Cognitive Modifiability, Neuroplasticity, and Ecology

Jo Lebeer

Modern neurosciences have generated compelling evidence about neuroplasticity, i.e., the capacity of the brain to organize and reorganize itself. This happens on the level of micro-anatomy (brain synapses), of functional networks, on the brain as a whole and on the level of the individual and even beyond individuals. New links are constantly being generated. The hardware of the brain continues to be shaped after birth and needs activation and “environmental enrichment.” What kind of activation is needed, however, is less clear. This more dynamic perspective on brain structure and functioning has far-reaching implications for rehabilitation, education and assessment, which currently are still largely based on rather static models. The plasticity of the brain is the basis of cognitive modifiability, which is highly dependent on the amount and quality of interactions with the human environment—ecology—of the individual. Without aiming to be complete, this chapter will report on the essentials of the relationship between brain structuring and functioning and the growth of the mind.

Knowledge about brain functioning and structure has been growing enormously during the past five decades, thanks to increasingly sophisticated brain imaging techniques.

At birth the brain is estimated to contain over a 100 billion neurons. Each neuron has hundreds of dendrites, receiving messages from other neurons, adjacent or far away, via the synapses, allowing for innumerable connection possibilities. The construction of the brain during nine months of intrauterine growth is a delicate process, in which many things can go wrong. It is a miracle that the brain can function as a cooperative whole, starting off with only two cells (Eccles & Robinson, 1985).

The construction of the brain's hardware, however, is not terminated at birth. It continues to grow into adulthood. There is much more than a simple growth in size, or in myelinisation. The final network structure of the neuronal connections is established after birth, not as an unfolding of a genetically determined structure; it is strongly influenced by early experience (Aoki & Siekevitz, 1988). Entire layers of neurons migrate to other places after birth. The brain has a capacity to adapt its structure and functioning, as a response to learning or to damage, in fact during an entire lifetime. This is called brain plasticity.

The human body has an impressive healing capacity. Wounds close, blood clots, broken bones grow together again. A human being can survive with one quarter of a liver left, with one quarter of only one of both kidneys left, without spleen, and only one lung. The whole continues to function in spite of damage to its parts. Similarly the brain, its most complicated organ, has this capacity, although it does not seem to be so “easy” to restore as other organs.

Neurobiologists have been “playing” with animals like Meccanos: displacing legs, ears and eyes, cutting out parts of the brain and looking at the functional effects. Studies into neuronal plasticity were performed in the nineteenth century, when the French biologist Flourens concluded that it was impossible to localize brain functions (Kolb & Whishaw, 1989). He strongly disagreed with his compatriot Broca, who believed that there are specific areas in the brain responsible for specific functions. Broca's discovery of the speech center on the left frontal side forced Flourens' ideas into oblivion. In the early twentieth century Karl Lashley carried out experiments on newborn rats. Whatever part of the brain was taken away, there was always a trace of memory (Lashley, 1950).

Recovery after brain damage is sometimes spectacular, at least in animal studies. For example, when parts or even half of the cortex of newborn rats were surgically removed, a regeneration of neuronal pathways could be observed with hardly any loss of functioning (Hicks, D'Amato, & Glover, 1984; Kolb & Whishaw, 1989). Mammals always retain a capacity to learn, whatever the extent of the ablation of the cortex (Meyer & Morgan-Meyer, 1984).

As a reaction to damage, nerve axons can grow out to make new connections. This phenomenon is called axonal sprouting. The number of dendrites—i.e., the branches of neurons that make synaptic connections—also increases, as does the number of synapses (Klintsova & Greenough, 1999). The cortex of the undamaged half becomes thicker (Kolb, 1989). It has long been believed that the number of neurons does not increase after birth, but some studies have shown that in adult rodents and primates new neurons are formed after damage (Rakic, 2002). In human beings there is also evidence of synaptic reformation through dendrites: hemiplegic children are paralysed on one side of the body, due to damage to the motor cortex on the opposite side of the brain because the motor descendant pathways cross in the medulla. It has been found that they develop compensatory non-crossing neuronal pathways on the affected side that came from the brain half of the paralytic side, provided they are actively stimulated (Farmer et al., 1991; Carr, 1996).

There are also neurochemical changes. Denervation hypersensitivity, a phenomenon indicating that the postsynaptic plate becomes more sensitive to the stimuli of the neurotransmitters, is an example. Neurotransmitter production is increased (Marshall, 1985). Trophins, which are substances promoting nerve and axon growth, acutely regulate synaptic plasticity. Activity-driven experience activates specific gene promoters (BDNF or brain derived neurotrophic factor), leading to enhanced transcription, elevated trophin levels, postsynaptic receptor activation and increased synaptic transmission (Black, 1999; Alder, Thakker-Varia, & Blade, 2002). A protein called MAP-2 (micro-tubule associated protein 2) has been found to play a leading role in the structuring of the neural network even after birth, and can account for modifiability in the early developing years (Aoki & Siekewitz, 1988). An injured nerve tissue secretes substances that provoke regeneration of nerve axons (Thanos & von Boxberg, 1990).

The same phenomena happen in the brain not only after damage, but also in learning. Each time we learn something new, the brain undergoes a structural change in its synapses. Donald Hebb (1949) launched this idea in his book The Organization of Behavior. Forty years later his hypotheses were confirmed in numerous experiments. The synapses of the hippocampus react to learning situations with an increased long-term potentiating (LTP) effect: the synaptic plate, which receives the message, becomes more sensitive to chemical substances (Teyler & Fountain, 1987; Morris, Kandel & Squire, 1988; Squire, 2004).

PLASTICITY: INFLUENTIAL FACTORS

Neuronal plasticity is subject to a number of influential factors.

Genetics

Like the whole brain organization, plasticity is modulated by genetic factors. We deliberately use the word “modulated” rather than “determined,” because not only genetic programs drive brain formation, but also experience and activation. There are, however, many instances where the natural capacity of neuronal networks to react and adapt are interrupted by a genetic defect. Rett syndrome is such an example, where it is believed that the gene MeCP2 hampers plasticity of early migration (Shabhazian & Zhoghbi, 2002).

Age

A second factor in plasticity is the role of age. Young children can absorb rapidly enormous quantities of information and their capacity seems much higher than in adults, indicating a greater capacity of plasticity of young brains. Margaret Kennard (1940) observed that in newborn apes sequels of damage to the brain cortex were less ravaging than in grown-up apes. Many other researchers confirmed this “Kennard principle” in other animals (Hicks, D'Amato, & Glover, 1984; Villablanca, Burgess, & Sonnier, 1984; Kolb, 1989; Steward, 1984). But each organism seems to have a critical age window beyond which there is little possibility for plasticity (Almli, 1984).

