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NAME : Muniroh Hanafiah

NIM : 070100392

GROUP : J 6

FACILITATOR: dr.RR SUZY INDHARTY, M.Kes, Sp.BS

DEPARTMENT OF NEUROSURGERY

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FACULTY OF MEDICINE ACMS-USU

JULY 2012

Introduction

An adult brain was thought to be a rather static organ in the past, on the other hand today it has been proven that the brain is able to reorganize and change itself in order to adapt to new situation such as learning a new dance step or in order to recover from an injury. (Kolb B, Gibb R, Robinson, T, 2003)

The theory of neuroplasticity was believed to have been introduced about 120 years ago by an American psychologist and philosopher, William James, in his book “Principle of Psychology”. However the first to mention the term neuralplasticity was by a Polish Neuroscientist, Jerzy Konorksi in 1948.Konorski suggested that over time neurons that are activated by the surrounding neurons may form new pathway which affects the plasticity of the brain. ( www.whatisneuroplasticity.com)

What is Neuroplasticity?

Neuroplasticity is defined as the ability of the brain to reorganizes neural pathway in the brain in order to accommodate the new information and ability attained. Neuroplasticity can occur in two ways; either by learning new things or the brain is adapting in order to adjust itself to the new situation for example when a person experience an accident and is unable to use his or her right hand then in order to cope the brain has to adapt by forming new neural pathway and learn how to use the left hand instead. (www.spineuniversity.com)

Nature of Neuroplasticity

Histology of Central Nervous system

Neuron

In order to understand how neuroplasticity occurs, it is important to understand the basic structure of the nervous system. The main histological components of the central nervous system are the neurons. (Wibowo, D.S,2008)

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Neurons are nerve cell that are responsible for the chemical reaction, transmission, sensing the stimuli, activating certain cell in response and releasing neurotransmitter. A neuron is made out of a gel like structure and is prone to trauma. The neuron structure is strengthened by the presence of neurofilament or neurofibril which acts as the cytoskeleton. The neurofilament also as the microtubule which transport metabolites good and regulates neurotransmitter. In the central nervous system the neurons are surrounded by myelin sheath which are formed by the oligodendrocyte. The myelin plays an important role in isolating the neurons from affecting other neuron nearby. (Wibowo, D.S, 2008)

In general neuron consists of three parts dendrite which plays a role in receiving the stimuli from the surrounding; cell body or perikaryon which act as the main centre of a single neurons and the axon which is a bump like structure which either generates new impulses or carry impulse from one cell to the next. (Wibowo, D.S, 2008)

Neurons can be classified either by its structure or by its function. According to structure the neuron can be classified as the following (1) multipolar neuron, which has more than has one axon and many dendrites;(2) bipolar neuron which has one dendrite and one axon;(3) pseudounipolar which contains an axon that has split into two branches; one branch runs to the periphery and the other to the spinal cord.

According to the function neurons can be classified into motoric (efferent) which controls the target organ such as muscle fiber, exocrine gland and endocrine gland; and the sensoric neuron (afferent) which involves receving sensoric stimulus from the environment.(Wibowo, D.S,2008)

Glia Cell

Neuroglia or glia cell is a group of cell that made up 10% of the total neuron which is found in the central nervous system. Glia cells are non-neuronal cells, their role mainly involves them maintaining honeostasis, supplying nutrients, fixing the damaged tissues, protection and support as well as acting as the phagocytes. Other types of Glia cells include astrocyte, oligodendrocyte, microglia and ependymal cell. (Wibowo D.S,2008)

Fig.1. The different types of Neurons

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Astrocyte binds the neuron to the capillary and pia matter. A single astrocyte cell forms expanded end feet which is connected to the endothelial cell through a junctional complex which forms a barrier between the central nervous system and the blood vessel. This appears to be the component of blood brain barrier. On its surface the astrocye cells have a few receptors and cells which releases metabolites substance and molecule which can either stimulate or inhibits the neuron function. Astrocyte also plays an important role in maintaining the optimal condition in order for the neurons to function properly. In cases of trauma or injury to the brain astrocyte cell proliferate to form scar tissue on the glial cell. (Wibowo D.S,2008)

Oligodendrocyte is found in the substantia grisea and substatia alba, these cell produces myelin sheath which acts as an electrical insulator for the axon in the central nervous system. The oligodendrocyte cells is similar to that of the Schwann cell in the peripheral nervous sytem, the only difference is that oligodendrocyte can surround a few myelin axon at the same time. (Wibowo D.S,2008)

