpublished observations) found that lifetime com-
plex housing reduced amphetamine-induced behavioral sensitization as well as the
dendritic changes in mPFC and nucleus accumbens.
Finally, Mychasiuk et al. (2012b) placed male rats in complex environments for
28 days before mating the males with control females and compared the epigenetic
effects to maternal housing as in the earlier Gibb (2004) study (Fig. 2). The offspring
of the complex-environment housed males showed a significant decrease in gene
methylation, reflecting the increased expression of about 1000 genes. More surpris-
ing, however, was that the levels of gene expression changes were remarkably sim-
ilar to those observed in the offspring of females who were housed in similar
complex environments while pregnant.
In sum, complex housing during development has profound and enduring effects
on brain development and function. A key question relates to exactly what it is about
the complex housing experience that is altering brain development.
10
* * * *
9
Spines / 10 mm
Tactile
7 stimulation
Control
5
AID Amygdala Cg3-basilar Cg3-apical
FIGURE 3
The effects of neonatal tactile stimulation on spine density in mPFC (Cg3), OFC (AID), and
amygdala. Similar results were shown for dendritic length and branching.
After Richards et al. (2012).
4.2 Sensory and motor experience

As noted earlier, one explanation for the complex rearing effects is that there was an
increase in maternal behavior, including licking and grooming of the infants.
Schanberg and Field (1987) showed that tactile stimulation of preterm infants accel-
erated growth and led to earlier release from hospital. More recently, it has been
shown that tactile stimulation in preterm infants accelerates EEG maturation and
visual functions, as well as increasing serum levels of insulin growth factor I
(IGF-I) and growth hormone paralleling results found in rats (Field et al., 2008;
Guzzetta et al., 2009). Further studies in rats have also shown that early tactile stim-
ulation improves motor and cognitive functions in adulthood as well as increasing
dendritic length and spine density in mPFC (Fig. 3) (Richards et al., 2012) and
the expression of fibroblast growth factor-2 (FGF-2) in skin and brain (Gibb,
2004). Early tactile stimulation (either stimulation of the pregnant dam or postnatal
stimulation of the pups) attenuates the behavioral and anatomical effects of amphet-
amine in adulthood (Muhammad and Kolb, 2011a,b; Muhammad et al., 2011). And,
as discussed below, tactile stimulation dramatically improves recovery from early
cortical injury (Kolb and Gibb, 2010). There is little doubt that tactile stimulation
has an effect on cortical development that is nearly as large, although somewhat
different from, complex housing.
4.3 Psychoactive drugs

Alcohol has long been associated with compromised brain development, but
only recently it has been shown that many other psychoactive drugs, including pre-
scription drugs, alter brain development. Exposure to psychoactive drugs in adult-
hood produces persistent structural changes to cells in both mPFC and orbital
prefrontal cortex (OFC) and nucleus accumbens (Robinson and Kolb, 2004). There
is now growing evidence that the prenatal administration of a wide range of psy-
choactive drugs including nicotine, diazepam, and fluoxetine chronically alters both
neuronal structure and cognitive and motor behaviors (e.g., Kolb et al., 2008;
Muhammad et al., 2013; Mychasiuk et al., 2013a,b). Similarly, administration
of amphetamine, methylphenidate, haloperidol, and olanzapine in the juvenile pe-
riod also leads to impaired behavior and dendritic aberrations in rats examined in
adulthood (Diaz Heijtz et al., 2003; Frost et al., 2010; Milstein et al., 2013; Vinish
et al., 2013).
One key question is whether early exposure to psychoactive drugs alters brain
plasticity later in life. If adult rats are given nicotine, cocaine, or amphetamine
and later placed in complex environments, neuronal plasticity is blocked
(Hamilton and Kolb, 2005; Kolb et al., 2003b). If rats are given nicotine
prenatally and placed in complex environments in adolescence, there is a complex
array of dendritic/spine changes including a partial reversal of the effects of
nicotine as well as a blockade of the effects of the complex housing
(Muhammad et al., 2013).
4.4 Parent–child relationships

