Alcohol Is a Teratogen That Can Slip Through the

Children prenatally exposed to booze can endure from serious cognitive deficits and behavioral problems as well equally from alcohol-related changes in encephalon structure. Neuropsychological studies have identified deficits in learning and memory also every bit in executive functioning both in children with fetal alcohol syndrome and in children with less severe impairments. Both groups of children also exhibit problem behaviors, such equally alcohol and drug apply, hyperactivity, impulsivity, and poor socialization and communication skills. Brain imaging studies take identified structural changes in various brain regions of these children including the basal ganglia, corpus callosum, cerebellum, and hippocampus that may business relationship for the cognitive deficits. Functional brain imaging studies besides have detected changes in booze-exposed children indicative of deficits in data processing and memory tasks. Cardinal WORDS: fetal alcohol syndrome; prenatal alcohol exposure; teratogenesis; encephalon imaging; neuropsychological assessment; cognitive and memory disorder; basal ganglia; corpus callosum; cerebellum; hippocampus; electroencephalography; magnetic resonance imaging; positron emission tomography; single photon emission computed tomography

Prenatal alcohol exposure can have serious and permanent adverse furnishings on children. The extent and severity of a child' south condition depends on several factors, such as how much booze the pregnant female parent consumed and how often and at what point during her pregnancy she drank. The most serious outcome is fetal alcohol syndrome ( FAS) , the diagnosis of which is based on three criteria: ( i) growth deficiency manifested past minor overall acme and small head size ( i. east. , microcephaly) ; �(2) central nervous system disorders; and ( 3) a distinctive pattern of abnormal facial features. Other children with histories of heavy prenatal booze exposure, withal, often exercise non meet the diagnostic criteria of FAS. These children, who typically lack the feature facial features of FAS, accept variously been labeled as having fetal alcohol effects ( FAE) , alcohol-related neurodevelopmental disorder ( ARND) , or prenatal exposure to booze ( PEA) . Both children with FAS and those with related disorders tin exist born to women known to drink in a heavy episodic manner or more regularly during pregnancy. For the remainder of this article, children with histories of prenatal alcohol exposure who do non encounter the diagnostic criteria of FAS are referred to as either having FAE or PEA. When available, data from such children are noted; otherwise, the results presented in this article refer to children diagnosed with FAS.

Children with histories of heavy prenatal alcohol exposure bear witness testify of changes in brain structure and function as well as a multifariousness of behavioral effects presumably resulting from this insult to the brain. Virtually of the research conducted amid alcohol-exposed children and adolescents has focused on either the structural or behavioral furnishings. Only recently accept studies begun to demonstrate the human relationship between the two areas that changes in encephalon construction could negatively touch on behavior. This article summarizes the results of neuropsychological studies analyzing alcohol' southward teratogenic ( i. e. , damaging to the developing fetus) effects on behavior and of encephalon imaging studies analyzing booze' southward effects on brain construction. It and then highlights the existing connections between those ii areas of research. For more than extensive coverage of these topics, the reader is referred to review articles by Mattson and Riley (1998) and Roebuck and colleagues (998) .

Results from Neuropsychological Studies

Generally, heavy prenatal alcohol exposure is associated with deficits in a wide range of areas of role, including both cerebral functioning ( e. thousand. , general intellectual performance, learning of new verbal information, and operation on visual-spatial tasks) and fine-and gross-motor operation. Neuropsychological studies accept analyzed the cerebral harm of children with histories of prenatal alcohol exposure. Although many of these studies have focused on children diagnosed with FAS, several analyses accept included children with FAE or PEA. Importantly, many studies show that strong similarities exist between children with FAS and children with FAE/ PEA.

For example, studies of overall cognitive ability in FAS children typically written report average IQ scores in the borderline range of functioning ( i. e. , in the low 70s) , although they tin can range from intellectually deficient ( ( IQ scores less than lxx) to average ( IQ scores between 90 and 109) . Children with FAE or PEA also show deficits in IQ scores, although these deficits typically are not as severe as in the children with FAS (Streissguth et al. 1991; Mattson et al. 1997) .

