There is a great need to understand the fundamental bases of complex behaviors such as language, memory, attention, music, emotion and affect, mathematical thinking, executive functions, visual cognition and mental imagery, and consciousness. These behaviors arise from intricate, developmental, and on-line interactions between genes and environment, having their ultimate effects at the molecular level. This understanding is difficult to achieve, as the interrelationships between genes and environmental factors that control the serial and parallel molecular events that build, adapt, and maintain the extremely complex neural structures that support these behaviors are great. The ultimate promise of neurogenetics research is the understanding of at least part of the molecular basis of behavior, which has to do with the influence of hard-wired genetic factors. As before in the history of this field, the study of disorders, in this case genetic disorders, is a reasonable start.

Identification of the genes and downstream events that lead to mental retardation and affective disorders will doubtlessly be invaluable in the diagnosis, treatment, and even prevention of human genetic disorders, with the desirable added effect of shedding light on the normal biology of behavior and cognition. There is a dearth of information about the participation of specific brain regions—and combinations thereof—in complex behaviors, which provides the opportunity for linking genes to behavior via the study of the brain. Thus, the brain represents the halfway point between genes and behaviors, and the first challenge is to understand how the brain is built from the functions of genes and their interactions with the early environment. At the same time, it is increasingly possible to link brain and behav-

From: Contemporary Clinical Neuroscience: Genetics and Genomics of Neurobehavioral Disorders Edited by: G. S. Fisch © Humana Press Inc., Totowa, NJ

ior, the other half of the trajectory. In addition to the traditional analysis of effects of focal brain injury, this is accomplished by using techniques of modern cognitive neuroscience, including structural imaging as well as activating and mapping techniques, which permit a more complete picture of the participation of the neural components involved in behavior. These, coupled with advances in cellular, molecular, and systems neurobiology using whole animal and tissue models, optimistically helps to round off the knowledge necessary for going from genes, through brain, to behavior.

Decades of research have revealed that the interaction between gene and brain can be quite complex and nonlinear. Furthermore, the effect of (aneu-ploidy) haploinsufficiency for even a single gene can have dramatic and widespread effects on brain structure and function. Neuroanatomical differences associated with neurobehavioral disorders resulting from genetic abnormalities encompass virtually every morphologic anomaly imaginable, from the microcephaly of Down syndrome, through the specific neuronal migration anomalies associated with the 7p13.3 deletion associated with the Miller-Dieker malformation, to the relatively targeted striatal atrophy of Huntington's disease. It cannot be assumed that a smaller brain is bad or a larger brain size (or portion thereof) is advantageous, as normal variation and some pathological conditions demonstrate. The writer Anatole France, for instance, seems to have had a small brain. Conversely, the fragile X syndrome is associated with increased brain volume in the presence of significant behavioral anomalies. Further, the possible mechanisms by which a gene may exert its influence on the brain are numerous. For example, a gene may produce a protein with a direct role in synaptic transmission during on-line execution of behavior, may be required for building a specific structure during neural development at a critical time point, or may be a transcription factor responsible for the expression of other genes. Thus, a single change in the molecular structure of a gene could, in principle, produce myriad downstream neuroanatomical effects that, at first glance, have no apparent relationship to one another.

Equally daunting is interpreting the relationship between neuro-morphology and behavior. Most studies investigating the neural substrates of behavior show that even a "simple" cognitive function or emotion can be immensely complex in its degree and pattern of brain involvement when compared to elementary sensory and motor processes. Further, unlike those neurologic diseases in which the symptoms are motoric or sensory, cognitive behavior often involves more widespread brain loci with significant individual variability. For example, it is not uncommon to find a brain lesion that produces cognitive loss in one patient and a different loss or nothing at all in another. Conversely, it is not uncommon to see similar behavioral profiles in two patients with different brain lesions. Thus, determining how and which of several behaviors is linked to a specific lobe, convolution, or cytoarchitectonic region can be problematic. Then there is the effect of learning and the environment, which modify the effects of lesion and change the expression of genes. A given language, for instance, because of its peculiar phonological properties, may be more or less resistant to the effects of genes that cause dyslexia, or may modify the details in aphasia-producing brain lesions. Or, a longer experience with formal education may modulate the time of clinical onset of Alzheimer's disease in a given patient.

Despite intellectual and methodological obstacles toward understanding the genetic impact on brain and behavior, the advent of modern neuroscience has brought impressive advances to the field of neurobiology. Improvements in cellular and molecular methods, such as patch clamping, high-resolution microscopy, hybridization, and cloning, have provided the well established fields of histology and cellular and molecular neuroscience with new tools to elaborate on their discoveries. The ongoing characterization of genetic sequences has allowed construction of probes that react with brain tissue with increasingly greater specificity, as well as construction of mouse models for genetic disease. In addition, the invention of positron emission tomography (PET) and structural and functional magnetic resonance imaging (MRI and fMRI) have allowed the in vivo investigation of brain structure and function in cognitive and behavioral disorders, including neurodevelopmental disorders, in addition to increasing our knowledge of normal brain function.

This chapter is an attempt to explore several neuroanatomical considerations specific to the examination of neurodevelopmental disorders. We describe herein several approaches toward a common goal: the discovery of the connections between gene, brain, and mind. In our presentation, we review some of the current advances in the field, discuss advantages and disadvantages of each approach, and try to provoke new thinking about how to proceed in this area of research.

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