Книги по МРТ КТ на английском языке / Functional Neuroimaging in Child Psychiatry Ernst 1 ed 2000

hormone, hydrocortisone) may have long-lasting eVects. Other global eVects may be iatrogenic or nutritional. It has been hypothesized that centrally acting drugs that are used during pregnancy may interfere with neurotransmitters, resulting not in gross physical malformations but rather in subtle behavioral symptoms such as hyperactivity and

sleep disturbances. Similarly, dietary variations in choline intake during pregnancy may inXuence the memory performance of oVspring, as shown by Zeisel (1997).

The fact that early changes in the levels of neurotransmitters may have lasting eVects into adulthood may be a consequence, in part, of the absence of neuronal stem cells

surviving the developmental period. The mature brain cannot regenerate damaged neurons. However, recent work with fetal transplants have shown a capacity for the mature brain to repair itself. The basis for this adult plasticity may relate to the regional grouping of neurotransmitters. For example, in the cerebellum, choline acetyltransferase (ChAT) activity is 10-fold higher in the fetus than in adults. In contrast, ChAT activity in the hippocampus is minimal or absent during the development but rises postnatally to reach a maximum in middle age. According to Perry and co-workers (1993), vulnerability of the hippocampus to age-related pathology may relate to the extended period of cholinergic synaptic sculpturing in this brain region. Pathoclisis (selective vulnerability of certain cells to insults) may also be related to the developmental proWle of diVerent neurotransmitters. Glycine, GABA, glutamic acid, aspartic acid, and their key metabolic enzymes progressively increase up to the mid portion of the third trimester of pregnancy (Das and Ray, 1997). Their levels may correlate with the rapid increase in nerve processes and myelination during this period.

Functional neuroimaging may oVer some insights into brain development and help to visualize temporal windows of selective vulnerability to damage (see Chapter 20). N-Acetyl-l-aspartic acid (NAA) can be assessed in the human fetal brain by high-resolution proton magnetic resonance spectroscopy (1H MRS, see Chapter 4). It is detected in the cerebral cortex and white matter by 16 weeks of gestation and increases gradually from 24 weeks of gestation to 1 year of age (Kato et al., 1997). Development abnormalities may result in NAA/creatine (Cr) decreases colocalized to structural malformation and extending into normal-appearing regions (Li et al., 1998). Functional imaging may help to deWne the extent of putative developmental lesions and provide guidance in future therapeutic interventions (Johnston, 1995).

Cortical organization acts like a distributed function system

It is important to realize that the historical and common perception of the brain as a collection of rigidly parceled and discrete areas, each of which is selectively associated with a particular behavior, is most likely a false one. Evidence from many sources, including functional neuroimaging with fMRI and positron emission tomography (PET), have shown that this notion is oversimplistic. While cellular anatomy is necessarily Wxed in place, columns allow for regional interactions that result in great dynamic properties and distribute the functions of the cortex

throughout many regions. Cross-talk between distant brain areas is the norm. The brain is not locked into selfcontained little units.

The columnar organization of the cortex permits a Wxed anatomic substrate to act as a Xexible distributed system. A distributed system is a collection of processing units, separated in space, that communicate by exchanging messages. A system is distributed if the message-transmission delay is a signiWcant fraction of the time between single events in a processing unit (Mountcastle, 1997).

Higher functions seem especially distributed and not locked into a localized region. There is a hierarchial distribution for multiple functions in a given region that serve to make local regions more complex and more plastic than previously thought. In the macaque monkey brain, researchers have so far identiWed in a single hemisphere 72 areas that are linked to each other by 758 connections. In addition, many of these connections are reciprocal. Columns can be seen both as structural units having a Wxed anatomy with speciWc cell properties and as dynamic units created by speciWc behavioral requirements for which multiple columns are recruited. Sensory discrimination and categorization are distributed in wide areas of the brain. How these sensory processes are uniWed and become part of the conscious experience is still a mystery.

Brain evolution and behavior

A striking outcome of comparative neurology is the general Wnding that, aside from size, nothing is strikingly unique about the human brain. Yet, it has always been assumed that the human brain contained some special area related to the unique level of consciousness in humans. Most anthropologists contend that human brains are basically ape brains that have undergone numerous small but highly signiWcant changes.