Microglia cell is small and oval in shaped with a few short bumps and is only found in a small number in the substatia grisea and substatia alba. Microglia cells originate from the mesoderm layer and migrated to the neuroectoderm layer at the of the embryonic phase. These cells acts similar to that of the phagocyte cell and is involved in inflammation reaction as well as repairing the damage that occurs to the central nervous system after an injury. In patient with multiple sclerosis the microglia cell will cause the degradation of the myelin surrounding the axon in the central nervous system. (Wibowo D.S,2008)

Empydemal cell is a cylindrical shaped cell and acts as a fluid transporting cell and in a few regions of the brain these cell modified themselves into epithelial choroidal cell and produce cerebrospinal fluid. (Wibowo D.S,2008)

Histology of Brain

The brain consists of cerebrum, cerebellum and brain stem. The brain does not have connective tissues, the organ has a gel like structure and appears to form a complex structure which consist of layered structure and non layered structure. (Wibowo, D.S, 2008)

The cerebral cortex is a structure with lots of fold and has a few regions with layer structures that each has their own function. Some part of the cortex region receives afferent impulses while other region produces impulses to control the voluntary movement. There are many types of important cell in the cerebral cortex such as the pyramidal cell which connects the cortex with the other brain parts. Cerebral cortex can be divided into the neocortex and allocortex. Neocortex has six layers of cell and is far more developed compare to allocortex which has only three layers of cell. The thickest layer of the neocortex layer is located at the Brodmann area 4 due to the giant Betz cell. In the allocortex layer the hippocampus can be found. (Wibowo, D.S, 2008)

The cerebellum also contains lots of folds within its structure and is arranged in layers. The cerebellum plays a very important role in controlling the motoric function of the

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muscle movement. The cortex of the cerebellum consist of three layer starting with a molecular layer on the outside, purkinje cell and the granular layer on the inside. Purkinje fiber has a large body cell with lots of branches on its dendrites. (Wibowo, D.S, 2008)

Histology of Medulla Spinalis

Medulla spinalis is a continuity of the brain stem which is divided into a few segment. Each segment is linked with the left and right spinal nerve. The main difference between the histology of the medulla spinalis and the brain is the position of the substantia grisea and the substantia alba. In the medulla spinalis the subtantia alba surrounds the substantia grisea whereas in the brain it occurs the other way round. (Wibowo, D.S, 2008)

Substansia grisea contain neuron cell body with its dendrite , axon and glial cell. Substansia grisea is divided into two cornu dorsalis and two cornu ventralis which is interlinked by the commisura substansia grisea. The sensory neuron has cell body outside of the medulla spinalis within the dorsal radix ganglion and ends at the posterior cornu substantia grisea where it will form synapse with interneuron. The interneuron cell will integrate the sensory impulse which it receives and sends the impulses to the brain. The brain will send the impulse back along the interneuron cell which is then send to the peripheral.(Wibowo, D.S,2008)

Anatomy of the brain

The brain is one of the largest and most complex organs in the human body. It is made up of more than 100 billion nerves that communicate in trillions of connections called synapses.The brain is made up of many specialized areas that work together. The cortex is the outermost layer of brain cells. Thinking and voluntary movements begin in the cortex. The brain stem is between the spinal cord and the rest of the brain. Basic functions like breathing and sleep are controlled here. The basal ganglia are a cluster of structures in the center of the brain. The basal ganglia coordinate messages between multiple other brain areas. The cerebellum is at the base and the back of the brain. The cerebellum is responsible for coordination and balance. .(Wibowo, D.S,2008)

The brain is also divided into several lobes; the frontal lobes are responsible for problem solving and judgment and motor function. The parietal lobes manage sensation, handwriting, and body position. The temporal lobes are involved with memory and hearing. The occipital lobes contain the brain's visual processing system. The brain is surrounded by a layer of tissue called the meninges. The skull (cranium) helps protect the brain from injury. .(Wibowo, D.S,2008)

The picture below shows the brain cross section area.

