Why is the first 8 weeks of pregnancy known as the critical period of human development?

Critical period for monocular form deprivation

There are multiple “plastic” periods for different visual functions in macaque monkeys (Fig. 40.6).19,51 Spectral sensitivity functions have relatively short critical periods that begin soon after birth and last for 3 months for scotopic spectral sensitivity and 6 months for photopic spectral sensitivity. The critical period for visual acuity loss is much longer, lasting over 24 months. Binocular vision development can be disrupted by monocular deprivation starting as late as 25 months of age (roughly equivalent to 8 years in humans).19 However, the “end” of the critical period for binocular functions has not been determined for monkeys.

Because the sensitivity of the visual cortex to deprivations varies substantially during the critical periods, the timing of deprivation, i.e.onset and duration, has significant effects on the severity of perceptual and neural deficits. At what age is monocular form deprivation likely to have the most damaging effects in monkeys? The perceptual development of contrast sensitivity and visual acuity in monkeys is most vulnerable to monocular form deprivation during the first 5 postnatal months. A sharp drop of sensitivity to deprivation occurs after this initial period of heightened sensitivity, followed by a gradual decline over an extended period of time, i.e. > 24 months (Fig. 40.6).19,51

For ocular dominance plasticity in V1 of monkeys, the most severe shrinkage of ocular dominance columns for the deprived eye occurs with theearliest onset age, e.g. 1 week of age.28 The degree of the shrinkage becomes progressively smaller as the onset of deprivation is delayed and there is no obvious shrinkage if the onset is set at the 12th postnatal week. Thus, contrary to a classic observation,27 the ocular dominance columns in layer IVC of monkey V1 are most sensitive to monocular deprivation right after birth.

These behavioral and anatomical studies reinforce theclinical view that removal of dense congenital cataract combined with good optical quality lenses or correction of ptosis at the earliest possible postnatal time is essential to minimize the negative impact of monocular form deprivation in humans.52–54

The critical period for ocular dominance in cats begins about 3–4 weeks of age when the optics of their eyes becomes relatively clear, peaks around 6–8 weeks, and gradually decreases during the next 12–14 weeks.25,55,56 A similar timing of the critical period for monocular deprivation has been reported for rats and ferrets with minor variations.57–59 The critical period is longer for monkeys than that in lower species and appears to be generally correlated with animal's life expectancy.15,60 It is difficult to determine the precise critical period of vision development for humans in part because of the difficulties associated with conducting experiments on human infants and dependence on clinical observations for data collection. Although the critical period for humans varies considerably for specific visual tasks as evidenced in animal studies, the critical period for experience-dependent changes in humans is thought to begin soon after birth (within 6 months or earlier), peak around 1–3 years of age, and decline slowly until 8–10 years of age or later.14

Critical periods of development

A critical period is a time during early postnatal life when the development and maturation of functional properties of the brain, its “plasticity,” is strongly dependent on experience or environmental influences. This concept plays an important role in the nature versus nurture debate (Sengpiel, 2007). However, not all neuroscientists agree on what defines a critical period for neural circuit development. One strict interpretation defines the critical period as a subset of sensitive periods. Sensitive periods are special time-windows in early development where experience has a profound effect on the brain, while critical periods are a special case wherein experience is absolutely required at fixed developmental periods for subsequent normal function. The critical period should include the onset of robust plasticity response to sensory experience, a defined period of time when induction of plasticity is possible. One of the major concepts currently being investigated in neuroscience is that such critical periods represent heightened epochs of brain plasticity, and that sensory experience during these periods produces permanent, large-scale changes in neuronal circuits. The various critical periods start very shortly after the relevant sensory information first becomes available and a certain level of intracortical inhibition marks the onset of the critical period. The development of cortical inhibitory circuitry initially lags behind that of the excitatory circuitry. The critical period is characterized by changes not only at the level of synaptic transmission, but increasingly by structural changes, which result in closure of the critical period. The most significant changes in the cortex towards the end of the critical period are those seen in the extracellular matrix, a network of macromolecules, which becomes more and more rigid during postnatal development. Thus, three phases of plasticity define the critical period: (1) pre-critical period: the initial formation of neuronal circuits that is not dependent on experience; (2) critical period: a distinct onset of robust plasticity in response to experience when the initially formed circuit can be modified by experience; and (3) closure of the critical period: after the end of the critical period, the same experience no longer elicits the same degree of plasticity (Hooks and Chen, 2007).