Like everything else in biology, human brains appear to be products of evolutionary mechanisms such as selection and genetic variation. Anatomic diVerences are ones of degree and do not represent totally new structures. The brain is conservative, and anatomic changes are often subtle rather than gross. Evolution has been likened to a tinkerer that builds upon existing structures rather than creating something entirely new and diVerent. In other areas of anatomy, seemingly small and insigniWcant alterations in anatomic structures may often give rise to large diVerences in function and behavior. The same mechanisms that brought about the evolution of all other biological systems can be applied to the study of the anthropoid brain.

126 M. F. Casanova, D. Buxhoeveden and G. S. Sohal

The anatomy and physiology of the human brain diVer from that of other primates only in a limited fashion because the human brain is built upon a basic mammalian template. It is the same with human behavior. The extent to which human behavior diVers from that of other animals, especially higher primates, is a matter of degree. Language and tool use among primates are sometimes matters of degree and specialization rather than novel in themselves. Claims have been made that apes have been taught American Sign Language (ASL) with varying success, and that vervet monkeys used verbal calls signals to refer to objects in their environment (Rumbaugh, 1977). The fact that apes could learn a novel form of communication such as ASL, outside of their evolutionary development, suggests that the primate brain already contains the basic design that could lead to a much more sophisticated mode of language. Both language and tool use in chimpanzees are not merely a product of the brain, however. The chimpanzee has a pharynx and tongue with characteristics that limit the number of sounds to about a dozen, prohibiting spoken language. Likewise, the upper limb of apes are primarily ªdesignedº for locomotion (some form of suspensory or knucklewalking), which results in a very poor precision and power grip. For ape behavior to become human-like, it is not only the brain that must undergo change, but also the body.

Perhaps the most signiWcant aspect of primate behavior is socialization. Many researchers feel this represents the selective push for human-like intelligence. Many animals use tools, and birds have extensive forms of vocalization and communication, but the complexity involved in human societal interaction is perhaps more unique and may have led to greater intelligence, which is manifested in technology and art. Chimpanzee social behavior is complex. Like humans, chimpanzees use bodily touch to communicate feelings of comfort and re-assurance. They can display aggression and have been shown to be capable of murder and even warfare. They are adept at using politics to obtain advantages in their society, gain favors and build alliances. Unlike more primitive mammals, the dominant chimpanzee is not necessarily the strongest one but often is the most ªcleverº one. The list of similarities to human behavior in all areas including sex (the sexual behavior of the bonobo chimpanzee is especially humanlike) is remarkable and suggests that human behavior is not unique and arises from the anthropoid model.

Political and social manipulation require a brain that is capable of hiding its true feelings. Neurologically, this means acquiring a degree of control over the limbic system. ªSimplerº animals are unable to mask their emotions such as anger, fear, or excitement. The dominance of

the cortex in higher primates, especially chimpanzees and humans, has created the ability to be deceitful. A smile may hide actual discontent but may Wt the complex political or social demands on the animal at a given time. Furthermore, socialization requires the ability to recognize feelings and emotional reactions in self and others. It is easy to see why socialization is such a strong force in the evolution of the mind.

Reorganization of the nervous system: from internally programmed behavior to sensory domination

During the evolution of the nervous system, certain general trends seem to have occurred. One of these is the movement away from internalized central programs (e.g., motor programs) to brains that rely heavily on sensory modulation. ªPrimitiveº nervous systems are more restricted in the amount of data they receive from the environment and in the processing of this information. Mammalian and especially primate evolution has been characterized by an increase in the input and processing of sensory data, which inXuenced the development and the working of the brain itself.

Central programming refers to the ability of the nervous system to generate behavioral output without the beneWt (or with limited use) of sensory information (Fig. 7.11). It is most often associated with motor programs but actually extends to nearly every type of animal behavior. Present in utero, many of these programs are genetically controlled (Hamburger, et al., 1966; Nottebohm, 1970, 1971; Berman and Berman, 1973; Taub et al., 1975; Landlesser, 1976; Taub, 1976). Invertebrate brains are noted for their centrally generated motor activity (Shik et al., 1966; Davis, 1969; Szekely et al., 1969; Davis and Davis, 1973; Dorsett, et al., 1973; Kashin, et al., 1974; Mayeri et al., 1974; Gardner, 1976). Central motor patterning was Wrst described in insect nervous systems and is a basic strategy for a spectrum of behaviors. Examples include song patterns in crickets (Bentley and Hoy, 1972), neural circulation in Aplysia (Mayeri, 1974), swimming in leeches and lobsters (Davis, 1969; Davis and Davis, 1973), wing beat of locusts, and escape behavior in Tritonia (Dorsett et al., 1973). Central motor programs are usually run by a command neuron that may trigger anything from a few interconnected neurons to a complex set of neuronal connections, utilizing interneurons, lateral inhibition, gamma eVerents, and Renshaw cells (Davis, 1976; Grillner, 1985). Invertebrates exhibit a wide variety of behavioral programs ranging from ones that are completely internalized (endogenous bursting cells,