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Neurogenesis

Neurogensis is a process where new nerve cells are generated. In neurogenesis, there is active production of new neurons, astrocytes, glia, and other neural lineages from undifferentiated neural progenitor or stem cells. Neurogenesis is considered a rather inactive process in most areas of the adult brain. (www.medterm.com)

In the past, it was believed that a human adult nervous system does not have the ability to regenerate itself partly because an adult brain contain neurons with complex structure and highly differentiated. As a result of this it was assumed that the neuron is unable to re-enter the cell cycle and further differentiate. Another reason is because if an adult neurons were able to divide itself how would the new cell with the new dendrites, axon and synapse function without disrupting the existing circuits. (Gage, F.H, 2002)

Several discoveries over the past few years had shown that there is an area within an adult brain new neurons are continually being created, the two predominant area include the sub ventricular zone which lines the lateral ventricle, where the neural stem cell and the progenitor generate neuroblast that migrate to the olfactory bulb via the rostral migratory stream; and the subgranular zone which is part of the denate gyrus of the hippocampus. The first evidence of neurogenesis in the cerebral cortex of an adult mammalian was discovered by Joseph Altman in 1962 followed by the demonstration of adult neurogenesis in the dentate gyrus of the hippocampus in 1963. In 1969 he discovered and named the rostral migratory stream. Unfortunately these discovery was ignored until later on in the 1990 when a demonstration was done proving hippocampal neurogenesis in humans and non primate. (Gage, F.H, 2002)

Even thought there has been a lot of research being done on the functional relevance of adult neurogenesis; the results still shows uncertainty, but there is some evidence that hippocampal adult neurogenesis is important for learning and memory. (Gage, F.H, 2002)

Multiple mechanisms for the relationship between increased neurogenesis and improved cognition have been suggested, including theories to demonstrate that new neurons increase memory capacity, and reduce interference between memories or add information

Fig.2 Cross section of the brain anatomy

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about time to memories Experiments aimed at ablating neurogenesis have proven inconclusive, but several studies have proposed neurogenic-dependence in some types of learning, and others seeing no effect. Studies have demonstrated that the act of learning itself is associated with increased neuronal survival.  However, the overall findings that adult neurogenesis is important for any kind of learning are still very vague. (Gage, F.H, 2002)

Neuroregeneration

Neuroregeneration refers to the regrowth or repair of nervous tissues cells or cell products. Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration in the peripheral nervous system is different in comparison with that of the central nervous system; by the functional mechanism, the extent and speed. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt to repair the axon. In the CNS, synaptic stripping occurs as glia foot processes invade the dead synapse. (Kandel, Schwartz, 2005)

Central Nervous system Regeneration

The regeneration of neuron in the central nervous system after an injury is not the same as the regeneration of the peripheral nervous system. After an injury occurs to the central nervous system it is not followed by extensive regeneration. It is limited by the inhibitory influences of the glial and extracellular environment. The hostile, non-permissible growth environment is, in part, created by the migration of myelin-associated inhibitors, astrocytes, oligodendrocytes, oligodendrocyte precursors, and microglia. The environment within the CNS, especially following trauma, counteracts the repair of myelin and neurons. (Recknor J.B, S.K. Mallapragda, 2006)

Slower degeneration of the distal segment than that which occurs in the peripheral nervous system also contributes to the inhibitory environment because inhibitory myelin and axonal debris are not cleared away as quickly. All these factors contribute to the formation of what is known as a glial scar, which axons cannot grow across. The proximal segment attempts to regenerate after injury, but its growth is hindered by the environment. It is important to note that central nervous system axons have been proven to regrow in permissible environments; therefore, the primary problem to central nervous system axonal regeneration is crossing or eliminating the inhibitory lesion site. (Recknor J.B, S.K. Mallapragda, 2006)

Glial scar formation is induced following damage to the nervous system. In the central nervous system, this glial scar formation significantly inhibits nerve regeneration, which leads to a loss of function. Several families of molecules are released that promote and drive glial scar formation. Transforming growth factors B-1 and -2, interleukins, and cytokines all play a role in the initiation of scar formation. The inhibition of nerve regeneration is a result of the accumulation of reactive astrocytes at the site of injury and the up regulation of molecules that are inhibitory to neurite extension outgrowth. The up-regulated molecules alter

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the composition of the extracellular matrix in a way that has been shown to inhibit neurite outgrowth extension. This scar formation involves contributions from several cell types and families of molecules. In response to scar-inducing factors, astrocytes up regulate the production ofchondroitin sulfate proteoglycans. Astrocytes are a predominant type of glial cell in the central nervous system that provide many functions including damage mitigation, repair, and glial scar formation. Chondroitin sulfate proteoglycans (CSPGs) have been shown to be up regulated in the central nervous system (CNS) following injury. (Recknor J.B, S.K. Mallapragda, 2006)

Brain injury

The brain injury mechanism is summarized in the diagram below:

(National Institute of Neurological disorder and stroke, 2003)