In human developmental psychology this has become generally known as the concept of critical period. For example, in squint, the brain, to avoid double sight, suppresses the function of the squinting eye. One of the remedies is to cover the well functioning eye in order to stimulate the amblyopic one (this is also a good example of experience-driven plasticity). But this covering needs to be done before the age of 3–4 years, because beyond that critical period the eyesight in the amblyopic eye may be permanently lost. Language development is also prone to a critical period. Based on clinical experience that aphasic children who did not speak before the age of 6 never learn to speak normally, the critical period of language development was believed to be limited to about age 6. Indeed, it is a common observation that preschool children easily learn the language(s) of the environment they are living in. Later, it becomes much more difficult to learn a second language.

However, it is far from certain how long the critical period extends. We came across a boy with Sturge-Weber disease, who during the first 8 years did not develop any speech and his language understanding remained at a low level. He was also severely behaviorally disturbed and functioned on a low cognitive level in the IQ range of 40–50. Because he had intractable epileptic spells he was operated on his brain at the age of 9 years, when half of his brain was removed on the left side (hemispherectomy). Because the critical period was assumed to have been passed, prognosis regarding cognitive and speech development was pessimistic. Surprisingly, a few months after the operation he started to speak his first words. He became quite fluent in speaking (Vargha-Khadem et al., 1997). He remained with a right sided hemiplegia, but that improved considerably and he learnt to walk and use both hands. Cognitively and academically he also improved, but very slowly.

In the special school he was taught to read, write and work with numbers but during three years, according to his mother, little progress was made. She reported that she was given a bad prognosis regarding school achievement and cognitive level. Because she did not want to give up, she went to Feuerstein's International Center for the Enhancement of Learning Potential in Jerusalem (ICELP), where her son became a resident pupil for a few years. There he was given more opportunities and challenges to learn to read, write, and do maths. With intensive investment in mediated learning, he made remarkable progress, up to the point of being able to attend a mainstream primary school, followed by high school, and eventually took a vocational training course in accounting. The mediation process was described in detail by his “coach” Rashmi Sharma (2002). This case also illustrates left to right compensation by the brain. There seems to be some early specialization, but it is only mild (Goodman & Whitaker, 1985). Last but not least, the case also defies the commonly held belief that cognitive development comes to a standstill or “mental ceiling.” Even after puberty there can be considerable modifiability.

Children with frontal lesions, which in adults would certainly lead to devastating symptoms, may experience good outcomes (Lebeer, 1998). Young children in whom the visual or acoustic areas of the brain are damaged recover quite well in most cases (Hécaen, Perenin, & Jeannerod, 1984). When an hemispherectomy is carried out in children, they recover better than adults (Austin & Grant, 1955). Hemispherectomy is a surgical procedure performed as a “last measure” in cases of therapy-resistant focal epilepsy.

The plasticity of the brain to reorganize and take over functions from neighboring areas seems to be better as long as the brain area is not too specialized. The immature brain compensates for neuronal injury better than the adult brain. In newborn infants, residual fetal neurons which disappear around the sixth month have been shown to be responsible for the greater plasticity of the newborn brain and thus its capacity to repair early damage (Kostovicz et al., 1989). However, cellular plasticity and nerve cell regeneration have been shown to exist in adult animals as well. Plasticity occurs over an entire lifetime (Kaplan, 1988).

LESION SIZE PARADOX

Children with very extensive damage to the cortex recover sometimes fairly well or completely: for example, in hydrocephalus (Smith, 1984;Bigler, 1988), porencephalic cysts (Zhang & Sheng-Yu, 1984; Blackman, McGuinness, Bale, & Smith, 1991) or cerebellar agenesia, absence of the small brain or Dandy-Walker syndrome (Maria, Zinreich, Carson, Rosenbaum, & Freeman, 1987). Also in hemispherectomy, where an entire hemisphere is taken away, in 90 percent of the cases epilepsy improves and sensorial and behavioral disturbances improve (Devlin et al., 2003). Sometimes some visual disturbances remain (a half-sided field defect). Other authors have reported full recovery in hemispherectomized adult patients (Arnott et al., 1982; Damasio, Lima, & Damasio 1975), but not always: when the language area is already specialized and then removed by an operation, aphasia resulted (Loddenkemper et al., 2004). In children there was no postsurgical decrease in IQ (Goodman & Whitaker, 1985; Devlin et al., 2003).

Animals, particularly rats, support a 70 percent cortex removal before showing any signs of dysfunction. The sensorial and motor cortex of the rat is able to perform all functions when only 30 percent is left of one side (Stein, Finger & Hart, 1983). The visual cortex does not tolerate the same amount of damage: after its abolition, rats are unable to recognize patterns, but only react well to visual discrimination and brightness tests (Kolb, 1989). On the other hand, in cats where the total posterior part of the brain had been removed, the subsequent half-field blindness was cured when the lateral geniculate body was put out of action (Irle, 1987). The geniculate body is considered a station in the visual pathway. In the frontal cortex sparing of function occurs depending on the extent of the lesion: no sparing in large bilateral lesions, and sparing in the case of removal of one half the frontal cortex (Kolb & Whishaw, 1989).

These findings are paradoxical. One would expect: the larger the lesion, the larger the subsequent functional loss. Mostly it is like that. But there are exceptions: in the visual cortex, the sensorial system, spinal section, and lesions of the hypothalamus, small lesions of the same area have consequences that are worse than large lesions. In the limbic system more loss of memory occurred when two zones were damaged than with one zone; but damage to three or more zones of the limbic system restored memory and behavior again (Irle, 1987).

The relationship between the extent of damage and functional loss is not linear but follows a U-shaped curve (Chugani, Muller, & Chugani, 1996). In the beginning, when the lesion is small, the effects are big enough to cause a big disturbance. The bigger the lesion, the greater the disturbance. But after a certain point, the more the damage, the lesser the functional loss. In grossly exaggerated terms: the lesser the brain, the better. This paradox may be explained by inhibitory effects: some brain zones inhibit others, and when the zone is neutralized, function of the other zones is reestablished. An example of this is the better recovery after a full hemispherectomy in children with intractable epilepsy than after partial lobectomies. Prudent surgeons, who took away only the disturbing part, saw more problems than the more daring ones who took away the whole hemisphere (Boon et al., 1996).

CHANGING PLACES

The brain has been “mapped” in detail. Most of the functions are now located precisely and this knowledge is still increasing. This is known as the localization theory (Pribram, 1971), which attributes to specific brain regions specific functions: the rear, occipital part is supposed to “encode” for visual perception; the left frontal part is the “motor cortex;” below it the “motor speech center” (area of Broca) is situated. The frontal part would be responsible for logical thinking, motivation, planning. The parts in the middle, right behind the cleft, are the sensorial part. The temporal parts (below in the middle) would code for verbal comprehension, etc. Knowledge of this detailed localization has been inferred from clinical observations in patients who lack certain functions and appear to have defects in certain parts of the brain. With increasing resolution of the modern scanners, ever more defects are located. However, in some cases there seems to be ample flexibility of localization. Children's brain regions are not yet fully specialized and can change places.