In addition to overall intellectual or cognitive deficits, researchers have evaluated a wide range of cognitive functioning areas in children with FAS, FAE, or PEA, including language skills, visual-spatial performance, fine-motor behavior, nonverbal learning, and academic performance. In general, alcohol-exposed children both with and without FAS prove significant impairments in all neuropsychological areas with few qualitative differences observed betwixt the FAS and PEA/ FAE groups. Similarly, loftier levels of prenatal alcohol exposure are related to an increased risk for cognitive deficits across a range of functioning areas, which again tin occur in children both with and without a diagnosis of FAS.

Learning and Memory

Both anecdotal information and results from beast studies take indicated that prenatal booze exposure can affect learning and memory. Studies of children with FAS generally have supported this observation, although the deficits in retentiveness may not be every bit global every bit was once thought. For example, one report investigated verbal learning and memory in children with FAS and in non-alcohol-exposed command children ( Mattson et al. 1996 b ) . The study establish that although the FAS children demonstrated some deficits in memorizing verbal data, these deficits resulted from difficulties with the acquisition of the data rather than with the ability to think the data over time. Other studies also have revealed like deficits in the conquering of nonverbal information in booze-exposed children ( Mattson and Roebuck in printing) , suggesting that learning deficits occur in both exact and nonverbal arenas and are probable to crusade significant impairment in diverse areas of functioning. It is unclear, even so, whether the degree of harm for each child differs between the verbal and nonverbal areas of function.

Some studies advise that children with FAS can perform well when retentivity role is tested in a unlike manner, for case in tests of implicit memory a blazon of memory that is not under conscious control. When subjects successfully perform implicit retentiveness tests, they may utilize information from previous tasks without being aware that they have done then. In one study, investigators showed children with FAS lists of words and asked the children to rate those words on likeability ( Mattson and Riley 1999) . ( This rating component served to enhance the children' s attention to the words. ) Afterwards in the testing session, the children were asked to consummate fractional words ( eastward. g. , MO or SM) with the first word that came to mind ( e. g. , MOUSE or Smile) . The children were not reminded of the previous words nor prompted to remember them by the examiner. Even so, both FAS and command children were more likely to complete the fractional words with words from the previous task than with new words. These results indicated that both groups of children used implicit memory and that prior exposure helped them learn and memorize the words. Taken together, these findings propose that although children with FAS may take significant impairments in learning new information, their overall memory office is complex and may not be as globally affected equally was commonly thought. Nonetheless, specific aspects of memory may be affected past prenatal alcohol exposure.

Executive Functioning

The term "executive performance" refers to a group of higher-level cognitive abilities, such as solving problems, thinking abstractly, planning ahead, and existence flexible in one' southward thought processes. These types of skills are independent of overall intellectual part and influence whether and in what manner a person can complete a chore. Conversely, tests of other cerebral abilities tend to appraise how well, or at what level, a person performs a skill ( Lezak 1995) . ( For more information on executive performance and the effects of prenatal alcohol exposure on these skills, see the article in this issue by Kodituwakkuand colleagues, pp. 192 198. )

Children with heavy prenatal alcohol exposure ( both with and without FAS) have demonstrated impairments on executive functioning tasks ( Kodi � tuwakku et al. 1995; Mattson et al. 1999) . Importantly, in these studies the children' s deficits in executive function were unrelated to their overall intellectual levels. This finding is supported past a recent report among adults with FAS or FAE, which found that the subjects deficits in executive functioning were greater than would have been predicted if they were related to overall IQ scores ( Connor et al. in press) .

Deficits in executive functioning can accept real-life implications for people prenatally exposed to booze. For example, people with heavy prenatal alcohol exposure may act without starting time considering the consequences of their behavior or they may have difficulties with activities that require problem solving or with planning a sequence of activities. These types of deficits may explicate why children with heavy prenatal booze expo-sure, fifty-fifty those with average IQ scores, have difficulty succeeding in school.