Developing mammals are dependent upon their parents and parent–child relation-
ships are critical for brain development. Variations in the pattern of early parent–
infant interactions can initiate long-term developmental effects that persist into
adulthood (Myers et al., 1989). This has been most extensively studied in
mother–infant interactions in rodents where the time spent in contact and the amount
of maternal licking and grooming of the infants correlate with a variety of somatic
and behavioral outcomes. For example, Meaney and his colleagues have shown that
maternal–infant interactions modulate a variety of emotional and cognitive behav-
iors in adulthood, in part through modifications of the hypothalamic–adrenal stress
response (e.g., Cameron et al., 2005) as well as changes in gene expression in
hippocampus (Weaver et al., 2005). Other studies have shown changes related to
maternal–infant interactions in the hypothalamus and amygdala (Fenoglio et al.,
2006; Moriyama et al., 2013), as well as mPFC and OFC (Muhammad and Kolb,
2011a,b).
4.5 Peer relationships

Peer relationships, and especially play, have been known to influence the develop-
ment since the studies of Harlow (e.g., Harlow and Harlow, 1965). The prefrontal
cortex plays a central role in play behavior and, in turn, its development is strongly
influenced by play. Perinatal injury to the mPFC or OFC regions compromises play
behavior, although in different ways (e.g., Pellis et al., 2006). Similarly, the amount
of play that young rats are allowed to engage in alters the development of prefrontal
cortex. Neurons of the mPFC region respond to the amount of play but not the num-
ber of playmates, whereas the OFC responds to the number of playmates and not the
amount of play (Bell et al., 2010). Furthermore, early experiences including prenatal
stress and tactile stimulation alter play behavior and prefrontal cortex (e.g.,
Muhammad et al., 2011). Indeed, it seems likely that any treatment that alters play
behavior will alter prefrontal development and function. For example, the manipu-
lation of juvenile play behavior also changes the brain’s response to psychomotor
stimulants (Himmler et al., 2013a,b).
4.6 Stress
Although it has long been known that stress alters the brain and behavior of adults, it
is only recently that the role of perinatal stress has been appreciated. For example,
prenatal stress is now known to be a risk factor in the development of schizophrenia
attention-deficit hyperactivity disorder (ADHD), depression, and drug addiction
(Anda et al., 2006; van den Bergh and Marcoen, 2004). Studies with laboratory an-
imals have also shown that perinatal stress produces a wide range of behavioral ab-
normalities, including an elevated and prolonged stress response, impaired learning
1. Dendritic branching
44 control c
a a
PS 21
41 MS
Branch order
Branch order
38 a,c 20
a,c
35
19
32
29 18
2. Excitatory synapses
a,c
# of synapses (x000)
# of synapses (x000)
2.6 a,c 1.6
a,c a b
2.3
1.5
2.0
1.7 1.4
3. Spine density
b,c
13
# of spines per 10 µm
12 a b
b,c
11
10 a,c
9 a
8
NAc AID Cg3B Cg3A
FIGURE 4
Mean ( SEM) total number of branch bifurcations (dendritic branching), number of
excitatory synapses, and spine density in Nucleus accumbens (NAc), OFC (AID), and mPFC
(Cg3Basilar field; Cg3Apical field). The mean branch order and number of synapses are in the
same scale shown on the right vertical axis for NAc, AID, and Cg3B but are in a different scale
for the Cg3A, which is on the left vertical axis. The letters “a” and “b” represent the
comparisons of the effects prenatal stress (PS) and maternal separation (MS), respectively,
compared to controls. The letter “c” represents comparisons between PS and MS
(ps <0.05 or better).
After Muhammad et al. (2012).
and memory, altered social and play behavior, increased anxiety, deficits in atten-
tion, and increased preference for alcohol (Weinstock, 2008).
Stress has long been known to alter the prefrontal cortex of adults (e.g., Liston
et al., 2006), but it has become apparent that the changes in the developing prefrontal
cortex are very different. For example, adult stress leads to a decrease in spine den-
sity in mPFC, but an increase in orbital cortex (Liston et al., 2006). In contrast,
Murmu et al. (2006) found that prenatal stress in degus from E16 to E21 produced
a decrease in both spine density and dendritic length in both mPFC and OFC in adult-
hood. Using a somewhat different paradigm, our laboratory exposed rats to gesta-
tional stress at E12–16 and found an increase in spine density in both mPFC and
OFC when the brains were examined at weaning or in adulthood (Muhammad
et al., 2012; Mychasiuk et al., 2012). We also compared the effects of prenatal stress
and postnatal maternal separation and found very different effects of the two
stressors (see Fig. 4). Thus, the effects of perinatal stress vary with the nature of
the stress, the precise embryonic age of the stress, and the age at which the brain
is examined.
One explanation for the difference between the Murmu results and our results
may be related to differences in epigenetic changes related to intensity of the stress.
Mychasiuk et al. (2012) found that mild gestational stress increased global methyl-
ation in prefrontal cortex (using a combined sample of mPFC and OFC), whereas
greater stress had the opposite effect. A whole-genome microarray showed that over
700 genes in the prefrontal cortex and hippocampus were differentially expressed
following prenatal stress, with most genes being downregulated.
The effects of gestational stress can be surprisingly subtle. Mychasiuk et al.
(2011a,b,c,d) housed pregnant females together for the duration of their pregnancies.
One rat received stress at E12–16 while the other (the bystander) did not. The off-
spring of both dams showed significant changes in methylation, gene expression, and
dendritic organization but the patterns of gene expression and dendritic changes were
qualitatively different (Mychasiuk et al., 2011a,b,c,d). It appears that both dams were
stressed but in different ways, which led to differential effects on the offspring brains.
One obvious question is to ask how prenatal stress affects the brain response to other
postnatal developmental experiences such as complex housing, tactile stimulation,
play, and so on.
4.7 Gonadal hormones