People with the occipital part lacking can learn to “see” with their parietal parts. Early-blind children learn to “read” Braille with their visual occipital cortex (Chen, Cohen & Hallett, 2002). This means that the “visual” cortex, which is specialized in visual recognition, can now decode sensory touch messages and translate them. People with the occipital part lacking can learn to “see” with their parietal parts. The speech center that is usually on the left side can go to the right side, but does so only after training, as is shown by PET scans of aphasic patients (Musso et al., 1999). An example of this was given earlier.

Brain maps and receptive fields are not confined to one sensory modality but can be replaced to other sensory modalities through learning (Edeline, 1999). Cells of the temporal cortex, which normally “code” for auditory processing, can be trained to behave like visual cortical cells in recognizing patterns of orientation, when the visual cortex is damaged (Roe et al., 1991; Merzenich, 2000). If it is possible to rewire the brain in experimental conditions, it can be imagined that similar mechanisms happen in natural situations.

ACTIVITY: USE IT OR LOSE IT

Activity is of key importance in driving plasticity. Animals growing up together in stimulating environment experience a better recovery and more plasticity.

Rosenzweig and Bennet (1996) examined the difference in learning behavior in brain damaged rats that were raised in standard conditions—an isolated position in a cage receiving just subsistence care—and others that were raised in an “enriched” environment—a few animals together in a large cage where they had ample opportunity to exercise with various devices. It appeared that the thickness of the cortex diminished in early lesions with an expected neuronal degeneration at a distance. However, this negative effect was partly compensated by environmental enrichment. Rats educated in environmental enrichment were better learners than rats educated in isolation. This also positively influenced the microstructure of their brain connections: neuron survival time increased, cortical thickness, neuron size, the size of the synaptic contact areas, neuronal metabolism, the number of synapses and the number of dendritic spines (Rozenzweig & Bennet, 1996). Although it was higher in new-borns, environmental enrichment effects also occurred in adult animals (Van Praag, Kemperman & Gage, 2000; Turkstra, Holland, & Bays, 2003).

Not only in animals but in human beings this effect has now been demonstrated. Maguire et al. (2000) found that the volume of grey matter in the right posterior hippocampus of London taxi drivers correlated significantly with their experience and time spent as a licensed driver. To obtain a licence, London taxi drivers need to pass an examination with high demands on their memory of street maps. Similarly, pianists' temporal lobe areas (related to auditory memory) have been shown to enlarge proportionally to the amount of time spent practising (Bangert & Altenmüller, 2003).

Exercise is Needed to Create Brain Circuitry: Function Drives Structure

In order to maximize recovery of function, one must minimize compensation. Because the brain has a tendency to shift activity to regions that are not disrupted, it tends to neglect chances of recovery by the lesioned system itself (Taub, Uswatte, & Morris, 2003). When animals are subjected to exercise, especially to “force” them to use their injured limb, they display significant alterations in their brain function and neurochemistry. This idea has been applied in the rehabilitation of hemiplegic adults after stroke with significant success, and has been termed “constraint-induced movement therapy” (Dettmers et al., 2005). People tend to neglect their paretic arm. This prevents recovery (DeLuca et al., 2003).

Visual Experience has a Profound Effect on the Maturation of the Visual System in Mammals (Kaplan, 1988)

On the other hand, deprivation of sensory and motor stimuli has a negative effect on neurological development. Nobel prize winners Hubel and Wiesel (1963) found that cats fix the visual patterns that they had been exposed to when they were young in their visual cortex. Cats raised in a cylinder exposed to only diagonal patterns were able to detect only diagonal patterns, and not vertical or horizontal, at adult age. When they grow up with one eye covered, the occipital visual cortex that receives the information from the uncovered eye grows thicker to compensate. This is similar to the effect of compensatory muscle growth in paralysis: unused potential atrophies (atrophy by lack of use). Deprivation of environmental stimulation occurs when young animals are separated from their mother. Examples of extreme environmental deprivation of stimuli in human beings, with lasting deleterious effects on intellectual, social and communicative development and only partial recovery, are some of the notorious cases such as “Victor,” the wild boy of Aveyron (Malson & Itard, 1972), Genie (Skuse, 1984) and in the hospitalism and deprivation studies (Gunnar, 2001). On the other hand, the same stories also demonstrate the enormous plasticity despite early and long-lasting deprivation, when an intensive activation program is set up (McVicker Hunt, 1986).

In summary: the brain grows by use, and it atrophies by deprivation. Use it or lose it.

It is not clear what kind of experience is needed to trigger brain development. Surely it is more complicated than just practice. It is likely that something more is needed, e.g., “mediation” and motivational-emotional activation, which we will discuss in more detail next.

CLINICAL EXAMPLES OF PLASTICITY IN HUMAN BEINGS

There are many other examples of plasticity in human beings. Ninety percent of children who showed signs of neurological abnormalities in their first week develop normally (Bierman-Van Eendeburg, Jurgens-van der Zee, Olinga, Huisjes, & Touwen, 1981). One-third of children with a tetraparesis at the age of one year were free of motor symptoms at age 7 years. In a qualitative study we did in the 1990s on the ecology of development of children with brain damage, we evaluated a number of children who had reached a level of functioning beyond what had been predicted on the basis of their diagnoses, degree of damage or testing. Some had large parts of the brain missing. There was a young man with half a brain missing because of hemophilia, yet he was able to walk and talk normally and take a computer course; a boy with the rear part of the brain missing, who had cognitive difficulties, but he was able to see and to walk; a boy with large damage to the frontal lobes without a marked “frontal syndrome” (Lebeer, 1998). We came across a man with a hydrocephalus who was well functioning—he had a driver's license, ran marathons, went to work, spoke normally and lived independently—despite possessing only 25 percent of a normal brain cortex. Similarly, Lorber described a “record” case: a man with so-called “hydranencephaly” (i.e., hydrocephaly, but with almost absence of the brain), who was believed to have only 5 percent of brain cortex left; yet this man studied mathematics at university level and was not aware of his brain damage until a scan was made at the age of 18 because of a persistent headache (Lewin, 1980).

Children with a genetic origin of cognitive developmental disability may show high cognitive modifiability. Down syndrome, with a full trisomy 21, although showing large variations in development, all have difficulties in language and understanding abstract concepts. Nevertheless many arrive at a higher level of functioning, capable of abstract thinking, independent living, planning, studying or working in a main-stream context (Feuerstein, Rand, & Rynders, 1988; Lebeer & Garbo, 1997; Buckley & Bird, 2003; Engels, 2006). This does not necessarily mean that their IQs normalize, because IQ contains a factor of speed and does not allow mediational intervention, for example asking a question differently. In individuals with Down syndrome, the way one asks questions or reformulates them, the way one intervenes in regulating behavior, influences a child's performance. In any case, it appears that the quality of life, including a capability of abstract thinking, symbolic communication, and functioning and participation considerably exceed what had been believed possible in the 1960s. Whether this increased level of functioning is due to increased plasticity, has not yet been demonstrated. What is known, however, is that people with Down syndrome are structurally cognitively modifiable and that “chromosomes do not have the last word” (Feuerstein & Spire, 2006).