Psychosocial Deficits and Problem Behaviors

Studies involving parent reports and interviews have suggested that alcohol-exposed children with or without FAS non merely have cognitive deficits merely likewise are at loftier risk for problem behaviors that tin interfere with their participation in home, schoolhouse, and social environments. For example, these children appear to be at increased gamble for psychiatric disorders, trouble with the police, alcohol and other drug abuse, and other maladaptive behaviors ( Streissguth et al. 1996) . Moreover, they are more likely than non-alcohol-exposed children to be rated every bit hyperactive, disruptive, impulsive, or delinquent ( Roebuck et al. 1999; Mattson and Riley 2000) . Similarly, on measures of adaptive power and skills necessary to perform age-advisable daily living activities, adolescents and adults with FAS often exhibit poor socialization and communication skills. In addition, the bulk of these adolescents and adults display significant maladaptive behaviors ( e. chiliad. , impulsivity) and are less likely to exist living independently ( Streissguth et al. 1991; Thomas et al. 1998) . It is noteworthy that these problems occur in people prenatally exposed to alcohol whether or not they run into the criteria of FAS and occur to a greater extent than would exist predicted by the person s full general intellectual functioning or demographic factors.

Results from Encephalon Imaging Studies

The neuropsychological and behavioral deficits described in the previous section stand for real-life manifestations of the effects of prenatal alcohol exposure. Although deficits on these measures are thought to provide evidence of underlying changes in brain structure or function, they represent but indirect measures of such brain changes. Booze' south directly effects on brain development were already noted in the earliest reports of FAS ( Jones et al. 1973) , however, and autopsy studies of brains from people with FAS noted numerous and wide-spread brain abnormalities. Because these cases represented only the nearly severely affected children, it is problematic to generalize the findings to all people living with FAS. With the advent of numerous structural imaging techniques, such every bit magnetic resonance imaging ( MRI) , and functional imaging techniques, such as electroencephalography ( EEG) , positron emission tomography ( PET) , and single photon emission computed tomography ( SPECT) , however, researchers tin now written report the living brains of alcohol-afflicted children in a relatively noninvasive manner.

Structural Brain Imaging

Imaging studies using MRI take revealed several differences between the brains of alcohol-exposed and non-exposed individuals. Consistent with the characteristic small head size, which is i of the diagnostic criteria for FAS, imaging studies show a decrease in the over-all size of the encephalon of FAS children (Roebuck et al. 1998) . To determine whether this size reduction results from global and diffuse alcohol furnishings on all brain areas or is limited to specific regions, researchers take assessed specific structures in proportion to overall brain size. This arroyo tin make up one's mind whether specific, asymmetry-ate reductions occur in some encephalon areas. These investigations take focused on several brain areas, including the basal ganglia, corpus callosum, cerebellum, and hippocampus (see figure 1) .

Figure1: Brain areas affected by prenatal booze exposure.

Basal Ganglia. The basal ganglia are a grouping of nerve jail cell clusters ( i. e. , nuclei) , including the caudate nucleus, putamen, and globus pallidus. They are involved in motor abilities and cognitive functions, such as the executive functions described earlier. MRI studies have revealed that the basal ganglia are affected by heavy prenatal alcohol exposure and are unduly reduced in volume in children with FAS and PEA. More de-tailed examination of the components of the basal ganglia found that the reductions are not uniform and that the caudate nucleus appears to account for most of the size reduction in the basal ganglia ( Mattson et al. 1996 a ; Archibald et al. 2001) .

The caudate nucleus is the portion of the basal ganglia involved in cognitive functions. For example, skills such as the power to shift from i task to another, inhibition of inappropriate behavior, and spatial retentiveness, which are dumb in people with prenatal alcohol exposure, have been related to the basal ganglia in other populations, such as patients with Huntington' s affliction ( Mattson et al. 1996 a ; Mattson and Riley 1999; Archibald et al. 2001) . Accordingly, it is possible that the reductions in the caudate nucleus account for some of the cognitive deficits seen in people with prenatal alcohol exposure. This hypothesis is particularly highly-seasoned because the caudate nucleus likewise has extensive neural connections to the frontal lobes of the brain, which traditionally are idea to mediate higher cognitive and executive functions.