In humans, critical periods are extended over years and there are different critical periods for different brain functions (for example binocular vision or language acquisition) and unless a certain function is learned during this period, the function will remain poor. The well-known classic experiments by Hubel and Wiesel showed how early sensory deprivation dramatically affects anatomy and functional organization of the visual cortex. These authors reported that occluding one eye (monocular deprivation) early in development led to a severe reduction in the number of visual cortical cells responding to that eye, with a very strong increment in the number of neurons activated by the open eye. They termed this the critical period during which synaptic connections in the primary visual cortex are modified by visual experience. The critical period shown by Wiesel and Hubel (1963) has remarkably influenced not only biologists but also psychologists, philosophers, physicians, politicy makers, parents, and educators. In fact, this sensitive period is also considered present in humans, involving language, music, sport, and even sociability. The brain continues to develop throughout infancy, childhood, and adolescence and psychologists assert that, through the same periods, one acquires increasingly higher mental functions. During growth, the brain accumulates information about the external world in order to build an internal world in the temporo-parietal association cortex. In thinking, the frontal association cortex exerts its executive function on the internal world to manipulate thought models such as images, ideas, and concepts to simulate what could happen in the external world. In fact we acquire knowledge and new skills over our entire lives; it is likely that there are differently timed sensitive periods for acquiring different types of knowledge and skills such as literacy, numeracy, music, art, and physical education. A new field of research, called “nurturing the brain,” is expected to provide accurate knowledge about sensitive periods, which will help formulate an efficient learning timetable for curricula in nurseries and schools (Hensch, 2004; Ito, 2004; Konishi, 2004).

Introduction

A critical period generally is thought of as a point in the life of an organism in which a specific type of environmental experience is likely to exert its greatest influence. The existence and nature of critical periods have been topics of considerable discussion among biologists and social scientists. Research on critical periods has come primarily from the fields of embryology, neurobiology, and ethology, relying on both naturalistic and experimental studies with animals. Considerable progress has been made, but much remains to be learned about the existence of critical periods and the basic underlying mechanisms by which they occur.

Critical periods in human development have been difficult to study scientifically because it is virtually impossible and likely unethical to perform experiments on humans to prove or disprove the presence of critical periods or the effects of variations in timing of basic sensory experiences. Recently, however, researchers have used naturally occurring instances of neglect or abuse to document their effects on the developing child. As we discuss some of these cases, it will be useful to keep in mind that unlike animal studies where presumed operative factors can be brought under strict experimental control, these studies provide only correlational evidence, albeit quite compelling in some cases. In general, however, strong bases for practical application of critical periods to justify social policy initiatives (e.g., early intervention programs for infants and toddlers) or specific educational practices or experiences (e.g., early exposure to certain types of music or to a second language) are still largely lacking. Typically, this debate pits the notion of a permanent deleterious effect of missed opportunities against concepts of plasticity that include the possibility of accommodative brain reorganizations when required by new situations, even when a critical period has been passed. Despite the constraints placed on human research and thus a lack of scientific proof in the usual sense, some important conclusions can be drawn about the timing of experiences in promoting optimal infant and early childhood development.

What Are Critical Periods?

CPs are similar to the related concept known as sensitive periods. Although both concepts have at times been interchangeable in the literature, they are best segregated to explain distinct but overlapping developmental phenomena. A sensitive period is a developmental stage where sensory experience has a relatively greater influence on behavioral and cortical development, but for which the influence is not necessarily exclusive to that time period (Knudsen, 2004; Lewis and Maurer, 2005; White et al., 2013). They are important for the acquisition of higher-order cognitive abilities such as learning a language or a musical instrument (White et al., 2013). A CP, in contrast, is a special class of sensitive period and is viewed as a time-limited epoch where sensory experience is necessary to shape the neural circuits involved in basic sensory processing (Hubel and Wiesel, 1970; Hensch, 2005). Unlike sensitive periods, the opening and closing of these epochs are well-defined.