Far from being a natural development, this seems to depend on a complex ecological process, in which early, intensive, consistent mediation and activation of cognitive functions and communication play a decisive role. The same is true for children with other kinds of genetic disturbances. Information about modifiability of these children is still scarce and mostly casuistic. Few publications concentrate on aspects of modifiability. Preliminary research, however, suggests that plasticity and modifiability are also taking place in the case of genetic disturbances. Sometimes the balance turns out to be negative, that plasticity does not compensate the degree of damage and the child remains very low functioning. But even in those cases, we have seen signs of modifiability of functioning (which is not the same as normalization).

HOW MUCH BRAIN DOES ONE REALLY NEED?

In the case of large brain lesions, such as in extreme hydrocephalus when 95 percent of brain substance is missing as in Lorber's boy with a mathematics degree, the problem is to explain where all the information is stored. Is 95 percent of our brain redundant? Such an explanation is unlikely. Why has evolution then spent so much time and trouble to increase the volume and complexity of the brain, which marks the difference between human beings and the rest of the animal world?

Paleontologists suggest that encephalization is the explanation for man's higher intellect. Encephalization is the evolution of the brain from a “simple” conglomerate of neurons in lower animals like worms, into larger and larger areas: during fetal development, the neural tube makes a kind of balloon at its top (later becoming the brain cortex with all its folds). In this way, it was possible to create much larger surfaces to increase the neural network capacity. This process goes wrong in spina bifida or hydrocephalus at a very early stage in the embryo formation.

The human species certainly has a brain with the highest developed encephalization compared to other mammals. Indeed, compared to his most intelligent animal “brother,” the chimpanzee, Homo Sapiens has 6.9 times higher brain storage capacity (Donald, 1991). However, Lorber's encephalic mathematician functions with one-twentieth of a normal cortex, hence with a brain size one-third that of a chimpanzee. Obviously, information capacity is not exclusively determined by neuron amount and volume, nor the size of the network. Hence, the answer to the title of this paragraph “How much brain does a mind need?” is 5 percent.

Microcephaly does not always lead to mental retardation. Sometimes there is a dominantly inherited form of microcephaly with normal cognitive development and usually short stature (Rossi et al., 1987; Hennekam, van Rhijn & Hennekam, 1992; Innis, Asher, Poznanski, & Sheldon, 1997). Neither atrophy of the brain nor focal lesion volume after traumatic brain injury is statistically related to postinjury IQ (Bigler, 1995).

Although frontal lobe growth has been claimed to be the most important factor in determining human intelligence, the brain has its compensatory mechanisms in the case of damage. If it's not the size of the brain, then what is it that really matters?

PLASTICITY IS COMMON BUT NOT NECESSARILY EFFECTIVE

To sum up this section on plasticity, a certain caution needs to be expressed. Plasticity is undoubtedly taking place all the time: in learning, in development, as a reaction to injury and disruption. However, it is not all such an easy picture (Finger, 1989). A small amount of damage to the brain, such as in adult cerebral bleed, can have far reaching functional effects, such as paralysis and loss of speech. Many situations have been found to cause lasting injury to the brain: a genetic defect, infectious or toxic influences during pregnancy, problems with brain nutrition and oxygenation around birth, accidents, bleeding, and infections after birth. It must be stressed that the majority of humans with severe brain damage do not function normally. In our own clinical research as well as throughout the referred literature we found people with large brain holes, and although a majority is perfectly normal, there are others who have severe disability. Many low functioning children may have dispersed minute lesions invisible on a brain scan.

Man's capacity for restoring brain function seems to be less perfect than in animals. Plasticity mechanisms are sometimes restoring function, sometimes not. It is possible that plasticity is operating like an incompetent electrician, who, for lack of knowledge of which fibers to connect, just tries to see the effect. It is probable, however, that there is not a blind disorder, that activation plays a role, that a positive emotional environment and challenging activities make a considerable difference. We still understand little of the brain.

PLASTICITY, ECOLOGY, AND DEVELOPMENT

Crazy Mothers Research

Our research project was nicknamed “crazy mothers research.” The analogy comes from the “madres locas” (crazy mothers) of the Plaza de Mayo in Buenos Aires who used to demonstrate each Thursday in front of the Parliament to force the government to give information about their sons and daughters, who had suddenly disappeared during Videla's military regime. These mothers' persistence in fighting for their children was analogous to the persistence found in the parents of the children we had examined. The common pattern which emerged from research was a certain powerful way of behaving and coping with problems (Lebeer & Rijke, 2003): parents defined problems in their own way (rather than adopting the way the child was defined by professionals, in diagnosis or testing); they held an optimistic and strong view on their child's potential; they were prepared to invest a lot of time and energy in activation; they did not leave things as they were; they constantly looked for solutions. To give an example: the mother of the boy with Sturge-Weber disease, described above, after the hemispherectomy did not want to become resigned to a pessimistic outlook; she spoke to him, taught him to pronounce, and let him repeat words. She did not passively wait. Neither was she satisfied with a perspective of a mentally retarded son, who was unable to learn or to be able to read, even after three years of hard work trying in the special school her son had been enrolled in after the operation. She believed he would be able to learn to read, and that's why she went to Israel. Another example is the father of the boy with hydrocephaly mentioned above: for four years he ran beside the bicycle holding its saddle, teaching his son to ride. Generally, these parents challenged their children continuously.

Two reservations must be made: firstly, not only parents have this attitude, some professionals have it too. Secondly, there is no direct deterministic relationship between “being active” and “having results in development.” It is much more complex.

Outer and Inner Aspects

If one analyzes remarkable developments, such as our research and other famous published cases (Keller, 1905; Grandin & Scariano, 1996, Feuerstein et al., 1988), a common pattern can be discovered in the ecology of these families. A distinction can be made between outer and inner aspects.

Outer aspects are what one does; inner aspects deal with the level of inner experiences. When analyzing behavior of educators with particularly high outcomes in development, one can see that they actively stimulated and mediated necessary steps that led to new functions by facilitating learning processes. They continuously provided new challenges, and did not stick to a status quo. They acted in a goal-directed way. They exposed the child to a rich variety of stimuli. This can be done using a variety of methods. There are many methods to activate cognitive development, but in fact the method is not the most important aspect. The painter is more important than the paint he uses, in other words: it is how one interacts with the child which is the most important, as well as with what degree of intensity.