During development the most obvious effect of exposure to gonadal hormones is the
prenatal differentiation of the genitals. But the same gonadal hormone receptors are
found in the brain, so it would be surprising if there were not sex differences there
too. There are clear differences in the adult human brain (e.g., Goldstein et al., 2001)
and MRI studies of human children have shown large differences in the rate of brain
development in the two sexes (O’Hare and Sowell, 2008), with the female brain
reaching its adult volume 2–4 years earlier than the male brain. Studies in rats have
shown that neurons in the mPFC have larger dendritic fields and higher spine density
in males than females, whereas the opposite is found in OFC (e.g., Kolb and Stewart,
1991). Furthermore, there are sex differences in the effects of many perinatal expe-
riences including gestational stress, complex housing, and injury (e.g., Kolb and
Stewart, 1995; Mychasiuk et al., 2011a,b,c,d).
4.8 Intestinal flora

Gut microbiota have adapted to a symbiotic relationship with many animals. Soon
after birth, the gut of mammals is populated by a variety of indigenous microbes that
influence both gut and liver functions (e.g., Bjorkholm et al., 2009; Hooper and
Gordon, 2001). There are many similarities in the neurochemical organization of
the enteric and central nervous systems, so it is reasonable to speculate that gut
microbiota might influence brain function. Indeed, epidemiological studies have
shown an association between neurodevelopmental disorders including autism and
schizophrenia and microbial infections early in life (e.g., Finegold et al., 2002;
Mittal et al., 2008). Diaz Heijtz et al. (2011) manipulated gut bacteria in newborn
mice and found that gut bacteria influence motor and anxiety-like behaviors, which
were associated with changes in the production of synaptic-related proteins in cortex
and striatum. This finding is important because it provides a mechanism whereby
infections during development could influence brain development as well as a reason
why results in different laboratories could be different depending upon dietary selec-
tion and which gut microbiota are present in the respective colonies.
4.9 Diet
There is an extensive literature on the effects of caloric- and/or protein-restricted
diets on brain and behavioral development (e.g., Lewis, 1990) but little research
on brain plasticity and restricted diets per se. Similarly, little is known about the
effects of enhanced diets on brain development. It is reasonable to predict that
brain development might be facilitated by vitamin and/or mineral supplements.
Dietary choline supplementation during the perinatal period leads to enhanced
spatial memory in various spatial navigation tasks (e.g., Meck and Williams,
2003; Tees and Mohammadi, 1999) and increases the levels of nerve growth fac-
tor in hippocampus and neocortex (e.g., Sandstrom et al., 2002). Halliwell and
Kolb (2003) did similar studies and found increased dendritic length in pyramidal
cells across the cerebral cortex and CA1 of the hippocampus with choline
supplementation.
Halliwell (2011) also studied the effects of a vitamin/mineral supplement to the
food of lactating rats. The same dietary supplement was reported to improve mood
and aggression in adults and adolescents with various disorders (Leung et al., 2011)
and reduced social withdrawal and anger in children with autism (Mehl-Madrona
et al., 2010). Analysis of the adult offspring of lactating rats fed the same supplement
found an increase in dendritic length in pyramidal neurons in mPFC and parietal
cortex but not in OFC. Furthermore, the same diet facilitated recovery from perinatal
mPFC lesions in rats.
5 BRAIN DEVELOPMENT AFTER EARLY BRAIN INJURY