(a)

(b)

(c )

Fig. 7.11. Basic simpliWed representations of the conceptual operations of some central motor programs. (a) This model does not require input or even a triggering device. It is based on a leaky sodium channel (pacemaker cell) that activates the neurons. Each neuron has an inhibitory connection to the other. As the depolarized neuron weakens, its inhibition also weakens and the other cell then Wres and inhibits the Wrst. One cell is connected to a Xexor (F) and the other to an extensor (E) muscle. This represents a truly internalized mechanism. (b) One way of building on this model is to have some kind of input to the command neuron (CN). This serves to make the system less autonomous. (c) Now the basic model receives input from many sources. The command neuron is no longer a pacemaker cell, and the system has lost its autonomy. Input circuits come from somatosensory regions, muscle spindles and Golgi tendon organs, and direct or indirect cerebellar input. Therefore, while the basic central mechanism has not disappeared, it cannot be easily detected because it has become heavily modulated by the rest of the brain. In essence, the brain has taken control of the central mechanism.

also known as pacemakers) to those that require some sensory input to modulate the program to the demands of the environment (Bullock, 1961; Willis, 1974; Barker and Gainer, 1975; Anderson, 1976).

In the evolution of mammalian brains, the mechanism of centrally generated programs did not disappear. Evidence of motor programming is found in Felis (cats) and primates, including humans (Bossom and Ommaya, 1968; Arshavsky et al., 1972; Pearson, 1976; Taub, 1976; Nashner, 1981; Grillner, 1985). However, they did lose their predominance, especially in the higher primates. Sensory systems have become more abundant and increasingly necessary to the normal operation of mammals. The shift to the larger primate brains (relative to body size) resulted in a new role for central programs. While still present for many behaviors, internalized programs became subordinate to the massive amount of sensory input that took over much of the control. Anthropoid brains have modulated the operation of the central programs to such an extent that it is diYcult to discern the presence of pattern generators. In mammalian brain evolution, sensory systems did not trigger the development of novel mechanisms but instead were integrated gradually into the existing protocols of genetic programs. The nervous system is conservative and generally has not invoked radical and abrupt changes; instead it has built up upon existing structures (Strumwasser, 1975).

In humans and other primates, there are direct corticospinal controls over the motor neurons of the spinal cord. Humans have monosynaptic contacts between the primary cortical motor area and the alpha motor neurons of the spinal cord (Carpenter and Sutin, 1983). The corticospinal tract in anthropoids has assumed an increasingly dominant role, especially compared with other primates (Nudo and Masterson, 1990). Central generators have a greater autonomy in organisms that lack a well-developed cerebrum. In encephalized mammals, the generators seem to get buried among the modulating sensory±motor systems (e.g., spinal motor units). Jerison (1977) considers the brains of some vertebrates as adapted to Wxed action patterns (in response to environmental stimuli) and to lack the plasticity of those in mammals with more complex sensory motor systems.

The development away from central programming was the result of the proliferation and complexity of sensory systems, which must have presented adaptive advantages. Kaas (1987) concluded that major evolutionary advances in the brain are marked by an increase in unimodal sensory areas but not an increase in association areas as often thought. Considerably more speciWc sensory information is being channeled into the existing association areas. It has been shown that humans do not have more association cortex than expected for a primate of our brain size