Corpus Callosum. The corpus callosum is a big bundle of nervus fibers connecting the two hemispheres of the brain, thereby allowing the left and right sides of the brain to communicate with one another. Corpus callosum abnormalities take been linked to deficits in attending, intellectual functioning, reading, learning, verbal memory, and executive and psychosocial performance, all of which are impaired in booze-exposed people. MRI studies and dissection reports suggest a vulnerability of the corpus callosum to prenatal alcohol exposure; such studies found that people with FAS exhibit abnormalities ranging from a thinning to complete absence ( i. e. , agenesis) of the corpus callosum ( Roebuck et al. 1998) . When specific regions of the corpus callosum were analyzed, researchers establish that the front-most expanse the human knee and the dorsum-most areas the isthmus and splenium were unduly reduced in size ( Riley et al. 1995) . Moreover, the charge per unit of agenesis of the corpus callosum may be higher in people with FAS than with whatsoever other developmental disorder ( Jeret and Serur 1991; Riley et al. 1995) .

Recently, researchers analyzed in more item the shape and location of the corpus callosum of FAS and PEA children also as of control children ( Sowell et al. 2001) . The report not only confirmed that the corpus callosum was reduced in size, specifically in the splenium, just that information technology was also significantly displaced in three-dimensional space ( see figure 2) . After equalizing all brains for brain size and the location of other structures located forth the midline of the brain, the boilerplate location of the corpus callosum for the alcohol-exposed children was compared with the average location for the command children. This analysis constitute that the corpus callosum in the alcohol-exposed children was displaced compared with the control children, with the biggest differences in the area of the isthmus and splenium, both of which are located in the back of the corpus callosum. Furthermore, this corpus callosum deportation was highly related to the� �children's performance on a verbal learning task. In other words, children with greater displacement exhibited more than substantial performance impairments.

Figure two ( Top) Boilerplate outlines of the corpus callosum ( i. due east. , the bundle of nerve fibers connecting the brain s right and left hemispheres) in alcohol-exposed subjects ( ALC) and non-alcohol-exposed control subjects. The corpus callosum is oriented and so that the front of the head is to the correct and the back of the head is to the left. The effigy shows that the corpus callosum of the ALC is displaced in iii-dimensional space compared with that of the control subjects, with the greatest displacement occurring in the isthmus and splenium at the back of the corpus callosum. ( Lesser) A map showing the average deportation in millimeters between the ALC and the control subjects. Darker area ( see arrow) indicates greater deportation between the two groups. Greater displacement is associated with greater performance harm in certain tasks.
SOURCE: Figure courtesy of Dr. Elizabeth Sowell.

Cerebellum. Another area of the brain that is affected past prenatal alcohol exposure is the cerebellum, which is involved in both motor and cerebral skills and is located at the base of the brain. For example, damage to the cerebellum has been implicated in learning deficits likewise as in rest and coordination, all of which are impaired by prenatal booze exposure. A contempo study found that the overall book of the cerebellum was disproportionately reduced relative to overall brain size in people with FAS compared with control subjects ( Archibald et al. 2001) . These findings partially replicate previous reports of reduced cerebellar size in FAS and PEA children ( Sowell et al. 1996) . In addition to the overall reductions in the size of the cerebellum, studies conducted in both humans and animals suggest that a specific region of the cerebellum the anterior portion of the cerebellar vermis is peculiarly affected by booze exposure earlier or shortly after birth¹ (Goodlett et al. 1990; Sowell et al. 1996) ( ¹ The studies in animals, primarily rodents, were conducted shortly afterward nascence, a menstruation that corresponds to the tertiary trimester of gestation in humans with respect to brain development).