The first systematic studies on the effect of brain injury in development were
done by Margaret Kennard, beginning in the 1930s (e.g., Kennard, 1942). She
made unilateral motor cortex lesions in infant and adult monkeys and found
milder impairments in her young animals. This led her to suggest that there
was some change in the cortical organization of the infants that supported more
normal behavior (Kennard, 1942). Although Kennard was aware that her monkeys
still had deficits, she is credited with the general idea that “earlier is better,” a
conclusion that Teuber (1975) referred to as the Kennard Principle. Hebb
(1945, 1949) reached a different conclusion, however. He was studying the
effects of early frontal lobe injury in children and concluded that these children
had worse outcomes than adults with similar injuries. He suggested that the early
frontal injury was interfering with the normal development of neural networks
needed to support many adult behaviors (see also Stiles, 2012). The conclusions
of Kennard and Hebb would appear to be at odds, but over the past 30 years’ ex-
tensive studies of monkeys, cats, and rats with cortical injuries have shown that
both views are partially correct. The outcomes depend upon the precise age at
injury, the behavioral measurements used, the age at assessment, and whether
the injury is unilateral or bilateral.
5.1 Age at injury

Age at injury refers not to the actual postnatal age of animals but to their develop-
mental age. Rodents and carnivores are born less mature than primates, so birth date
is not helpful in comparing across species. We will consider the effects of cortical
lesions in rats first, with an emphasis on frontal lesions because as in monkeys
and cats, this is where most of the studies are focused. Although it is common in
the perinatal ischemia literature to make lesions on postnatal day 7 (P7) with rats
to mimic birth asphyxia in humans, this age misses much of the story.
It has become clear that in rats and mice, damage on days 1–5 has devastating
consequences on behavior, with the effect generally being worse the earlier the post-
natal injury, regardless of which cortical region is damaged. In contrast, similar dam-
age on days 7–12 permits much better functional outcome, and depending upon the
behavioral measure, there can be surprisingly normal behavior, despite the fact that
the brain is significantly smaller than normal (see Table 2). There is still a better out-
come than observed in adults when mPFC lesions are incurred in early adolescence.
We are aware of only one study of prenatal cortical lesions in rats and there was re-
markably normal behavior, in spite of a highly abnormal brain (Kolb et al., 1994a,b).
5 Brain Development After Early Brain Injury 49
There were, however, a series of studies by Sam Hicks in the 1950s in which ionizing
radiation was used to alter brain development, which in some cases led to surpris-
ingly good outcomes in spite of abnormal brains, provided there was no hydroceph-
alus (e.g., Hicks and D’Amato, 1961).
In sum, functional outcome is good if injury is during the latter part of neurogen-
esis (E18) but poor if it is during migration and the beginning of synaptogenesis. It is
better again after migration is done and synaptogenesis is burgeoning. We must note
that although we have focused on mPFC lesions, a similar pattern is seen after OFC,
motor cortex, posterior cingulate cortex, posterior parietal cortex, visual cortex, and
auditory cortex lesions (see review by Kolb et al., 2010). As might be expected, how-
ever, recovery is not equivalent across all regions, with posterior injury allowing less
recovery than anterior lesions.
Results from studies of cats and monkeys present a similar pattern, although the
dates vary because of differences in gestational rate. Villablanca and his colleagues
conducted an extensive series of studies on the behavior of cats with frontal or pre-
frontal injuries (e.g., Villablanca et al., 1993). Cats are an interesting comparison to
the rat and monkey because they are embryologically older than rats at birth with a