This can be summarized by Feuerstein's concept of an Active Modifying Environment (Feuerstein et al., 1988), which has four aspects: (1) participate in everyday life and be exposed to a variety of experiences;(2) create positive stress by causing disequilibrium; (3) offer challenging activities which provoke problem solving and thinking; and (4) offer adequate and adapted mediation.

Placing an individual in a stimulating environment therefore is not enough. There is a difference between stimulation and mediation. One can overload children with stimuli coming from television, electronic games, toys, voices, etc. This is not beneficial, because an overstimulated brain will also overreact, with, for example, attention deficit hyperactivity disorder (ADHD) or behavioral disturbance. The environment should be mediated, i.e., the stimuli should be adapted, selected, and filtered in such a way that the child is able to benefit from it in a structural, lasting way. How this can be done is explained elsewhere (Feuerstein, Klein, & Tannenbaum, 1991). An example of language learning will make this clearer: one can live as a stranger in a foreign-language-rich environment, yet not benefit from it for lack of an interpreter. This is the situation of children with Down syndrome in their own language environment, because they have an auditory perception and interpretation problem (Buckley & Bird, 2003). People in their environment should learn to speak clearly, slowly, in short and simple messages and with emphasis, so as to ensure that the child picks up the message and understands it. This can make quite a difference in speeding up speech development. Visual support media such as using augmentative communication and later printed word may greatly enhance speech development.

Similarly, placing a child in a mainstream school (inclusive education) is a more enriching environment than a special school, but it is not necessarily more advantageous to the child, when no extra mediation is offered by the people around the child, be it peers or adults. The child may really benefit only when inclusive education is accompanied by enhanced mediation (Lebeer, 2006).

On a more fundamental level, inner aspects greatly influence modifiability. By inner aspects we mean experiences of which the individual is consciously aware or not. This is not the same as feelings or emotions. Emotions may be blinding true experiences. Motivation, will, experience of energy, vitality, drive, unity, love (or the opposites) operate primarily on an inner level (Assagioli, 1973; Rijke, 1993). They are barely visible to inexperienced observers. Verbal declarations are unreliable. They are inaccessible to questionnaires or superficial interviews. Yet everyone knows that they are keys to the more visible aspects of what one does. For example, it makes quite a difference to listen to a piece of music played by a skilled musician who plays “with heart and soul” or one who plays mechanically. Similarly, it makes quite a difference to work with a child who has motivation and energy, than to work with a resistant child. Or when using a program such as Feuerstein's Instrumental Enrichment, to work with a mediator with or without “energy.” The outcome will greatly depend on these inner factors, which are related to choice. On an inner level, even a small child chooses or not to engage in the interaction. In this way one can understand that sometimes children with autism may show high structural modifiability, while others are very difficult to modify. This is beautifully described by Temple Grandin, an agricultural engineer with autism. These inner aspects render quantitative evidence seeking research highly difficult in this area.

Levels of Ecology

To understand a child's intellectual, motor, social and inner developments, it is necessary to look at the ecology of human development (Moen, Elder, & Luscher, 1995). The study of human ecology in relation to development owes a lot to its “founder” Uri Bronfenbrenner, who taught psychology at Cornell University. He proposes a theoretical model of development containing four concentric contexts (Bronfen-brenner, 1981). The micro-system is the nuclear family, the extended family and school; the meso-system is the interaction between the systems of the micro-system; then the exo-system is the environment that comprises the neighbourhood and the family social support systems; and finally the macro-system is the cultural context of society, with its conceptions, socio-economic situation, definitions of classes, laws, norms, values, habits, rituals, opinions, etc. If an intervention in child development aims to be effective, one should depart from the classic intrapsychic or physical point of departure and address interaction on micro-, meso-, exo- as well as macro-social levels (Bronfenbrenner, 1973). Thus, when analyzing effectiveness of whatever method, one should not only look at the method, but at what happens outside the “methodical therapy” or teaching hours, i.e., at what happens on all these system levels. Activation programs alone, when applied in an otherwise secluded context, hardly work. Intelligence can only develop when the situation does not stay the same, when the child is confronted with problematic situations, which it must learn to solve (in the beginning with a mediator, later more and more autonomously). Bronfenbrenner's view on the ecology of development comes close to Bateson's views on the ecology of mind (Bateson, 2000).

Development of the brain's structure, and accordingly of intellectual capacities, is not a simple unfolding of an innate capacity, limited by genetic predispositions (although genes might influence the process of brain construction), but is the result of a brain which is properly activated. Vygotsky puts a main emphasis on activation through language. Higher cognitive development (in the sense of development of abstract thinking) is contingent on transfer of human language-rich culture. Feuerstein emphasized the process of adequate mediated learning experience (MLE) in constructing an individual's structural cognitive modifiability (Kozulin, 1998). Mediation has outer as well as inner, more intangible energetic, affective aspects and is thus taking place on the microlevel of interaction as well as a sub-microlevel.

Brain Development Needs Affective Mediating Environment

Early handling of newborn animals—stroking, caressing, and caring—not only increases wellbeing, it also has marked neurobiological effects: increase of nerve growth factor, triggering dendritic spine formation, long-term potentiation of the hippocampus; increased cortical and hippocampal thickness, and as well as effects on dopamine release and a number of neurotransmitters (Meaney et al., 1991; Fernandez-Teruel et al., 2002). Caressed laboratory rodents learn better than those left in an isolated cage. The mechanism probably has to do with anxiety reduction, which has various neurotransmitter effects.

Colwyn Trevarthen found that a positive emotional relationship is primary in development of brain function. By filming at the same time newborns and their mothers, interacting in a playful way, he observed that the baby is fully responsive, in contact and takes initiative. Babies can get depressed when they are not responded to. This primary inter-subjectivity triggers neuronal development and connections (Trevarthen, 1990). Similarly Greenspan and Wieder (2006) observed that the disturbed affective interaction of children with autistic spectrum disorder can be reversed in a positive sense by enriched affective interaction—which they call the “floortime approach”—and DIR (developmental, individual-difference, relationship-based) model, triggering an autistic child's social and emotional-cognitive development.

When early emotional bonding with caring adults is seriously disrupted, as happens in extreme emotional and physical deprivation, cognitive development is also hampered. Van den Bergh and Marcoen (2004) found that high antenatal anxiety of the mother is related to ADHD symptoms and increased anxiety in school age children.

Animals respond to situations of novelty in a dual way: with exploratory behavior and with anxiety and withdrawal. Both have substantial neurobiological effects. They can reinforce the animal's brain construction or deteriorate it. Tinbergen in the early 1970s, before there was such a vast knowledge about brain-emotional neurochemistry, suggested that human autism is “caused” by a motivation conflict, which is analogous to the approach and withdrawal ambiguity of animals in the wild (Tinbergen & Tinbergen, 1983). Although Tinbergen's hypothesis on autism has been criticized as “too psychogenic” and in current thinking a “brain damage aetiology of autism” is more accepted, he showed many instances of reversibility of autistic behavior, confirming his hypothesis. However, in principle, there should be no mutual exclusion of a psychogenic or brain damage approach to autism, as long as one is prepared to look at the modifiability and plasticity of autism despite brain damage.