During the CP, an optimal neural representation of the surrounding environment is established (Hensch, 2005; Hooks and Chen, 2007). If sensory experience is abnormal or absent during this time, it can have profound effects on sensory representation in adulthood, resulting in quasi-permanent adaptations that can make it nearly impossible to learn certain skills or process certain stimulus properties later on in life (Fine et al., 2003; Lewis and Maurer, 2005). Studies of prolonged visual or auditory deprivation during the CP have shown that this is, in part, because sensory cortices become wired to preferentially process nondeprived modalities (Singh et al., 2018; Voss, 2019). Even though processing of the deprived input is still possible if it is restored later on in life, it is not optimal and results in functional deficits that are permanent (Hubel and Wiesel, 1970).

After the CP has closed, abnormal sensory experience has a much less drastic effect on the brain and generally leads to reversible changes—with the exception of direct insults to the central nervous system itself (Rodgers, 2013; Mckee and Daneshvar, 2015). However, the contrast is also true, where restoring normal sensory perception after the CP will not completely reverse developmental adaptations. The timing of cochlear implantation—a prosthesis that restores auditory input in cases of sensorineural hearing loss by bypassing the damaged cochlea—is a perfect example of this situation. Individuals that receive an implant before 2 years of age are much more likely to benefit from it than those who are implanted later in life (Kral and Eggermont, 2007; Lenarz, 2017). The deprivation caused by infant cataracts on the visual system produces similar epoch-specific consequences. When cataracts are removed during early infancy, individuals can still develop relatively normal vision; if the cataracts are not dealt with until adulthood, it will result in substantially poorer visual abilities in these individuals (Martins Rosa et al., 2013).

CPs have been observed in various systems across a wide variety of species. In particular, primary sensory areas have been exceptionally well studied as they are the brain's gateway to the outside world (Zhang et al., 2002; de Villers-Sidani et al., 2007; Hooks and Chen, 2007; Erzurumlu and Gaspar, 2012). Much of what we know about CPs has been ascertained via animal studies, where it is possible to exert far greater control over the key variables being investigated. We now know that there are various distinct CPs, with seemingly each possible stimulus parameter having its own narrow window of maximal plasticity (Hooks and Chen, 2007; de Villers-Sidani and Merzenich, 2011). Some of the key CPs identified in the visual and auditory systems over the years are discussed in the following Section Key Critical Periods of Sensory Systems.

Language acquisition is a classic example of the importance of sensitive periods during early development (Kuhl, 2010; White et al., 2013). However, not all aspects of language share the same time window of prime sensitivity. For instance, shortly after birth, infants can readily perceive and discriminate speech sounds from any language, even those to which they have not been exposed (Eimas et al., 1971; Jusezyk and Luce, 2002). Subsequently, beginning around the age of 6 months, exposure to the primary language in the infant's environment guides the formation of language-specific phonetic representations (Kuhl et al., 2003), which strengthens the neural representations for speech sounds of the native language, while weakening those of unused sounds (McClelland et al., 1999). In turn, vocabulary learning, which continues throughout life, experiences a rapid growth around 18 months of age (Long, 1990; Kuhl, 2010).

The study of second language acquisition also provides a unique perspective into how sensitive periods operate. Indeed, the difficulties encountered by late second language learners has been taken as evidence that successful phonetic learning may not be possible beyond a given sensitive period (Long, 1990). Similarly, several lines of evidence have suggested that sensitive periods also may exist in the domain of music acquisition, where the onset of music training can significantly affect changes at the motor, sensorimotor, and perceptual levels (Penhune, 2011).

2 Critical Periods: Pruning Circuits by Early Experience

Critical periods have been observed in various systems across species (Hensch, 2004). Primary sensory areas in particular—the brain’s first filters to the outside world—exhibit especially striking examples of experience-dependent plasticity during defined windows of early life. Such periods are needed to establish an optimal neural representation of the surrounding environment to guide future action. Given the extraordinary biological resources that must be devoted to rewiring neural circuitry, concentrating the construction of accurate, immutable maps early in life for use throughout adulthood may be an efficient strategy. However, this poses limitations on future revisions to the circuitry. Recent cellular and molecular insights indicate that biological mechanisms are expressed to ensure that adaptive changes are preferentially set in place early in life while leaving the door open for lifelong plasticity.