Hippocampus. The hippocampus is a structure that lies deep within the temporal lobe of the brain and is involved in memory. Although the precise function of the hippocampus in specific aspects of retention is controversial, it probably plays a role in the consolidation of memories. For example, in adults with hip �pocampal harm, the about obvious upshot is a loss of the power to store new memories ( i. e. , anterograde amnesia) . Brute studies have long suggested that this area is affected by prenatal booze exposure ( Berman and Hannigan 2000) . Moreover, an MRI report of children with FAS documented volume asymmetries in the hippocampus, with the absolute volume of the hippocampus in the left temporal lobe smaller than that of the respective area in the right temporal lobe ( Riikonen et al. 1999) . Although such differences also exist in adults with normal neurological office, the extent of the disproportion was greater in the FAS children than in the control children. Conversely, another study found that the hippocampus was less afflicted than some other encephalon regions in FAS children ( Archibald et al. 2001) . In that study, the reduction in the volume of the hippocampus was proportionate to the reduction in overall brain size, whereas other brain areas showed greater reductions in volume.

Behavioral studies have supported the hypothesis that the hippocampus might exist affected in children with prenatal alcohol exposure. For example, people with prenatal booze exposure accept been reported to exhibit deficits in spatial memory as well as other retentiveness functions associated with the hippocampus ( Uecker and Nadel 1996) . Withal, the memory deficits in alcohol-exposed children crave more detailed written report and should exist integrated with information about the integrity of the hippocampus. This outcome too points out a limitation of structural imaging, namely that this approach only determines the size of a particular brain structure merely does non point whether the structure is operation correctly. To determine how a particular brain area functions under dissimilar conditions and whether these functions are altered past prenatal booze exposure, researchers are turning to functional encephalon imaging approaches, discussed in the post-obit section.

Functional Encephalon Imaging

Functional imaging techniques allow researchers to report how the brain works, either at rest or when presented with a task. Because some functional techniques are more invasive or technically difficult to conduct with children, only a small number of studies using these techniques have been conducted in FAS children. The most commonly used technique in these studies is electroencephalography ( EEG) .

EEG. The EEG measures the brain s spontaneous electrical activeness past recording signals from the brain with electrodes placed on the scalp. These signals can exist visualized as waves with specific frequencies, such as alpha, beta, and theta waves. Early studies on infants suggested that EEG may be a sensitive measure out of changes in brain role resulting from prenatal alcohol exposure (Ioffe and Chernick 1990) . More recent studies of children and adolescents with FAS found that approximately half of these subjects had clinically suspect EEG readings ( Kaneko et al. 1996 b ) . Furthermore, subjects with FAS exhibited reductions in the power or strength of the alpha frequencies, which is the predominant type of activity when a person is relaxed. These reductions were seen predominantly in the left hemisphere and advise immature brain activity.

Using like techniques, information technology is possible to mensurate the brain south electrical response to specific sensory stimuli ( i. e. , result-related potentials) . These issue-related potentials can be visualized as spikes in certain brain waves. One of these spikes is chosen P300, because information technology typically occurs approximately 300 milliseconds after the stimulus; it appears to reflect the cerebral aspects of information processing. Using EEG analyses, researchers establish that the P300 spikes occur with a delay ( i. e. , have a prolonged latency) in a certain brain region, the parietal cortex, in FAS children ( Kaneko et al. 1996 a , b ) . This finding suggests that children with FAS may have deficits in information processing. Thus, electrophysiological measurements are powerful tools in the study of FAS; future studies combining them with localizing brain imaging may provide further data nearly brain function.

PET. The PET technique allows researchers to monitor the activity of specific brain regions by generating images of metabolic or physiologic processes, such as blood flow or breakup of sugar molecules, in the tissue. For this arroyo, the bailiwick is injected with small amounts of radioactive material so that encephalon activity in the region of interest can exist measured while the subject performs a job. These tasks tin can range from the simple, such every bit moving a finger, to the complex, such every bit recalling information. One PET study assessed encephalon activeness in adolescents and adults with FAS who showed no astringent mental retardation ( i. eastward. , who were loftier performance) . The study revealed reduced metabolic activity in the caudate nucleus and in the thalamus when the subjects were at residuum ( Clark et al. 2000) . These functional data support the structural data, such every bit the reduced size of the caudate nucleus, suggesting that subcortical brain regions may exist especially sensitive to prenatal alcohol insult.