gestation period of about 65 days, but they are much younger at birth than monkeys.
Overall, Villablanca has found that although cats with prefrontal lesions shortly after
FIGURE 5
Photographs of brains of animals given midline frontal cortrex lersions on postnatal day 10
and then sacrificed on postoperative days 1, 3, 8, or 23. The lesion cavity is evident at day 1 but
by day 23 is only visible as a scar. By day 90 (not shown) the scar is no longer visible.
After Kolb et al. (1998a,b).
birth show good recovery relative to animals with lesions later in life, cats with pre-
natal lesions have severe behavioral impairments. Thus, the newborn cats appear
similar to P10 rats, whereas the prenatal cats are similar to P1–6 rats.
Monkeys are different again. They are born much older than rats, cats, or even
humans. Although Kennard reported better outcomes with infant lesions, as did
Harlow et al. (1964), the bulk of the later evidence largely by Goldman and col-
leagues did not report this (see reviews by Goldman, 1974; Goldman et al.,
1983). In contrast, however, prenatal lesions in monkeys allow substantial recovery
(Goldman and Galkin, 1978). The prenatal lesions are more similar in embryological
time to newborn cats and P10 rats. We can predict that if Goldman and Galkin had
made their prenatal lesions even earlier, the outcome would be similar to the prenatal
lesions in cats and lesions in newborn rats.
But what are the anatomical correlates of this recovery? Studies of unilateral mo-
tor cortex lesions (e.g., Hicks and D’Amato, 1975) found anomalous projections
from the intact hemisphere to the spinal cord, leading to the presumption that these
projections supported the functional recovery. They likely did. Similarly, there are
anomalous projections in the cat visual system that are associated with functional
recovery (Payne and Lomber, 2001) as well as extensive anomalous connections af-
ter neonatal hemidecortication in both rats and cats that are correlated with recovery.
But anomalous projections are also associated with poor outcomes. For example,
whereas rats with P1 mPFC lesions have significant abnormal connections, P10 an-
imals do not (Kolb et al., 1994a) but it is the P10 animals that show recovery, not the
rats with the rewired brain. There are several other types of anatomical changes that
support recovery in P10 rats. For example, there is widespread dendritic hypertrophy
of cortical pyramidal neurons as well as increased spine density. Furthermore,
there is evidence that for at least some types of P10 lesions, namely mPFC and pos-
terior cingulate, there is spontaneous neurogenesis that fills the lesion cavity (Fig. 5)
(Kolb et al., 1998a,b). The neurons that reform the frontal region establish connec-
tions with subcortical regions such as the striatum and have electrical activity that is
nearly normal (Driscoll et al., 2007). In the process of studying the apparent regen-
eration of the lost cortex, we discovered serendipitously that injections of the mitotic
marker, bromodeoxyuridine (BrdU), on E12–14 disrupt the postnatal activity of stem
cells (Kolb et al., 1999) and completely block the postinjury neurogenesis (Kolb
et al., 1998a,b, 2012). Not surprisingly there is no functional recovery if there is
no neurogenesis.
Finally, one other mechanism appears to be the survival of neurons in the thal-
amus that should have degenerated after the injuries. Normally, if cortical regions are
damaged, the thalamocortical projection cells die. This is true after neonatal visual
cortex lesions but not after prefrontal lesions. Cells in the dorsal medial thalamus,
which projects to prefrontal cortex, survive and form connections with remaining
frontal regions in both monkeys and rats (Goldman and Galkin, 1978) and rats
(Kolb and Nonneman, 1978), although this likely depends on the age at injury.
Van Eden et al. (1998) used unbiased stereology to count neurons after P6 mPFC
5 Brain Development After Early Brain Injury 51
lesions and found no difference from adults with similar lesions. This study should be
repeated with P10 lesions.
5.2 Behavior specificity