Perhaps the best-studied model of a critical period is the enduring loss of responsiveness in primary visual cortex (V1) to an eye deprived of vision. The behavioral consequence, amblyopia (poor visual acuity), afflicts 2–5% of the human population and remains without a known cure in adulthood (Holmes and Clarke, 2006). From the initial discovery by Hubel and Wiesel 50 years ago, a picture has emerged that inputs from the two eyes compete with each other when they first converge in V1 onto individual neurons (Wiesel and Hubel, 1963). With the advent of gene targeting in mice, it has become possible to directly manipulate the factors which may mediate such functional and structural rewiring in response to imbalanced sensory experience.

Binocular interactions are detected by the integrated action of local excitatory and inhibitory connections in the neocortex. Strikingly, an optimal balance is required for plasticity to begin. Gene-targeted deletion of the synaptic isoform of the GABA-synthetic enzyme, GAD65, reduces stimulus-evoked inhibition without compromising animal survival because normal levels of the GAD67 isoform remain (Hensch et al., 1998; Tian et al., 1999). In GAD65 knockout (KO) mice, the effects of monocular deprivation are not observed until inhibitory transmission is restored by enhancing the postsynaptic sensitivity to GABA with benzodiazepines (Fagiolini and Hensch, 2000; Hensch et al., 1998). Agonists, such as diazepam (valium) or zolpidem (ambien), increase the chloride flux through particular GABAA channels when they are bound together with endogenous transmitter (Cherubini and Conti, 2001), effectively compensating for poor presynaptic GABA release.

Both GAD65 KO mice (at any age) as well as immature wild-type animals just after eye opening (around postnatal day P12 in mice) exhibit weak GABA release and no loss of visual responsiveness to an eye deprived of vision. However, plasticity can be rapidly “switched on” by just 2 days of local diazepam infusion into V1 (Iwai et al., 2003). This represents the first direct control over critical period timing in any system, and is surprisingly dictated by the late maturation of inhibitory function. Unless a favorable E–I balance is achieved, plastic changes are not engaged. Recently, this principle has been extended to the cerebellum, where elimination of excessive climbing fiber inputs onto Purkinje cells during an early critical period is regulated by GABA levels (Nakayama et al., 2012).

Downstream of the E–I trigger, lies a sequence of structural changes which ultimately execute circuit rewiring and its consolidation (Hensch, 2005). Regulated release of proteases such as tissue-type plasminogen activator (tPA) cleaves the physical connections between pre- and postsynaptic partners to induce dendritic spine motility (Mataga et al., 2004; Oray et al., 2004). This requires 2 days of monocular deprivation once GABA function is mature, and persists for about 1 week. During this time, spines are lost and then gradually recover as tPA levels return to baseline (Mataga et al., 2002, 2004).

Finally, the classical shrinkage of deprived eye axons and later sprouting of open eye axons from the visual thalamus (LGN) is observed, requiring new protein synthesis (Antonini and Stryker, 1993; Antonini et al., 1999; Taha and Stryker, 2002; Trachtenberg and Stryker, 2001). Several factors have further been identified to couple E–I circuit balance to the physical rewiring process, such as protein kinases (CaMKII, PKA, ERK; Di Cristo et al., 2001; Fischer et al., 2004; Taha et al., 2002; Yang et al., 2005) and homeostatic regulators which ultimately strengthen open eye connections (TNFα; Kaneko et al., 2008a).

Recently, an experience-dependent MicroRNA (miRNA), miR-132, has been identified in mouse V1 that is important for ocular dominance plasticity. miRNAs are small non-coding RNAs that regulate post-transcriptional gene expression. Visual experience induces histone mark modifications at CRE loci close to the miR-132 coding sequence (Tognini et al., 2011). Such modifications may underlie the developmental upregulation of miR-132 that occurs after eye opening and persists throughout the critical period. Manipulating miR-132 in vivo, by either increasing levels with a double-stranded mimic (Tognini et al., 2011) or decreasing them with a competitive inhibitor (sponge)-expressing lentivirus that sequesters endogenous miR-132 (Mellios et al., 2011), completely blocks ocular dominance plasticity during the critical period. miR-132 elevates the percentage of mushroom/stubby spines, suggesting that it may play a role in the structural modifications that occur during critical periods.