IMPLICATIONS OF PLASTICITY

The new findings on brain functioning that depict the brain as a constantly changing system, changing structurally and functionally as a response to its environment, dependent on activation and mediation, have some important implications for education, rehabilitation, and child guidance.

1. Teach your brain how to learn. From early infancy, parents and caregivers should be aware that a baby's brain structure could be greatly influenced by the way they interact with the child. This means offering a rich variety of adapted, adequate and sufficiently interesting stimuli, in an affective environment, without overloading the child with bombardments of stimuli, but in a more dosed way, while challenging and mediating how to deal with the stimuli. This puts great responsibility on modern parents who have a tendency to leave education to machines or professionals. The development of a generation of children is endangered. Parents and teachers should (again) learn to become mediators.
2. As plasticity goes on during an entire lifetime, it is important to continue to engage in stimulating learning activities during adulthood and old age.
3. Teachers should drop the rigid categories of dividing children into “bright,” “not so bright,” and “hopelessly retarded” groups, and instead depart from an inherent capacity of every child to be modifiable. This will partly depend on their efforts to mediate the children on how to think, and how to learn. A more optimistic attitude in teachers is much needed.
4. Stop addiction to prediction. In the “old” paradigm of deterministic thinking about development, prediction of future development occupies an important place. However, in view of plasticity and the non-deterministic properties of the brain as a system, prediction is no longer possible, and neither does it make sense. It does not make sense to invest in tests trying to find out which preschool child is going to be dyslexic, learning disabled or behaviorally disturbed.
5. Where tests continue to be administered, care should be taken on how to interpret the results. A more dynamic way of evaluation, which allows for modifiability and is able to demonstrate modifiability, is needed.

Acknowledgements

This research has been made possible thanks to a grant from the Foundation for Ecological Health Care, Capelle a/d Ijssel, The Netherlands. We also express our gratitude to Alice Seng for reading the manuscript.

References

Alder, J., Thakker-Varia, S., & Black, I. B. (2002). Transcriptional analysis in the brain: Trophin induced hippocampal synaptic plasticity. Neurochemical Research, 27(10), 1079–1092.

Almli, C. R. (1984). Early brain damage and time course of behavioral dys-function: Parallels with neural maturation. In C. R. Almli, & S. Finger (Eds.), Early Brain Damage, Vol. 2, Neurobiology and Behavior (pp. 99–116). Orlando & New York: Academic Press.

Aoki, C., & Siekevitz, P. (1988). Plasticity in brain development. Scientific American, 259, 56–64.

Arnott, G., Guieu, J. D., Blond, S., Charlier, J., Vanceloo, F. M., Lejeune, E., et al. (1982). Hémispherectomie droite totale. Etude neurophysiologique après vingt ans. Revue Neurologique, 138, 305–316.

Assagioli, R. A. (1973). The Act of Will. New York: Viking Press.

Austin, G. M., & Grant, F. C. (1955). Physiologic observations following total hemispherectomy in man. Surgery, 38, 239–257.

Bangert, M., & Altenmüller, E.O. (2003). Mapping perception to action in piano practice. Biomed Central Neuroscience, 4, 26.

Bateson, G. (2000). Steps Towards An Ecology of Mind. Chicago: The University of Chicago Press.

Bierman-van Eendenburg, M. E. C., Jurgens-van der Zee, A. D., Olinga, A. A., Huisjes, H. H., & Touwen B. C. L. (1981). Predictive value of neonatal neurological examination: A follow-up study at 18 months. Developmental Medicine and Child Neurology, 23, 296–305.

Bigler, E. D. (1988). Good outcome associated with cerebral reconstitution in hydrocephalus. Journal of Child Neurology, 3, 297–298.

Bigler, E. D. (1995). Brain morphology and intelligence. Developmental Neuropsychology, 11(4), 377–403.

Black, I. (1999). Trophic regulation of synaptic plasticity. Journal of Neurobiology, 41(11), 108–118.

Blackman, J. A., McGuinness, G. A., Bale, J. F., & Smith, W. L. (1991). Large postnatally acquired porencephalic cysts: Unexpected developmental outcomes. Journal of Child Neurology, 6, 58–64.

Boon P., Vandekerckhove, T., Calliauw, L., Achten, E., De Reuck, J., Thiery, E., et al. (1996). Epilepsy surgery in Belgium: The Flemish experience. Acta Neurologica Belgica, 96, 6–18.

Bronfenbrenner, U. (1973). Social ecology of human development. In F. Richardson (Ed.), Brain and Intelligence: The Ecology of Child Development. Hyattsville: National Educational Press.

Bronfenbrenner, U. (1981). The Ecology of Human Development Experiments by Nature and Design. Mass: Cambridge.

Buckley, S., & Bird, G. (2003). Teaching reading to teach talking and thinking. In J. Lebeer (Ed.), INSIDE: How to promote cognitive development of children with developmental or learning difficulties inside the educational system. Southsea, Hampshire: Down Syndrome Educational Trust.

Carr, L. J. (1996). Development and reorganisation of descending motor pathways in children with hemiplegic cerebral palsy. Acta Paediatrica Supplement, 416, 53–57.

Chen, R., Cohen, L. G., & Hallett, M. (2002), Nervous system reorganization following injury. Neuroscience, 111(4), 761–773.

Chugani, H. T., Müller, R. A., & Chugani, D. C. (1996). Functional brain reorganisation in children. Brain and Development, 18, 347–356.

Damasio, A. R., Lima, A., & Damasio, H. (1975). Nervous function after right hemispherectomy. Neurology, 25, 89–93.

DeLuca, S. C., Echols, K., Ramey, S. L., & Taub, E. (2003), Pediatric constraint induced movement therapy for a young child with cerebral palsy: Two episodes of care. Physical Therapy, 83(11), 1003–1013.

Dettmers, C., Teske, U., Hamzei, F., Uswatte, G., Taub, E., & Weiller, C. (2005). Distributed form of constraint induced movement therapy improves functional outcome and quality of life after stroke. Archives of Physical Medicine and Rehabilitation, 86(2), 204–209.

Devlin, A. M, Cross, J. H., Harkness, W., Chong, W.K., Harding, B., Vargha-Khadem, F., et al. (2003). Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence. Brain, 126, Pt 3, 556–566.

Donald, M. (1991). Origins of the Modern Mind: Three Stages in the Evolution of Culture and Cognition. Cambridge, MA: Harvard University Press.