Factors affecting Brain Plasticity

By using Golgi-staining procedures, various investigators have shown that housing animals in complex versus simple environments produces widespread differences in the number of synapses in specific brain regions. In general, such experiments show that particular experiences embellish circuitry, whereas the absence of those experiences fails to do so (e.g., Greenough & Chang, 1989). Until recently, the impact of these neuropsychological experiments was surprisingly limited, in part because the environmental treatments were perceived as extreme and thus not characteristic of events experienced by the normal brain. It has become clear, however, not only that synaptic organization is changed by

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experience, but also that the scope of factors that can do this is much more extensive than anyone had anticipated. Factors that are now known to affect neuronal structure and behavior include the following:

Experience (both pre- and postnatal) Psychoactive drugs (e.g., amphetamine, morphine) Gonadal hormones (e.g., estrogen, testosterone) Anti-inflammatory agents (e.g., COX-2 inhibitors) Growth factors (e.g., nerve growth factor) Dietary factors (e.g., vitamin and mineral supplements) Genetic factors (e.g., strain differences, genetically modified mice) Disease (e.g., Parkinson’s disease, schizophrenia, epilepsy, stroke) Stress Brain injury and disease

Two examples of the effect are described below:

Early Experience

It is generally assumed that experiences early in life have different effects on behavior than similar experiences later in life. The reason for this difference is not understood, however. To investigate this question, an experiment was carried out with an animals being placed in complex environments either as juveniles, in adulthood, or in senescence (Kolb, Gibb, & Gorny, 2003). The result expected was that there would be quantitative differences in the effects of experience on synaptic organization, however it was also a qualitative differences was found in the result. And like many investigators before, it was also found that the length of dendrites and the density of synapses were increased in neurons in the motor and sensory cortical regions in adult and aged animals housed in a complex environment (relative to a standard lab cage). In contrast, animals placed in the same environment as juveniles showed an increase in dendritic length but a decrease in spine density. In other words, the same environmental manipulation had qualitatively different effects on the organization of neuronal circuitry in juveniles than in adults.

To pursue this finding, an infant animals was given 45 min of daily tactile stimulation with a little paintbrush (15 min three times per day) for the first 3 weeks of life. The behavioral studies results showed that this seemingly benign early experience enhanced motor and cognitive skills in adulthood. The anatomical studies showed, in addition, that in these animals there was a decrease in spine density but no change in dendritic length in cortical neurons; yet another pattern of experience-dependent neuronal change. The result of the studies showed that experience can uniquely affect the developing brain which leads to wonder if the injured infant brain might be repaired by environmental treatments. It was not surprising when it was found that post injury experience, such as tactile stroking, could modify both brain plasticity and behavior because it has been proven that such experiences were powerful modulators of brain development (Kolb, Gibb, & Gorny, 2000). What was surprising, however, was that prenatal experience, such as housing the pregnant mother in a

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complex environment, could affect how the brain responded to an injury that it would not receive until after birth. In other words, prenatal experience altered the brain’s response to injury later in life. This type of study has profound implications for preemptive treatments of children at risk for a variety of neurological disorders. (Kolb B, Gibb R, Robinson, T, 2003)

Psychoactive Drugs

Many people who take stimulant drugs like nicotine, amphetamine, or cocaine do so for their potent psychoactive effects. The long-term behavioral consequences of abusing such psychoactive drugs are now well documented, but much less is known about how repeated exposure to these drugs alters the nervous system. One experimental demonstration of a very persistent form of drug experience-dependent plasticity is known as behavioral sensitization. For example, if a rat is given a small dose of amphetamine, it initially will show a small increase in motor activity (e.g., locomotion, rearing). When the rat is given the same dose on subsequent occasions, however, the increase in motor activity increases, or sensitizes, and the animal may remain sensitized for weeks, months, or even years, even if drug treatment is discontinued.