128M. F. Casanova, D. Buxhoeveden and G. S. Sohal

(Armstrong, 1990). In advanced brains, stimuli activate multiple cortical areas that are interconnected, and cortical areas tend to receive more direct sensory inputs (Kaas, 1987). For example, in the owl monkey, each Weld in the visual cortex, of which there are about 10, are interconnected with three to six other Welds in the same hemisphere. The individual Welds are also connected callosally with their counterparts in the other hemisphere. Added to this are subcortical connections to the pulvinar complex, the lateral geniculate nucleus, the claustrum, the basal ganglia, the superior colliculus, and the pontine nuclei (Weller and Kaas, 1983). Similar, if not more complex, interconnections are found in the temporal lobes of the primate (Galaburda and Pandya, 1983; Pandya et al., 1988). Based on clinical studies, the areas subserving Wernicke's speech area include Brodmann's area 13, 14, 15, 22, 39, 40, 41, 42, 44, and 45 (Kreig, 1963). Kaas (1987) further states that in less-advanced to moderately advanced mammals, sensory processing is the dominant cortical function, but most processing involves a single modality. In advanced mammals, there is co-activation from many cortical Welds (5±20) for even simple stimuli.

Plasticity and a prolonged maturation process

An event that seems to be occurring in the evolution of the human brain is the prolongation of maturation, which is not to be confused with neoteny. (Neoteny refers to the retention of fetal anatomy in development. For example, during the fetal stages the skulls of humans and monkeys are very similar, but whereas the adult human skull remains similar to its fetal anatomy, the skulls of monkeys and apes continue to change.) This prolongation of development might be part of the mechanism that allows the environment to interact with the ªhardwareº of the brain. The cortex does not develop simultaneously, but rather in stages. A cortical area is characterized by the types of cell that it contains, its external connections with other cortical and subcortical areas, and its internal connections. Laminar diVerentiation occurs Wrst, callosal and eVerent connections are next, thalamocortical connections follow, and the last is the microcircuitry of intracortical connections (Sur et al., 1990). This plasticity is manifested anatomically as well as functionally and, therefore, may be detected by various forms of neuroimaging.

One feature of the cortex that demonstrates anatomic plasticity is the radial column. These columns develop in the cortical plate (Rakic, 1978, 1988a,b) before lamination and are the Wrst anatomic organization of the cortex. There is overlap between the completion of lamination and thalam-

ocortical input, and the latter may inXuence the migration of neurons into the cortical plate (Rakic, 1976). In fact, there is already potential for environmental input at the earliest stages. The input/output connections of cortical cells are also susceptible to outside inXuences (O'Leary and StanWeld, 1989; Rakic, 1990; Rakic et al., 1991; Koester and O'Leary, 1992; O'Leary et al., 1992). Each stage has a period of time in which environmental input can modify the development scheme. This malleability occurs within the anatomic and physiologic determinants laid down by genetic factors. The use of quantiWed computer imaging of microscopic slides of tissue from the brains of individuals with Down Syndrome may have detected evidence that cell columns attain adult conWguration very early compared with normal tissue, i.e., by 4 years of age (D. Buxhoeveden, unpublished data). Cell column spacing was approximately 71% and 83% of adult volumes in normal 4- and 6-year-old children, respectively. These numbers Wt approximately the rate of expected brain size development in the normal brain where adult size is reached by the middle of the second decade (Dekaban and Sadowsky, 1978). One implication is a loss in the ability of cortex to learn or to adapt to new information to the same degree as possible in the normal brain.

It is not possible to consider one aspect (genetic or epigenetic) as truly dominant in large mammalian brains since they are co-dependent: the wiring of the brain dictates the nature, amount, and temporality of the sensory information input, which sets the range within which environment can act. The environment aVects cortical circuitry through aVerent inputs. Indeed, the plasticity of circuits has been demonstrated by rerouting sensory projections (Lund and Mustari, 1977; Jaeger and Lund, 1981; Chang et al., 1984, 1986), which shows that sensory axons will innervate other areas, even across sensory modalities, if there is a disruption of their normal target (Sur et al., 1990). There are simply not enough genes to permit a consideration of genetic control of behavior. Rather, clinical evidence indicates that cognitive functions are learned via the route of self-organization processes that assist the genetic blueprint. In this scenario, experience-dependent self-organization is an active dialogue between the brain and its environment.

O'Leary et al. (1992) suggested that the early cortex is devoid of area speciWcity and that a ªproto cortexº is generated by the neuroepithelium that has generalized features but lacks a rigid regional speciWcity. The degree of plasticity associated with the Wnal stage of cortical development (internal cortical microconnectivity) is critical because it will become the substrate for behavior.

AVerents greatly aVect the regulation of intrinsic cortical connections and possibly contribute to synaptic weights

and increased lateral inhibition. Therefore, epigenetic input can inXuence the Wnal design of the neural system (Teyler and Fountain, 1987).