SPECT. The SPECT technique is similar to PET, and although it is less powerful, information technology is more ordinarily available. Notwithstanding, only one written report of FAS children has used this technique. In that study, the investigators found that FAS children exhibited similar metabolic activeness in both hemispheres of the brain ( Riikonen et al. 1999) . Normally developing children, in contrast, show greater resting activeness in the left hemisphere than in the correct hemisphere. These results are consistent with the EEG findings described in a higher place and may support verbal or linguistic communication deficits in FAS children.

Functional Magnetic Resonance Imaging ( fMRI) . The newest functional technique used to study activeness in the living brain is fMRI. Its main reward is that information technology is less invasive than PET or SPECT because it does not involve injecting the subject field with radioactive substances; moreover, it is more ordinarily avail-able. Similar to PET and SPECT, fMRI allows researchers to visualize encephalon reports be of fMRI studies in people with prenatal alcohol exposure; nevertheless, such studies are currently underway. One preliminary report described an fMRI study of working memory using information held in memory for a curt period of time in 4 adults with FAS or FAE ( Connor and Mahurin 2001) . The study revealed activation in an area chosen the dorsolateral prefrontal cortex in the FAS subjects but non in control subjects. This area is idea to play a role in college cerebral functions, such as the executive functions described to a higher place. This event suggests that the working retentiveness task was more difficult for the alcohol-exposed subjects and required greater involvement of this region of the frontal lobe compared with the control subjects.

New Prototype Analysis Techniques

In addition to improvements in brain imaging techniques, new means of analyzing the data obtained with these techniques are providing scientists with insights about the dissentious effects of prenatal booze exposure. One of those techniques is called encephalon mapping. Information technology uses a structural MRI assay simply provides greater visualization of all brain structures. As a event, researchers can study the whole encephalon at once, rather than focus on specific brain regions, and therefore tin can localize brain abnormalities more easily than with previous techniques.

Sowell and colleagues ( 2001 b ) have used the encephalon mapping technique to analyze and compare encephalon images of people with FAS or PEA and not-booze-exposed control subjects. Consequent with the results of Archibald and colleagues ( 2001) , the report detected disproportionate reductions in the brain s white matter, which contains the nerve cells extensions (i. e. , axons) that connect nervus cells with each other. Conversely, the brain' s greyness matter, which contains the nerve prison cell bodies, showed reductions that were not as not bad. In improver, the parietal lobe, which is involved in visual-spatial processing and in the integration of sensory data, appeared to be especially susceptible to alcohol' southward effects. Thus, once overall brain size was deemed for, both the volume ( Archibald et al. 2001) and the density ( Sowell et al. 2001 b) of white affair in this region were significantly reduced ( see figure 3) . Conversely, the gray affair density in the parietal cortex was significantly increased ( Sowell et al. 2001 b ) . These findings lend additional back up to the proposition that booze due south outcome on the developing encephalon is not global in nature but, rather, affects specific encephalon regions selectively.

Figure 3 Changes in brain tissue density in children with heavy prenatal alcohol
exposure. A representative brain is shown with the back of the brain facing
the reader s right. Encephalon-mapping studies detected areas of increased
gray matter density ( shown in xanthous on the left) as well as areas of reduced
white thing density ( shown in red on the right) in the parietal lobe.
SOURCE: Figure courtesy of Dr. Elizabeth Sowell.

Hereafter Directions

The studies reviewed here provide clear evidence that both brain structure and brain office are affected by heavy prenatal alcohol exposure. More than recent studies betoken that the effects of this alcohol exposure are not global in nature but seem to bear on sure areas more than others in both the neuropsychological and neuroanatomical arenas. Continuing studies are focusing on the relationship between neuropsychological and neuroanatomical data and hopefully will outcome in a clearer motion picture of the strengths and weaknesses of people with a history of heavy prenatal alcohol exposure, thereby allowing researchers and clinicians to develop more than targeted and effective intervention approaches.

Acknowledgments

The authors admit the assistance of Dr. Elizabeth Sowell.

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