Eccles, J. C., & Robinson, D. (1985). The Wonder of Being Human. Boston & London: Shambhala.

Edeline, J. M. (1999). Learning-induced physiological plasticity in thalamocortical sensory systems: A critical evaluation of receptive field plasticity, map changes and their potential mechanisms. Progress in Neurobiology, 57(2), 165–224.

Engels, P. (2006), “It's a nice life.” My experiences with inclusive education. Transsylvanian Journal of Psychology—Erdély Pszichológiai Szemle, Special issue Vol. Supplement 2006, part 1, 25–30.

Farmer, S. F., Harrison, L. M., Ingram, D. A., & Stephens, J. A. (1991). Plasticity of central motor pathways in children with hemiplegic cerebral palsy. Neurology, 41, 1505–1510.

Fernández-Teruel, A., Giménez-Llort, L., Escorihula R., Gil L., Aguilar R., Stemier T., & Tobeña, A. (2002). Early-life handling stimulation and environmental enrichment: Are some effects mediated by similar neural mechanisms? Pharmacology Biochemistry and Behavior, 73(1), 233–245.

Feuerstein, R., & Spire, A. (2006). La pédagogie à visage humain. Bordeaux: Les Bords de l'Eau.

Feuerstein, R., Klein, P. S., & Tannenbaum, A. (1991). Mediated Learning Experience: Theoretical, Psychological and Learning Implications. London: Freund Publishing House.

Feuerstein, R., Rand Y., & Rynders, J. E. (1988). Don't Accept Me as I Am: Helping “Retarded” People to Excel. New York: Plenum.

Finger, S. (1989). Reflections on the possible maladaptive consequences of injury-induced reorganization. Neuropsychology, 3(1), 41–47.

Goodman, R. A., & Whitaker, H. A. (1985). Hemispherectomy: A review (1928–1981) with special reference to the linguistic abilities and disabilities of the residual right hemisphere. In C. T. Best (Ed.), Hemispheric Function and Collaboration in the Child (pp. 121–155). Orlando: Academic Press.

Grandin, T., & Scariano, M. M. (1996). Emergence, Labelled Autistic. New York: Warner Books.

Greenspan, S. I., & Wieder, S. (2006). Engaging Autism: Using the Floortime Approach to Help Children Relate, Communicate, and Think. Cambridge, MA: Da Capo Press.

Gunnar, M. (2001). Effects of early deprivation: Findings from orphanagereared infants and children. In C. Nelson & M. Luciana, Handbook of Developmental Neuroscience. Cambridge, MA: MIT Press.

Hebb, D. O. (1949). The Organisation of Behaviour. New York: Wiley.

Hécaen, H., Perenin, M. T., & Jeannerod, M. (1984). The effects of cortical lesions in children: Language and visual functions. In C. R. Almli & S. Finger (Eds.), Early Brain Damage, Volume 1: Research Orientations and Clinical Observations (pp. 277–298). Orlando: Academic Press.

Hennekam, R. C., van Rhijn, A., & Hennekam, F.A. (1992). Dominantly inherited microcephaly, short stature and normal intelligence. Clinical Genetics, 41(5), 248–251.

Hicks, S. P., D'Amato, C. J., & Glover, R. A. (1984). Recovery or malformation after fetal radiation and other injuries. In C. R. Almli & S. Finger (Eds.), Early Brain Damage, Volume 1: Research Orientations and Clinical Observations (pp. 127–147). Orlando: Academic Press.

Hubel, D. H., & Wiesel, T. N. (1963). Receptive fields of cells in striate cortex of very young, visually inexperienced kittens. Journal of Neurophysiology, 26, 994–1002.

Innis, J. W., Asher, J. H. Jr., Poznanski, A. K., Sheldon, S. (1997). Autosomal dominant microcephaly with normal intelligence, short palpebral fissures, and digital anomalies. American Journal of Medical Genetics, 71(2), 150–155.

Irle, E. (1987). Lesion size and recovery of function: Some new perspectives. Brain Research, 434, 307–320.

Kaplan, M. S. (1988). Plasticity after brain lesions: Contemporary concepts. Archives of Physical Medicine and Rehabilitation, 69, 984–991.

Keller, H. (1905). The Story of My Life. London: Hodder & Stoughton.

Kennard, M. A. (1940). Relation of age to motor impairment in man and in subhuman primates. Archives of Neurology and Psychiatry, 44, 377–397.

Klintsova, A., & Greenough, W. T. (1999). Synaptic plasticity in cortical systems. Current Opinions in Neurobiology, 9(2), 203–208.

Kolb, B. (1989). Brain development, plasticity, and behavior. American Psychologist, 44, 1203–1212.

Kolb, B., & Whishaw, I. O. (1989). Plasticity in the neocortex: Mechanisms underlying recovery from early brain damage. Progress in Neurobiology, 32, 235–276.

Kostovic, I., Lukinovic, N., Judas, M., Bogdanovic, N., Mrzljak, L., Zecevic, N., et al. (1989). Structural basis of the developmental plasticity in the human cerebral cortex: The role of the transient subplate zone. Metabolic Brain Disease, 4, 17–23.

Kozulin, A. (1998). Psychological Tools: A Sociocultural Approach to Education. Cambridge, MA: Harvard University Press.

Lane, H. (1977). The Wild Boy of Averyon. London: Allen & Unwin.

Lashley, K. (1950). In search of the engram. Symposium of the Society for Experimental Biology, 4, 454–482.

Lebeer, J. (1998). How much brain does a mind need? Scientific, clinical and educational implications of ecological plasticity. Developmental Medicine and Child Neurology, 40, 352–357.

Lebeer, J. (2006). Clues to inclusive and cognitive education: Reconciling needs to integrate and to activate learning processes. In Erdélyi Pszichológiai Szemle (Transsylvanian Journal of Psychology), special issue on inclusive and cognitive education, 2006 Supplement, 31–66.

Lebeer, J., & Garbo, R. (1997). Ecological influences in development of brainimpaired children: A multi-dimensional approach. In A. Kozulin (Ed.), The Ontogeny of Cognitive Modifiability (pp. 239–258). Jerusalem: International Centre for the Enhancement of Learning Potential.

Lebeer, J., & Rijke, R. P. C. (2003). Ecology of development in children with brain impairment. Child: Care, Health & Development, 29(2), 131–140.

Lewin, R. (1980). Is your brain really necessary? Science, 210, 1232–1234.

Loddenkemper, T., Dinner, D. S, Kubu, C., Prayson, R., Bingaman, W., Dagirmanjian, A. et al. (2004). Aphasia after hemispherectomy in an adult with early onset epilepsy and hemiplegia. Journal of Neurology, Neurosurgery, and Psychiatry, 75(1), 149–151.