As a rule of thumb, cognitive functions show better functional recovery than motor
functions, which in turn show better recovery than species-typical behaviors, which
show virtually no recovery regardless of the age at injury (e.g., Kolb and Whishaw,
1981). It appears that it is easier for the brain to form new neuronal ensembles to
solve cognitive tasks than motor tasks and the neural circuits underlying species-
typical behaviors are relatively hard-wired and not easily replaced.
One surprising effect of early lesions is seen in spatial behaviors. Rats with P1–5
show poor recovery, which is not surprising given that adult rats with similar lesions
are also impaired. What is unexpected, however, is that lesions elsewhere in the ce-
rebral cortex at P1–5 also produce deficits in spatial behaviors even though similar
adult lesions do not. This effect is not unique to rats, however, as children with early
cortical lesions in either hemisphere show the same result (e.g., Akshoomoff et al.,
2002). This is in marked contrast to the recovery of language in children with peri-
natal injuries to the speech areas, although the recovery of language is less complete
than was originally believed (Thai et al., 1991).
5.3 Age at assessment

One of challenges in assessing the effects of early brain injury is the problem of
knowing when to investigate the behavior. This is nicely illustrated by the early stud-
ies of Goldman (e.g., Goldman, 1974). She was initially impressed with apparent re-
covery of functions after frontal lobe injuries in infant monkeys but as she continued
her studies it became clear that she, and others before her, had overestimated the ex-
tent of recovery because the animals were tested when they were still young. Thus,
she found that animals with dorsolateral prefrontal lesions became progressively
more impaired at cognitive tasks such as delayed alternation as the brain developed
(Goldman et al., 1983).
She tested the idea that age was important directly by studying the behavioral
effect of reversibly cooling the otherwise normal prefrontal cortex of monkeys at
different ages. On a task that monkeys with adult lesions are impaired at (delayed
response), she found that when she cooled the cortex at 9–16 months of age the an-
imals performed as well as they did in the uncooled state. However, when tested at
19–31 months the animals were impaired, and this impairment grew progressively
larger as they grew older. Thus, she was able to show that animals with early cortical
lesions “grow into their deficits,” an observation also made in children with congen-
ital brain injuries (Banich et al., 1990) and hamsters with mPFC lesions on P2 (Kolb
and Whishaw, 1985).
But age at assessment can work in reverse as well. When rats were given mPFC
lesions on P1 or P10 and then behaviorally tested at P22–25, both groups were
severely impaired relative to controls (Kolb and Gibb, 1993). However, when the
rats were tested at P52–55, the P10 rats were no longer impaired whereas the P1 rats
were. The recovery of the P10 rats was correlated with hypertrophy of cortical
pyramidal neurons that was not present in the brains of P25 animals. Thus, not only
can animals grow into deficits but out of them too.
Ipsilateral forelimb
80
Neonate
70
Adult
60
*
50
Hit percent
40
30
20
10
80
Contralateral forelimb
70
60
50
Hit percent
40
30
20
*
10
*
*
0
Control Small Med Large Hemi
FIGURE 6
Performance on a skilled reaching task by rats with adult or P5 unilateral lesions of
varying sizes (small, medium, and large) of the motor cortex or the entire neocortex
(hemidecorticate). Reaching was affected bilaterally, although more severely in the
contralateral forepaw and increased with lesion size. Rats with neonatal lesions showed
significantly better reaching with the contralateral paw than the adults.
After Whishaw and Kolb (1988).
6 Unilateral Versus Bilateral Injury 53
6 UNILATERAL VERSUS BILATERAL INJURY

An obvious difference between the unilateral and bilateral injuries is that in the for-
mer case there is an intact region homologous to the injured region, whereas in the
bilateral case there is not. Two predictions from this difference are that we would
expect better recovery from unilateral injury and the postinjury sequelae of brain
changes are likely different. Both predictions are borne out.
Hicks and D’Amato (1975) were the first to show that when infant rats sustained
unilateral lesions of the corticospinal projection neurons, they were subsequently
found to have an anomalous ipsilateral pathway from the intact hemisphere to the
spinal cord. They presumed that this pathway was responsible for the improved mo-
tor outcomes of the infants relative to adults with similar injuries. One prediction
from their study is that rats with bilateral lesions in infancy (P1) should not show
recovery because they would not have a normal hemisphere to project to the spinal
cord. This is the case (Kolb et al., 2000a,b). Furthermore, in contrast to unilateral
operates, the bilateral operates are impaired at tests of spatial navigation, in contrast
to rats with adult lesions. This spatial deficit may be related to anomalous connec-
tions from the posterior cortical regions to the spinal cord, connections that likely
were present at birth and failed to die after the early motor cortex lesions (e.g.,
O’Leary, 1989).
Although unilateral focal lesions provide an advantage in recovery, this advan-
tage is reduced as the size of the lesion increases (Whishaw and Kolb, 1988). Fur-
thermore, the larger the lesion, the greater is the impairment not only of the
contralateral limb but also of the ipsilateral limb (Fig. 6).
Table 4 Summary of the effects treatments on recovery from early brain injury
Treatment Outcome Basic reference
Behavioral therapy
Complex housing Improved behavior Kolb and Elliott (1987)
Tactile stimulation Improved behavior Kolb and Gibb (2010)
Chemical therapy
FGF-2 (P3 mPFC) Improved behavior Comeau et al. (2007a,b)
FGF-2 (P10 Motor) Nearly normal behavior Monfils et al. (2006)
Manipulation of gonadal Impaired recovery Kolb and Stewart (1995)
hormones
Prenatal experiences
FGF-2 Improved behavior Comeau et al. (2007a,b)
Tactile stimulation Improved behavior Gibb (2004)
Diazepam Improved behavior Kolb et al. (2008)
Fluoxetine Blocked recovery kolb et al. (2008)
Excessive exercise Reduced recovery Gibb (2004)
Gestational stress Blocked recovery Halliwell (2011)
The extreme form of a unilateral lesion is hemidecortication or hemispherec-

tomy. As shown in Fig. 3, hemidecorticates are severely impaired with both limbs,
but the neonatal (P2) hemidecorticates are significantly better with their contralateral
limb than the adult decorticates. This is correlated both with considerable rewiring of
the normal hemisphere and also with hypertrophy of pyramidal neurons throughout
the intact hemisphere (Kolb et al., 1992). Curiously, whereas rats with bilateral focal
lesions on P10 are always functionally advantaged relative to those with lesions at
P1–6, this is not true with hemidecortication (Kolb and Tomie, 1988). In contrast, the
early operates fare better and have more extensive anatomical remodeling. The dif-
ference between age-related differences between focal lesions and hemidecortication
begs for more study.
7 FACTORS INFLUENCING BRAIN DEVELOPMENT IN THE