Lateralization as evidence of internal reorganization in the language area

Lateralization represents one possible way to alter the organization of a given area without creating an entirely new one. Laterality in the cortex of humans represents a behavioral and morphologic reorganization within the brain. Lateralization creates inequality of spatial arrangements in conjunction with physiologic alterations. When a cortical area in one hemisphere is larger than the other, it displays lateralization. Rosen et al. (1989) found that when laterality is present the combined size of both hemispheric areas yields a smaller total size than when there is no lateralization. Symmetrical brains have relatively larger amounts of callosal Wbers, whereas asymmetric brains have a relative deWcit of callosal connections (Galaburda et al., 1987).Weiskrantz (1977) suggested that the mechanism for cerebral dominance revolves around the nature of callosal connectivity. Laterality not only causes inequality of neuronal space between the hemispheres but also can alter the nature of connectivity simply on the basis of the dendritic tree lengths and patterns and the horizontal distance between cellular columns (Seldon, 1981a,b). EVerents on the right side spread to more columns, but left hemisphere temporal association areas columns collect information from more aVerents (Seldon, 1981b). Scheibel (1984) noted that, during development, there is a greater increase in higher-order dendritic branches in the speech area on the left side than on the right side, which coincides with the beginnings of conceptualization and speech function. He noted that, in neonates, only the lower-order dendrites are present. Lateralization in the temporoparietal area of the temporal lobe in humans indicates a change in organization that relates, at least in part, to the evolution of language. Frost (1990) stated that initial lateralization may have been a consequence of handedness in conjunction with tool use, and that the neural reorganization served as a pre-adaptation for later development of language (Falk, 1980). Laterality of handedness and behaviors are present in extant primates (Sanford et al., 1984; Macneilage et al., 1987; Hopkins and Morris 1989; Hopkins et al., 1990; Dodson et al., 1992). Therefore, lateralization in the temporal lobe is not solely a function of language and handedness; it probably evolved much earlier than language.

In vitro computer imaging demonstrated that cell column morphology in human brains is markedly lateral-

ized. Human laterality at the cell column level is seen predominantly in the left hemisphere and consists of more horizontal separation between cell columns and more non-neuronal spacing in the periphery. This pattern is not found in the chimpanzee, which has left±right equality nor in the rhesus monkey. The mean diVerence in the horizontal distance between columns of the two hemispheres in humans is 16% and ranges from 6 to 23%. The rhesus brains exhibit slight laterality on the right side and display a pattern that is diVerent from the human pattern.

The shift in columnar morphology found in in vivo comparative histologic imaging studies from a monkey-like to a human pattern may be a result of the internal reorganization for language (Buxhoeveden et al., 1996). The implication is that this shift has been underway for a long time, though it is seemingly initiated by functions other than language. Evidence from fossil hominoids suggests the possibility that cerebral laterality extends as far back as the earliest human ancestors, the Australopithecines. Perhaps the more clearly deWned examples of cerebral laterality in the speech areas is found in Neanderthals such as La Chappelle-Sux-Saints Homo erectus fossils and Australopithecus africanus (Le May, 1976).

There is less disputed evidence that early Homo sapiens was persistently right-handed. This is derived from sources such as art works of 5000 years ago (Coren and Porac, 1977). Microscopic analysis of wear patterns on Upper Paleolithic tools (about 35000 years ago) indicate righthandedness. Tools from a few hundred thousand years ago (Middle Paleolithic) suggest the same (Keeley, 1977). Flakes manufactured by Homo habilis also suggest that the majority of users were right-handed.

Cases for bilateral symmetry (the absence of lateralization) are thought to be related to left-side dominance. In most studies, about 25% of human brains show little or no asymmetry in an area of the temporal lobe called the planum temporalis (Geschwind and Levitsky, 1968; Geschwind and Galaburda, 1985). Corbalis (1989) suggested that handedness is a response to bipedalism and the freeing of hands and subsequent tool use. In any case, there is no compelling reason to believe that the development of sophisticated language was present until around the time of the Upper Paleolithic ªrevolutionº, about 30000 years ago. Recall that human language involves the use of symbolism, self-aware- ness, and belief systems, not just basic communication (Gazzaniga, 1989). The evidence that behavior was complex enough to mimic modern human behavior is only found in the Upper Paleolithic age with the advent of symbolism, art, adornment of jewelry, ceremonial burial, and much more.