Notably, neither the release of tPA, pruning of spines, nor the rewiring of thalamocortical afferents occurs readily in adulthood. Rather than a simple loss of plasticity machinery, recent evidence detailed below reveals that further rewiring is actively gated in the mature brain. This notion of molecular “brakes” on plasticity is already evident during the critical period. Spine maturation is normally slowed down by cell adhesion molecules like Icam-5 (aka telencephalin; Matsuno et al., 2006). Genetic deletion of Icam-5 accelerates tonotopic map changes in primary auditory cortex (A1), effectively shortening the duration of the critical period (Barkat et al., 2011). Windows of plasticity, therefore, arise between the maturation of an optimal E–I balance controlling the machinery of synaptic pruning and a later set of emerging brake-like factors, which persistently offset them (Fig. 1A).

Paleocortical and neocortical development and epilepsy

Brain disease manifests itself through the brain; therefore the expression of epilepsy is highly dependent on the developmental stage of the brain. The immature brain often expresses an epileptic phenotype very different from the adult. In return, epilepsy and seizures can affect the brain and its development in an age-specific manner. Some of the rules that govern the interaction between disease and brain development are highly relevant to epilepsy.

The concept of “the immature brain” is, of course, a gross oversimplification. At birth, humans, rats, and mice have a cortex with few synaptic connections, a fraction (20% in humans) of the number of cells in the adult brain, and a very low metabolic rate (at least an order of magnitude lower than the adult's), while children and rats around 1 month of age have more synaptic connections, more cells, and a higher cerebral metabolic rate than adults. Epilepsy and its consequences must differ in these very different brains.

2.2.1 Environmental and individual social context

When critical periods occur early in ontogeny for information relevant to sexual competition, developmental plasticity will often result in canalization of morphology or physiology (Kasumovic & Brooks, 2011) and this can shape the range of behavioral options available to adults (Snell-Rood, 2013). This should be most likely under coarse-grained environmental variation, when the social context sensed during development is still relevant at maturity. However, this does not exclude the concurrent use of other cues on finer scales by that mature adult (Scheiner, 2013). In fact, understanding adaptive plasticity requires consideration of both the complexities of fluctuations in the natural environment (Elias et al., 2011), and the layering of cues that can provide information at the different scales of variation that may be relevant to phenotype-environment matching (e.g., Danks, 2007; Dore et al., 2018). Social context may provide information that affects plasticity of traits in different ways during different critical periods, and together these will contribute to an integrated set of phenotypic traits that may be employed in a particular set of conditions. These will inevitably also involve trade-offs in function in other conditions. To fine-tune predictions about adaptive plasticity, it may be helpful to consider how, at the coarse-grained level of variation, the environmental social context might indicate the average set of traits that will be favored by sexual selection within a given cohort (divergent from that in their parents). Adaptive developmental plasticity may be most likely in response to such variation, and individuals will mature with a set of traits that will, on average, match the environment. However, since any given set of interactions can be displaced from the average for that environment due to fine-grained heterogeneity, the individual social context relevant to local performance can also trigger plasticity. Individual social context could tune broader developmental effects and is also likely to affect activational plasticity either through transient responses, or adaptive updating that can have longer term effects on behavioral and other phenotypes (Fawcett & Frankenhuis, 2015; Stamps & Frankenhuis, 2016). Similarly, layering of responses to temporal and spatial effects may be important in some species or populations, where broader-scale cues (e.g., seasonal patterns of variation, overall population density) set the range of phenotypes that are possible, while individual cues specific to a given micro-habitat (e.g., proximity of potential mates) tune the phenotype to fit spatially explicit variables (e.g., Danks, 2007; Scheiner, 2013). Such interactive effects can also lead to plastic responses that appear to be maladaptive if considered outside the natural context (Scheiner, 2013). For example if there is a reliable, negative correlation between the social context at the time of perception and the context at the time of selection, then reaction norms (phenotype × environment curves) may be opposite to that expected when the focus is on perceived cues only. Considering layering of effects of environmental heterogeneity, given the natural history of the species under study, is thus critical for designing realistic studies of plasticity that allow strong inference about links between context and phenotype (Kasumovic, Bruce, et al., 2009).