INJURED BRAIN
The obvious place to look for beneficial modulating effects on the early-injured brain
is at the animals with the earliest focal lesions. After all, these are the animals with
the worst functional outcomes in the absence of treatment. Because most of the stud-
ies on modulating factors have been using rats with medial frontal lesions, our dis-
cussion will focus on this preparation, with reference to other lesions where
appropriate. We have grouped the factors into (1) behavioral therapy, (2) pharmaco-
logical therapy, and (3) prenatal therapy (see Table 4). We discuss each in turn.
7.1 Behavioral therapy

Although behavioral therapy would seem to be the most obvious type of treatment to
study, there are surprisingly few studies in either laboratory animals or human chil-
dren and virtually no evidence regarding when the optimal time might be or how
intense it ought to be. We began our studies by looking at complex housing. Placing
animals with bilateral P1–7 mPFC lesions in complex housing for 90 days beginning
at weaning stimulates significant functional improvement on tests of both cognitive
and motor behaviors and this is correlated with increased cortical thickness, brain
weight, and dendritic length (Kolb and Elliott, 1987). In contrast, placing the animals
in the complex environments as adults was ineffective (Comeau et al., 2008), unless
the lesions are unilateral (Williams et al., 2006).
Tactile stimulation is also an effective treatment. Rats were given mPFC on P3
and then beginning on P4 they received two weeks of tactile stimulation for 15 min
3 per day (Kolb and Gibb, 2010). The improvement on both spatial learning and
skilled motor function was remarkable (Fig. 4) and was correlated with increased
spine density in the tactile-stimulated mPFC rats. One possible mechanism for the
effect of tactile stimulation is that the tactile stimulation increases the expression
of FGF-2 in both skin and brain providing a possible mechanism for the therapeutic
7 Factors Influencing Brain Development in the Injured Brain 55
FIGURE 7
Sagittal brain sections illustrating normal motor cortex (A), a P10 motor cortex lesion
(B), and a P10 motor cortex lesion and FGF-2 treatment (C). Compared to control cortex,
the FGF-2 stimulated regrowth does not illustrate a laminar distribution. Scale bars in
(A), (B), and (C) are 550 mm. Scale bars in (D) and (E) are 250 mm.
After Monfils et al. (2008).
abilities of tactile stimulation (Gibb, 2004). We note parenthetically that complex

housing also increases FGF-2 expression in cortex (Kolb et al., 1998).
7.2 Chemical therapy

In view of the apparent role of FGF-2 in recovery, we subcutaneously administered
FGF-2 directly as a therapy after P4 mPFC lesions and found significant functional
improvement (Comeau et al., 2007a,b, 2008). In parallel studies, we administered
FGF-2 to rats with P3 or P10 motor cortex lesions. The FGF-2 essentially reversed
all of the motor deficits in the P10, but not the P3 lesion animals, but more impor-
tantly, the lost motor cortex tissue regenerated and formed corticospinal connections
(Monfils et al., 2006, 2008) (Fig. 7). Pretreating the rats with BrdU on E12 blocked
the FGF-2-mediated regeneration and prevented functional recovery, just as it did
after the spontaneous regeneration after P10 mPFC lesions (see above).
Not all chemical treatments are beneficial, however. Perinatal depletion of nor-
adrenaline on P1–3, administration of testosterone to female rats on P1, or blockade
of gonadal hormones by gonadectomy on P1 both block recovery and the associated
dendritic changes following P7 mPFC lesions (Kolb and Stewart, 1995; Kolb and
Sutherland, 1992). Furthermore, even FGF-2 can be detrimental. In one study
performed in our laboratory, we gave FGF-2 and placed animals in complex housing
at weaning (Hastings, 2003). This combination made the animals worse, possibly
because the combined treatments raised FGF-2 to a toxic level.
7.3 Prenatal therapy