Laterality per se is not speciWc to the anthropoid human and can be found elsewhere in the animal kingdom. The

130M. F. Casanova, D. Buxhoeveden and G. S. Sohal

key to ascertaining the signiWcance of lateralization is to Wnd the peculiar form of lateralization utilized for a given area for a given species. Heilbroner and Holloway (1989) state that the left temporoparietal cortex, but not the right, started to change before the divergence of humans from the apes. Our research supports their view. It is even possible that the change began with the divergence of the apes from earlier Old World monkeys. Chimpanzees, which are perhaps the closest extant nonhuman relatives and which have some limited degree of linguistic ability, do not manifest a humanoid structural pattern for laterality. Yet, they also do not share the right-hemispheric emphasis that is present in rhesus monkeys.

As pointed out by Armstrong (1990), the presence of gross anatomic asymmetry in the posterior temporal regions is not a suYcient link to language because of the variations in human asymmetries and the presence of asymmetries in nonhuman primates. Most examinations of left Sylvian Wssural length consistently reveal left-sided laterality in humans and apes (LeMay and Geschwind, 1975; LeMay, 1976) and more recently in monkeys (Heilbroner and Holloway, 1989). (Apes are genetically and anatomically much closer to humans than are monkeys. In fact, apes are taxonomically much closer to humans than they are to monkeys and it is incorrect to refer to an ape as a ªmonkeyº.) Asymmetrical left Sylvian Wssural lengths in fossil hominoids must be interpreted with caution since they may reXect another aspect of laterality, i.e., handedness, instead of language. Hopkins (Hopkins and Morris, 1989; Hopkins et al., 1990) has pointed out that behavioral laterality can be found for many diVerent functions within primates, and that individual species manifest varying degrees of laterality. Language is only one aspect of asymmetrical neuronal distribution. Laterality is a generalized trait of the primate nervous system. However, laterality in nonhuman primates does not necessarily imply humanoid qualities. Further studies on prosimians and other monkeys should shed more light on this topic, particularly the speciWc role played by language-area asymmetry. It has been proposed that lateralization and language are causal elements in schizophrenia (Crow et al., 1989; Crow, 1997). Evidence from MRI indicate certain morphologic Wndings for schizophrenia that appear to be consistent; an enlargement of the lateral ventricles, reduction in brain volume, possibly smaller left temporal lobe volume, and generalized decrease or absence of cortical asymmetry (Crow, 1997; Buckley, 1998). There is an interesting model that synthesizes the evolution of language with the advent of psychosis (especially schizophrenia). It is hypothesized that there is a genetic basis for psychosis and cerebral asymmetry that is located on the sex chromosomes (Laval

et al., 1998). It is argued that the independent development of each hemisphere is concomitant with both language and schizophrenia (Crow, 1997), thereby linking language, evolution, and schizophrenia.

The circuitry of the brain has undergone many changes at all levels from the callosal Wbers that connect the two hemispheres, the interconnections between cortical and subcortical regions, to the microcircuitry of cell columns. Yet another indication of re-organization is the addition of new pathways. While a primary visual cortex may exist in two species, it may connect to 10 other areas in one species and to 15 in the other species. The trend in higher primate brains is to have far more intercommunication between sensory areas within their brains.

The unequal use of neurotransmitter pathways is another way that brain demonstrates lateralization. Asymmetry of neurotransmitters has also been documented in the mammalian brain in relation to motor and positional functions, especially with dopamine (Cabib, et al., 1995; Louilot and Choulli, 1997; Alonso, et al., 1997). A recent study seems to clearly support right hemisphere lateralization for dopamine. Dopaminergic neurons were found to be involved in aVective perception, suggesting hemispheric roles for aVective perception in normal and pathologic states (Besson and Louilot, 1995). Stress response may also be linked to asymmetrical dopamine systems (Carlson, et al., 1996; Sullivan and Gratton, 1998). Lateralization of noradrenaline (norepinephrine) in the olfactory bulbs of mice is also part of the generalized pattern of the asymmetrical distribution of neurotransmitters (Dluzen and Kreutzberg, 1996). Dopaminergic receptors are already lateralized in the fetal rat brain (Varlinskaya, et al., 1995). In humans, there is a growing body of evidence supporting early onset of laterality, including the asymmetrical distribution of metabolites in children (Hashimoto et al., 1995) and human growth hormones for handedness (Tan, 1995). Binding sites for sero- tonin-regulated gender diVerences, such as sexual behavior, aggression and impulse control, and serotonergic mental disorders were found to be sex-linked and asymmetrically distributed between hemispheres (Arato, et al., 1991). By comparison, other studies found no lateralization of serotonin (5HT2) receptor binding sites in human cortex (Yates et al., 1991).