As an example of how such layering of response can be beneficial to the animal, consider plasticity in development and behavior of crickets in response to exposure to calling song. In Telleogryllus crickets, juvenile males exposed to cues of a high density of adult competitors (calling song) develop more slowly and mature at larger body sizes, in better condition, and with higher investment in gonadal tissue than males reared without such cues (Bailey et al., 2010; Kasumovic, Hall, Try, & Brooks, 2011). On average, these traits, (particularly body size) can confer success in the environmental social context indicated by the presence of male songs—intense inter-male competition, including fighting (Hack, 1997). In many taxa, including crickets however, although larger males are typically more aggressive, males that have lost fights in the past are more likely to avoid, rather than confront, newly encountered rival males (e.g., “loser effects,” Kasumovic, Elias, Punzalan, Mason, & Andrade, 2009; Reaney, Drayton, & Jennions, 2011). Even a large male may shift to less dominant behavior in the face of repeated losses (Hsu & Wolf, 2001). Such activational plasticity may arise because fight performance provides information on the individual social context, and thus a more fine-grained estimate of an individual's rank in the local hierarchy of competitors than body size alone. Males that update their assessment of the optimal behavioral response with new, local, information (Fawcett & Frankenhuis, 2015; Stamps & Frankenhuis, 2016) will save energy, time, and risk on fights they are statistically unlikely to win. Interestingly, for crickets, one bout of flying resets aggressive behavior to a level predicted by body size (reverses the behavioral plasticity). Presumably, movement to a new competitive micro-habitat with a new constellation of competitors (Hofmann & Stevenson, 2000) negates the value of the previously-acquired individual social information. Self-assessed body size may once again be the best predictor of fighting outcomes given the reality of spatial heterogeneity in competitive landscape.

Another analogy is suggested by game theory models for sperm allocation. Allocation to gonads and sperm production increases across species based on the risk of sperm competition (overall likelihood of occurrence)—an evolutionary effect (Harcourt et al., 1981; Hosken, 1997). For a given mating within a species, however, the perceived intensity of sperm competition (number of ejaculates competing in this particular mating) can be the best predictor of sperm and ejaculate investment (Parker, 1998; Parker, Ball, Stockley, & Gage, 1996; Parker, Immler, Pitnick, & Birkhead, 2010). The distinction is important because, unlike the cross-species relationship, game theory predicts that sperm allocation may decrease as the number of perceived competitors for a given mating (individual social context) increases past the average expectation (environmental social context), although this depends on various features of natural history of the species being considered (Parker et al., 1996). We can translate this insight into speculation about how developmental decisions may affect the nature of activational effects on sperm allocation in the wild. Juvenile males that detect a high risk of sperm competition on average (e.g., male-biased sex ratio in a species where females mate multiply) may show elevated gonadal investment and have the capacity at adulthood to produce more sperm at a higher frequency than males that perceive a low risk of sperm competition. As adults, however, allocation decisions in a particular mating will depend on the perception of cues related to the local socio-sexual context (Cornwallis & Birkhead, 2006; Kelly & Jennions, 2011). Thus allocation can change across mating opportunities despite an overall ramping up of capacity in response to environmental context.

Consider a hypothetical example of a male that encounters a solitary, unmated female with no rivals present. If that male has developed under cues indicating a high prevalence of competition on average, the current context may suggest the female is of particularly high reproductive value compared to the average female in the population. The result of adaptive updating (Stamps & Frankenhuis, 2016) in this case might be higher than average mating investment by the male in terms of courtship effort, sperm allocation, and other mediators of mating and fertilization success, despite the apparent absence of competition. In contrast, if the same male encounters a female with rivals present, that female might accrue only average mating investment, despite males having developed the capacity to invest more, and despite the higher risk of sperm competition in that context.

Thus, plasticity of a set of related traits may be shaped across more than one critical period, based on spatial or temporal heterogeneity, and developmental and/or activational effects may combine to affect the same trait. Complex responses to environmental heterogeneity at different scales are possible, and may present considerable challenges to experimental design, and particularly to interpretation if these complexities are not considered. Below I outline how individual and environmental social context affect fitness components for male spiders in the focal genera Nephila, Argiope, and Latrodectus. I consider these different determinants of variation may be used to provide an integrative lens on our understanding of plasticity in these developing models. I start by reviewing relevant features of phenology and natural history that relate to sexual selection and variable social context in these spiders, and the types of cues that may be used to detect relevant scales of environmental variation.