Changes in behavior that occur as a consequence of past experience, and can persist for months or years, like memories, are thought to be due to changes in patterns of synaptic organization. The parallels between drug-induced sensitization and memory led to the question whether the neurons of animals sensitized to drugs of abuse exhibit long-lasting changes similar to those associated with memory (e.g., Robinson & Kolb, 1999). A comparison of the effects of amphetamine and saline treatments on the structure of neurons in a brain region known as the nucleus accumbens, which mediates the psychomotor activating effects of amphetamine, showed that neurons in the amphetamine-treated brains had greater dendritic material, as well as more densely organized spines. These plastic changes were not found throughout the brain, however, but rather were localized to regions such as the prefrontal cortex and nucleus accumbens, both of which are thought to play a role in the rewarding properties of these drugs. Later studies have shown that these drug-induced changes are found not only when animals are given injections by an experimenter, but also when animals are trained to self-administer drugs, leading us to speculate that similar changes in synaptic organization be found in human drug addicts. (Kolb B, Gibb R, Robinson, T, 2003)

Other Factors

All of the factors outlined above have effects that are conceptually similar to the two examples that have just been discussed. For instance, brain injury disrupts the synaptic organization of the brain, and when there is functional improvement after the injury, there is a correlated reorganization of neural circuits (e.g., Kolb, 1995). But not all factors act the same way across the brain. For instance, estrogen stimulates synapse formation in some structures but reduces synapse number in other structures (e.g., Kolb, Forgie, Gibb, Gorny, & Rowntree, 1998), a pattern of change that can also be seen with some psychoactive drugs, such as morphine. In summary, it now appears that virtually any manipulation that produces

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an enduring change in behavior leaves an anatomical footprint in the brain. (Kolb B, Gibb R, Robinson, T, 2003)

Applications and Examples

Treatment of brain damage

A surprising consequence of neuroplasticity is that the brain activity associated with a given function can move to a different location; this can result from normal experience and also occurs in the process of recovery from brain injury. Neuroplasticity is the fundamental issue that supports the scientific basis for treatment of acquired brain injury with goal-directed experiential therapeutic programs in the context of rehabilitation approaches to the functional consequences of the injury.

The adult brain is not "hard-wired" with fixed neuronal circuits. There are many instances of cortical and subcortical rewiring of neuronal circuits in response to training as well as in response to injury. There is solid evidence that neurogenesis (birth of brain cells) occurs in the adult, mammalian brain—and such changes can persist well into old age. The evidence for neurogenesis is mainly restricted to the hippocampus and olfactory bulb, but current research has revealed that other parts of the brain, including the cerebellum, may be involved as well.

In the other areas of the brain, neurons can die, but they cannot be regenerated. However, there are numerous amount of evidence for the active, experience-dependent re-organization of the synaptic networks of the brain involving multiple inter-related structures including the cerebral cortex. The specific details of how this process occurs at the molecular levels and are still an active topic in neuroscience research. The manner in which experience can influence the synaptic organization of the brain is also the basis for a number of theories of brain function including the general theory of mind and epistemology referred to as Neural Darwinism and was developed by immunologis Gerald Edelman. The concept of neuroplasticity is also central to theories of memory and learning that are associated with experience-driven alteration of synaptic structure and function in studies of classical conditioning in invertebrate animal.

Paul Bach-y-Rita, deceased in 2006, was the "father of sensory substitution and brain plasticity.” In working with a patient whose vestibular system had been damaged he developed BrainPort, a machine that "replaces the vestibular apparatus and send balance signals to the brain from the tongue."] After the machine was used for some time it was no longer necessary, as the patient then regained the ability to function normally.

Plasticity is the major explanation for the phenomenon. Because the patient’s vestibular system was "disorganized" and sending random rather than coherent signals, the apparatus found new pathways around the damaged or blocked neural pathways, helping to reinforce the signals that were sent by remaining healthy tissues. Bach-y-Rita explained plasticity by saying, "If you are driving from here to Milwaukee and the main bridge goes out, first you are paralyzed. Then you take old secondary roads through the farmland. Then

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you use these roads more; you find shorter paths to use to get where you want to go, and you start to get there faster. These "secondary" neural pathways are "unmasked" or exposed and strengthened as they are used. The "unmasking" process is generally thought to be one of the principal ways in which the plastic brain reorganizes itself." (Colota V.A, Rita P.B, 2002)

Randy Nudo's group found that if a small stroke (an infarction) is induced by obstruction of blood flow to a portion of a monkey’s motor cortex, the part of the body that responds by movement will move when areas adjacent to the damaged brain area are stimulated. 

Understanding of interaction between the damaged and undamaged areas provides a basis for better treatment plans in stroke patients. Current research includes the tracking of changes that occur in the motor areas of the cerebral cortex as a result of a stroke. Thus, events that occur in the reorganization process of the brain can be ascertained. Nudo is also involved in studying the treatment plans that may enhance recovery from strokes, such as physiotherapy, pharmacotherapy and electrical stimulation therapy. (Frost S.B, Barbay S., Friel K.M, et el, February 2003)

Neuroplasticity is gaining popularity as a theory that, at least in part, explains improvements in functional outcomes with physical therapy post stroke. Rehabilitation techniques that have evidence to suggest cortical reorganization as the mechanism of change include Constraint-induced movement therapy, functional electrical stimulation, treadmill training with body weight support, and virtual reality therapy. Robot assisted therapy is an emerging technique, which is also hypothesized to work by way of neuroplasticity, though there is currently insufficient evidence to determine the exact mechanisms of change when using this method.