Conclusion: genes and the environment

This chapter reviewed the development of the human brain from conception to adult age and its evolution across time and species. The combination of ontogenetic and

phylogenetic knowledge of the human brain can oVer insights into the mechanisms that can lead to neurodevelopment disorders. In fact, the editors of the Journal of the American Academy of Child and Adolescent Psychiatry have initiated a 1998 series of invited columns that cover brain development in recognition of its critical importance in understanding childhood psychiatric disorders.

The examination of comparative structural and functional anatomy of the brain among species can help in the understanding of the phylogenetic role of the processes that orchestrate brain development. Not only do these processes support the concept of evolution by natural selection (e.g., inXuences of environment on neurogenesis), but they also help place into perspective behaviors called ªmaladaptiveº that can be at the junction of evolutionary changes by being either obsolete or too precocious for the present time. For example, attention-deWcit hyperactivity disorder represents a set of behaviors that may be adaptive in a diVerent cultural milieu but are dysfunctional in our present society.

Disruption at any of the various steps of cortical development (neuronal migration, axonal formation, interneuronal connections) can result in disorders of higher brain functions, such as psychiatric disorders. Symptoms may appear only later in life when the higher cortical function is developmentally ready to be used (e.g., language, reading skills). Subtle disruptions of neuronal migration and synaptic formation have been proposed for disorders such as dyslexia and psychosis.

Genetic programs are the necessary (but not suYcient) factors that control brain development. Genes that contribute to the early events of brain development are being discovered, and it is possible that variants of these genes may be responsible for various developmental disorders. For example, one such gene, LS1 on chromosome 17, was shown to regulate the early migration of neurons, and its defect leads to lissencephaly: disorders of brain formation in which the surface of the cortex appears smooth. How this genetic defect results in disturbances of neuronal migration is not fully understood. Mutant mouse strains, reared on the basis of abnormal behavior, have been useful in identifying molecular mechanisms underlying brain development. For example, the ªreelerº gene, responsible for an abnormal laminar pattern of the cortex, was recently cloned.

Abnormality in the regulation of gene expression (e.g., how often, how much, how long, or at what developmental period a gene (DNA) is transcribed into a protein (RNA)) is another mechanism that can induce developmental disorders. This regulation is assumed by transcription factors. These transcription factors are proteins that bind to the

ªpromoterº region of the gene. The promoter region regulates the initiation of transcription. Disruption of the regulatory function of transcription has been linked to neuropsychiatric disorders such as Waardenburg syndrome, Prader±Willi syndrome, and fragile X syndrome. Many transcription factors are expressed in the brain. Often their patterns of expression respect boundaries of brain structures (e.g., dlx-1 and dlx-2 are expressed in the developing basal ganglia, hox in the hindbrain, engrailed genes in the cerebellum and midbrain; emx and otx in the cerebral cortex). Regionally limited brain abnormalities detected by functional neuroimaging studies can help the molecular geneticist to focus a search to speciWc genes that control the development of the identiWed regions. Defects in these genes can induce regionally speciWc abnormalities in given cell types, or in the ªwiringº within the brain. Current theories propose that disruption in transcription factors plays a critical role in common psychiatric disorders.

Once the genetic program is in place (the necessary component to brain development), the environment contributes to the molding and consolidation of the developing brain. Indeed, environment inXuences the forming and strengthening of synaptic connections, which is mediated by growth factors. Recently, it was shown that early experiences can change cortical rearrangements and that these changes last into adulthood. Clearly, environmental events can signiWcantly aVect brain development during critical periods of maturation (e.g., windows of increased plasticity, increased vulnerability to insult, or opportunity for enrichment or treatment).

Brain maturation is a protracted process throughout childhood. Clearly, functional neuroimaging early in life has a better chance to clarify the trajectories of brain development and to help to trace back the normal and deviant maturational processes that underlie neuropsychiatric disorders. Genetic mechanisms need to be explored, and functional neuroimaging and molecular biology research conducted in synergy can optimize our understanding of the origin of brain disorders.

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