Sensitive periods

Sensitive or critical periods are windows in time when the potential for experience-dependent plasticity is optimal. They are ubiquitous, occurring in virtually every species, from fruit flies to humans (Berardi et al., 2000) and for a wide range of sensory functions. Hubel and Wiesel's Nobel prize winning work showed the importance of sensory experience in shaping neural connections during a sensitive period early in life. This was inspired by the 18th century notion that early visual deprivation (e.g., blindness at birth) results in brain changes that lead in turn to defective visual perception (Wiesel, 1982). Based on the work of Hubel and Wiesel and subsequent anatomic and physiological studies, it is now clear that the visual cortex is by no means a Tabula Rasa, and there is a good deal of specification already at birth. However, it is also clear that there is an important role for maturation and experience.

It is also now apparent that there are different sensitive periods for different functions, even within the same sensory system (e.g., Harwerth et al., 1987), and for different parts of the brain, even for different layers of the primary visual cortex (Levay et al., 1980). There is also evidence for multiple sensitive periods for the development of different visual functions in humans (Lewis and Maurer, 2005). In addition, there are different critical periods for the effects of deprivation and for its converse, the recovery of function (Berardi et al., 2000).

It has long been held that there is a close correspondence between sensory development in childhood and sensitive periods (e.g., Teller and Movshon, 1986). The idea that experience-dependent plasticity is closely linked with the development of sensory function is still widely held (Berardi et al., 2000). However, as discussed later, there is also growing evidence that plasticity exists in the adult nervous system.

Timing

Although the critical period for intervention in CP and other neurologic diagnoses may occur at a young age, exploring the potential effect of brain stimulation on the younger brain demands recognition of potential lifelong developmental impact.23 The immediate and long-term effects of brain stimulation intervention must therefore be explored, beginning with older children and working into earlier developmental timeframes as safety and tolerability evidence accumulates. In addition, as these children may be involved in other medical care, it is important to include assessment of concurrent rehabilitation interventions as well as surgical procedures, spasticity management, and pharmacologic seizure management. These aspects of care of a child with CP potentially affect behavioral outcomes, as well as cortical excitability. As an example of a research team recognizing these potentially confounding interventions, Valle et al.6 reported in their rTMS study that the number of patients taking centrally acting medications did not differ across the 1-Hz, 5-Hz and sham groups. Future trials could incorporate such components such as a stratification factor in randomization to protect against potential imbalances across treatment arms. As another example, botulinum toxin, as used in CP for spasticity management, has been reported to have negligible effects after 6 months.24 Consideration of this wash-out period may indicate the appropriate time at which to enroll a child with CP in a brain stimulation trial. For example, Gillick et al.10 excluded children who had received botulinum toxin or phenol blocks within 6 months before enrolling in the study.

Masculinization of the Brain

During a critical period of fetal development, boys' testicles produce a burst of prenatal testosterone, which alters their brains in ways most females do not experience. As a result, boys and men tend to prefer somewhat higher levels of rough-and-tumble play, rowdy activities, and vigorous physical movements, compared with girls and women. There is a great deal of variation in optimal activity levels in both males and females, but males tend to prefer higher activity levels than females do. These differences often persist well into adulthood. This does not mean that boys cannot learn to control themselves and play gently with others, but many males continue to prefer higher levels of activity and sensory stimulation than do females well into adulthood. This contributes to a commonly observed gender difference in the activities that males and females gravitate toward. For example, it is easier for males than females to learn to love football, soccer, and dirt biking.

There are genes that lead some males not to secrete enough testosterone to fully masculinize the brain, and this may predispose these males to become homosexual. The biologically heritable component of male homosexuality is about 50%. Lesbians appear to have about a 25% heritable component to their sexual orientation. Personal learning, culture, and many other variables complement the heritable influences in the development of homosexuality.

In summary, both biology and learning are important in the development of sexual behavior and both are intertwined starting from infancy. The following sections show how nature and nurture continue to interact after the onset of puberty.