Jon Kaas, a professor at Vanderbilt University, has been able to show "how somatosensory area 3b and ventroposterior nucleus of the thalamus are affected by long standing unilateral dorsal column lesions at cervical levels in macaque monkeys. Adult brains have the ability to change as a result of injury but the extent of the reorganization depends on the extent of the injury. His recent research focuses on the somatosensory system, which involves a sense of the body and its movements using many senses. Usually when people damage the somatosensory cortex, impairment of the body perceptions are experienced. He is trying to see how these systems (somatosensory, cognitive, motor systems) are plastic as a result of injury. (Young J.A, Tolentino, M., 2011)

Meditation

A number of studies have linked meditation practice to differences in cortical thickness or density of gray matter. One of the most well-known studies to demonstrate this was led by Sara Lazar, from Harvard University, in 2000. Richard Davidson, a neuroscientist at the University of Wisconsin, has led experiments in cooperation with the Dalai Lama on effects of meditation on the brain. His results suggest that long-term, or short-term practice of meditation results in different levels of activity in brain regions associated with such qualities as attention, anxiety, depression, fear, anger, the ability of the body to heal itself, and so on.

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These functional changes may be caused by changes in the physical structure of the brain. (Davidson, R. J, 2008)

Chronic Pain

Individuals who suffer from chronic pain experience prolonged pain at sites that may have been previously injured, yet are otherwise currently healthy. This phenomenon is related to neuroplasticity due to a maladaptive reorganization of nervous system, both peripherally and centrally. During the period of tissue damage, noxious stimuli and inflammation cause an elevation of nociceptive input from the periphery to the central nervous system. Prolonged nociception from periphery will then elicit a neuroplastic response at the cortical level to change its somatotopic organization for the painful site, inducing central sensitization. For instance, individuals experiencing complex regional pain syndrome demonstrate a diminished cortical somatotopic representation of the hand contralaterally as well as a decreased spacing between the hand and the mouth. Additionally, chronic pain has been reported to significantly reduce the volume of grey matter in the brain globally, and more specifically at the prefrontal cortex and right thalamus. However, following treatment, these abnormalities in cortical reorganization and grey matter volume are resolved, as well as their symptoms. Similar results have been reported for phantom limb pain, chronic low back pain and carpal tunnel syndrome. (www.spineuniversity.com)

Conclusion

The structure of the brain is constantly changing in response to an unexpectedly wide range of experiential factors. Understanding how the brain changes and the rules governing these changes are important not only for understanding both normal and abnormal behavior, but also for designing treatments for behavioral and psychological disorders ranging from addiction to stroke. Although much is now known about brain plasticity and behavior, many theoretical issues remain. Knowing that a wide variety of experiences and agents can alter synaptic organization and behavior is important, but leads to a new question: How does this happen? This is not an easy question to answer, and it is certain that there is more than one answer.

Other issues revolve around the limits and permanence of plastic changes. After all, people encounter and learn new information daily. Is there some limit to how much cells can change? It seems unlikely that cells could continue to enlarge and add synapses indefinitely, but what controls this? We saw in our studies of experience-dependent changes in infants, juveniles, and adults that experience both adds and prunes synapses, but what are the rules governing when one or the other might occur? This question leads to another, which is whether plastic changes in response to different experiences might interact. For example, does exposure to a drug like nicotine affect how the brain changes in learning a motor skill like playing the piano? Consider, too, the issue of the permanence of plastic changes. If a person stops smoking, how long do the nicotine-induced plastic changes persist, and do they affect later changes?

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One additional issue surrounds the role of plastic changes in disordered behavior. Thus, although most studies of plasticity imply that remodeling neural circuitry is a good thing, it is reasonable to wonder if plastic changes might also be the basis of pathological behavior. Less is known about this possibility, but it does seem likely. For example, drug addicts often show cognitive deficits, and it seems reasonable to propose that at least some of these deficits could arise from abnormal circuitry, especially in the frontal lobe. (Kolb B, Gibb R, Robinson, T, 2003)

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