Maguire, E. Gadian, D. G., Johnsrude, I., Good, C. D. Ashburner, J., Frackowiak, R. S., & Frith, C. D. (2000). Navigation-related structural change in the hippocampi of taxi drivers. Proceedings of the National Academy of Sciences, 97, 4398–4403.

Malson, L., & Itard, J. (1972). Wolf Children: The Wild Boy of Aveyron. London: New Left Books.

Maria, B. L., Zinreich, S. J., Carson, B. C., Rosenbaum, A. E., & Freeman, J. M. (1987). Dandy-Walker syndrome revisited. Pediatric Neuroscience, 13, 45–51.

Marshall, J. F. (1985). Neural plasticity and recovery of function after brain injury. International Review of Neurobiology, 26, 201–247.

McVicker-Hunt, J. (1986). The effect of variations in quality and type of early child care on development. New Directions for Child Development, 32, 31–48.

Meaney, M. J., Mitchell, J. B., Aitkin, D. H., Bhatnagar, S., Bodnoff, S. R., Iny, L. J., et al. (1991). The effects of neonatal handling on the development of the adrenocortical response to stress: Implications for neuropathology and cognitive deficits in later life. Psychoneuroendocrinology, 16, 85–103.

Merzenich, M. (2000). Seeing in the sound zone. Nature, 404, 820–821.

Meyer, D. R., & Morgan-Meyer, P. (1984). Bases of recoveries from perinatal injuries to the cerebral cortex. In C. R. Almli & S. Finger (Eds.), Early Brain Damage, Volume 2: Neurobiology and Behavior (pp. 211–227). Orlando: Academic Press.

Moen, P. H., Elder, G., & Luscher, K. (1995). Examining Lives in Context: Perspectives on the Ecology of Human Development. New York: The Free Press.

Morris, R. G., Kandel, E. R., & Squire, L. R. (1988). The neuroscience of learning and memory: Cells, neural circuits and behavior. Trends in Neurosciences, 11, 125–127.

Musso, M. C., Weiller, C., Kiebel, S., Müller, S. P., Bülau, P., & Rijntjes, M. (1999). Training-induced brain plasticity in aphasia. Brain, 122, 1781–1790.

Pribram, K. H. (1971). Languages of the Brain. Englewood Cliffs, NJ: Prentice Hall.

Rakic, P. (2002). Neurogenesis in adult primates. Progress in Brain Research, 138, 3–14.

Rijke, R. P. C. (1993). Health in medical science: From determinism towards autonomy. In R. Lafaille, & S. Fulder (Eds.), Towards a New Science of Health (pp. 74–83). London: Routledge.

Roe, A., Pallas, S., Kwon, Y., & Sur, M. (1991). Visual projections routed to the auditory pathway in ferrets: Receptive fields of visual neurons in primary auditory cortex. Journal of Neurosciences, 12, 3651–3664.

Rosenzweig, M. R., & Bennet, E. L. (1996). Psychobiology of plasticity: Effects of training and experience on brain and behavior. Behavioural Brain Research 78: 57–65.

Rossi, L. N., Candini, G., Scarlatti, G., Rossi, G., Prina, E., Alberti, S. (1987). Autosomal dominant microcephaly without mental retardation. American Journal of Diseases of Children, 141, 655–659.

Shahbazian, M. D., & Zoghbi, H. Y. (2002). Rett syndrome and MeCP2: Linking epigenetics and neuronal function. American Journal of Human Genetics, 71(6), 1259–1272.

Sharma, R. (2002). My two years in the life of Alex: Mediated learning experience with a boy who had undergone a left hemispherectomy. Doctoral dissertation, University of Exeter, Exeter (UK).

Skuse, D. (1984). Genie: A Psychological Study of a Modern Day “Wild Child.” New York: Academic Press.

Smith A. (1984). Early and long-term recovery from brain damage in children and adults: Evolution of concepts of localization, plasticity, and recovery. In C. R. Almli, & S. Finger (Eds.), Early Brain Damage, Volume 1: Research Orientations and Clinical Observations (pp. 299–324). Orlando: Academic Press.

Squire, L. (2004). Memory systems of the brain: A brief history and current perspective. Neurobiology of Learning and Memory, 82(3), 171–177.

Stein, D. G., Finger, S., & Hart, T. (1983). Brain damage and recovery: Problems and perspectives. Behavioral and Neural Biology, 37, 185–222.

Steward, O. (1984). Lesion-induced neuroplasticity and the sparing or recovery of function following early brain damage. In C. R. Almli, & S. Finger (Eds.), Early Brain Damage, Volume 1: Research Orientations and Clinical Observations (pp. 59–77). Orlando: Academic Press.

Taub, E., Uswatte, G., Morris, D. M. (2003). Improved motor recovery after stroke and massive cortical reorganization following Constraint Induced Movement therapy. Physical Medicine and Rehabilitation Clinics of North America, 14(1 Suppl), S77–91.

Teyler, T. J., & Fountain, S. B. (1987). Neuronal plasticity in the mammalian brain: Relevance to behavioral learning and memory. Child Development, 58, 698–712.

Thanos, S., & von Boxberg, Y. (1990). Factors influencing regeneration of retinal ganglion cell axons in adult mammals. Metabolic Brain Disease, 4, 67–72.

Tinbergen, N., & Tinbergen, E. A. (1983) Autistic Children: New Hope for a Cure. London: George Allen & Unwin.

Trevarthen C. (1990). Growth and education of the hemispheres. In C. Trevarthen (Ed.), Brain Cricuits and Functions of the Mind: Essays in Honour of Roger W. Sperry. New York: Cambridge University Press.

Turkstra, L. S., Holland, A. L., & Bays, G. A. (2003). The neuroscience of recovery and rehabilitation: What have we learned from animal research? Archives of Physical Medicine and Rehabilitation, 84(4), 604–612.

Van den Bergh, B. R. H., & Marcoen, A. (2004). High antenatal maternal anxiety is related to ADHD symptoms, externalizing problems, and anxiety in 8- and 9-year-olds. Child Development, 75(4), 1085–1097.

Van Praag, H., Kempermann, G., & Gage, F. H. (2000). Neural consequences of environmental enrichment. Nature Review of Neurosciences, 1(3), 191–198.

Vargha-Khadem, F., Carr, L. J., Isaacs, E., Brett, E., Adams, C., & Mishkin, M. (1997). Onset of speech after left hemispherectomy in a nine-year-old boy. Brain, 120(Pt 1), 159–182.

Villablanca, J. R., Burgess, J. W., & Sonnier, B. J. (1984). Neonatal cerebral hemispherectomy: A model for postlesion reorganization of the brain. In C. R. Almli & S. Finger (Eds.), Early Brain Damage, Volume 2: Neurobiology and Behavior (pp. 179–210). Orlando: Academic Press.

Zhang, X., & Sheng-yu, Y. (1984). Report of ten cases of porencephaly. Chinese Medical Journal, 97, 786–788.