Given that prenatal events such as gestational stress alter brain development, we
wondered if prenatal events might influence recovery from perinatal injury. They
do. Prenatal tactile stimulation (i.e., of the pregnant mom), prenatal diazepam,
and prenatal FGF-2 all enhance recovery from P3 mPFC lesions (Comeau et al.,
2008; Gibb, 2004; Kolb et al., 2008). In contrast, prenatal administration of fluox-
etine, prenatal stress, or excessive maternal exercise block recovery of rats with
P7 mPFC lesions (Day et al., 2003; Gibb, 2004; Halliwell, 2011). The powerful ef-
fects of prenatal events, both positive and negative, demand further study as they
likely can account for some of the variance in outcomes observed in children with
perinatal perturbations such as ischemia.
8 SUMMARY
We have shown that the developing normal and injured brain shows a remarkable ca-
pacity for plastic change, both for better and worse. A key remaining question is how
this happens. Although we have not discussed it here one consistent observation in both
the normal and injured brain is a sex difference in experience-dependent plasticity. It is
not simply that one sex is more plastic but rather that there is a sexual dimorphism in
both the functional and anatomical effects of experiences. One clear example is the
effect of prenatal stress on gene expression (Mychasiuk et al., 2011b). Although there
are large changes in gene expression in the prefrontal cortex of each sex, there are few
overlapping gene expression changes. But both sexes show a marked alteration in den-
dritic organization, suggesting that there are multiple mechanisms underlying the ob-
served plastic changes. This is clearly grist for future studies.
Acknowledgments
This research was supported by NSERC of Canada grants to B. K. and R. G.
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Brain Plasticity in the Developing Brain

Article in Progress in brain research · December 2013

Bryan Kolb Richelle Mychasiuk

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The effect of prenatal auditory stress on mouse reproduction, behavioral performance

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Brain Plasticity in the

Bryan Kolb1, Richelle Mychasiuk, Arif Muhammad, Robbin Gibb

36 CHAPTER 2 Brain Plasticity in the Developing Brain

2 STAGES OF BRAIN DEVELOPMENT

Table 1 Stages of brain development

2 Stages of Brain Development 37

38 CHAPTER 2 Brain Plasticity in the Developing Brain

3 GENERAL TYPES OF BRAIN PLASTICITY

Table 2 Levels of analysis of plasticity

3 General Types of Brain Plasticity 39

imaging is appropriate to study experience-dependent changes in humans but is far

40 CHAPTER 2 Brain Plasticity in the Developing Brain

Table 3 Summary of the effects of frontal cortical injury at different ages

4 FACTORS INFLUENCING BRAIN DEVELOPMENT IN THE

4.1 Complex housing

4 Factors Influencing Brain Development in the Normal Brain 41

42 CHAPTER 2 Brain Plasticity in the Developing Brain

4 Factors Influencing Brain Development in the Normal Brain 43

4.2 Sensory and motor experience

4.3 Psychoactive drugs

44 CHAPTER 2 Brain Plasticity in the Developing Brain

4.4 Parent–child relationships

4.5 Peer relationships

4 Factors Influencing Brain Development in the Normal Brain 45

46 CHAPTER 2 Brain Plasticity in the Developing Brain

4.7 Gonadal hormones

4 Factors Influencing Brain Development in the Normal Brain 47

4.8 Intestinal flora

48 CHAPTER 2 Brain Plasticity in the Developing Brain

5 BRAIN DEVELOPMENT AFTER EARLY BRAIN INJURY

5.1 Age at injury

5 Brain Development After Early Brain Injury 49

50 CHAPTER 2 Brain Plasticity in the Developing Brain

5 Brain Development After Early Brain Injury 51

5.2 Behavior specificity

5.3 Age at assessment

52 CHAPTER 2 Brain Plasticity in the Developing Brain

6 Unilateral Versus Bilateral Injury 53

6 UNILATERAL VERSUS BILATERAL INJURY

54 CHAPTER 2 Brain Plasticity in the Developing Brain

The extreme form of a unilateral lesion is hemidecortication or hemispherec-

7 FACTORS INFLUENCING BRAIN DEVELOPMENT IN THE

7.1 Behavioral therapy

7 Factors Influencing Brain Development in the Injured Brain 55

abilities of tactile stimulation (Gibb, 2004). We note parenthetically that complex

7.2 Chemical therapy

56 CHAPTER 2 Brain Plasticity in the Developing Brain

7.3 Prenatal therapy

58 CHAPTER 2 Brain Plasticity in the Developing Brain

Hebb, D.O., 1945. Organization of behavior. McGraw-Hill, New York, NY.

60 CHAPTER 2 Brain Plasticity in the Developing Brain

62 CHAPTER 2 Brain Plasticity in the Developing Brain

64 CHAPTER 2 Brain Plasticity in the Developing Brain

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