MRI volumetry

Table 15 shows the absolute and relative volumes of the groups. The intracranial volume was significantly smaller in the FAS/FAE cases than in the control subjects (p  .000). When laterality (left/right) in different groups (FAS/FAE vs. control subjects) was analyzed with analysis of variance (ANOVA), the following significant differences were found: the absolute volumes of all nuclei were smaller in the FAS/FAE group than in the control group (amygdala p  .001, hippocampus p  .002, nucleus caudatus p  .006, putamen p  .001). There was a significant difference in hippocampal volumes between the left and right hemisphere; the right hippocampus was larger than the left one in both groups. There were also no statistical differences in this asymmetry between groups.

There were also no significant differences between the groups or gender after normalization. Importantly, the right hippocampus was larger than the left after normalization in both groups (p  .003).

8.4.3 SPECT

Serotonin and dopamine transporter binding in different brain areas in the FAS/FAE patients and in control children are shown in Table 16. In the MFC, SERT binding was lower than in control subjects (p  .02), Figure 12. In basal ganglia, DAT binding was higher than in the control subjects (p  .03) (Table 16, Figure 13).

There was a significant negative correlation between internal- ization score and striatal DAT specific binding (r  .65; p  .02) (Figure 14). Figure 15 shows the regression analysis between DAT specific binding and normalized striatal volume. No significant correlation was found.

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Figure 12. Serotonin transporter binding in children with FAS/FAE and control children. SERT was significantly lower than in the patients

compared with control subjects (p=.02). Abbreviations: M: mean value; FAS:

fetal alcoholsyndrome; FAE, fetal alcohol effects

Figure 13. Dopamine transporter binding in children with FAS/FAE and in the control children. DAT was slightly higher (p=.03) in the patients

compared with control subjects. Abbreviations: M: mean value; FAS: fetal alcohol syndrome; FAS: fetal alcohol effects.

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Figure 14. Linear regression between the DAT binding and internal score.

Figure 15. Linear regression between the striatal DAT binding and normalized volumes. Although the correlation did not reach a statistical significance in this small patient population, it indicates that the normal striatal DAT binding is involved in greater (=normal) striatal volume.

8.5 DISCUSSION

This study included 12 children aged 5 to 16 years who were exposed to ethanol before birth. All had dysfunction of the CNS. The combination of tests clearly demonstrated permanent CNS involvement. The overall range of IQ was between 39 and 100. Mild to moderate mental retardation was seen in four children. All had attention-deficient disorder.

8.5.1 MRI volumetry

All children with FAS/FAE had a small absolute volume of the brain. The absolute volumes of midbrain nuclei, amygdala, nucleus caudatus, and putamen were smaller than the control subjects. When relative volumes were compared with the control subjects, however, no significant

differences were found. Hippocampal asymmetry was seen in the sense that the left h pocampus was smaller than right (p  .003). This asymmetry was seen also in the control group, and there were no significant

differences between groups in this asymmetry. The left-right asymmetry was larger than normally seen in adults (up to 10%) (Kalviainen et al., 1998;

Pennanen et al., 2004). Riley et al. (Riley, E., Barron, & Hannigan, 1986) suggested that many behavioral deficits resembling

attentiondeficit/hyperkinetic disorder (ADHD) commonly seen in FAS/ FAE children may be attributed to the morphological changes in the

hippocampus. The left-right dominance was lacking in an earlier brain perfusion SPECT study in children with FAS (Riikonen et al., 1999) and in the study of Autti-Rämö et al. (Autti-Ramo et al., 2002) in which 3 of 17 children had small hippocampus on the left side. This would mean an impairment of the function of the left hemisphere. However, our present study did not confirm this hypothesis, and in the recent study of Archibald et al.

(Archibald et al., 2001), no changes in the temporal lobe in the subjects mixed with FAS andFAE could be seen. In the FAS group, excluding FAE, hippocampal volumes were even proportionally larger than in control subjects.

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8.5.2 SPECT

To our knowledge, this is the first report of serotonin and dopamine

transporter binding in FAS/FAE children. Our main finding was that FAS/FAE children had decreased serotonin ( 20%) and slightly increased dopamine transporter binding. Serotonin binding was decreased especially in the medial frontal cortex (anterior cingulus). Nor--CIT binding to serotonin transporters may be affected, either due to a difference in the density of transporters or a difference in endogenous serotonin concentrations in the synapse. Low 5-HT concentrations in the synapse and high 5-HT

transporter ability would have similar effects on radioligand binding (Heinz, Higley et al., 1998; Heinz, Ragan et al., 1998).

Serotonin dysregulation has been implicated in depression (Risch &

Nemeroff, 1992). Decreased levels of 5-HT transporters have been

observed in the midbrain regions of subjects with major depression (Staley, Malison, & Innis, 1998). We did not observe any correlation between the midbrain 5-HT transporter density and depression scores. In fact, none of the FAS/FAE or control children were considered to have a depression at the time of SPECT study.

Monoamine neurotransmitters such as serotonin, dopamine, and

norepinephrine appear to function as maintenance growth factors because they must be present to produce their maturational actions (Azmitia, 2001). Diminished serotonergic function in FAS children might be due to vulnerable effects of prenatal alcohol exposure. Animal studies

demonstrated deficits of serotonin in the brain stem as early as the 15th day of gestation (Druse, Kuo, & Tajuddin, 1991). Animal experiments suggest that ethanol may alter serotonin neurotransmission in discrete brain regions permanently (Azmitia, 2001; Zafar et al., 2000). Decreased serotonin availability can lead to behavioral symptoms frequently associated with decreased 5-HT transmission (Mazer et al., 1997).

The highest levels of axonal DAT are found in striatum (Donnan et al., 1991; Kaufman, Spealman, & Madras, 1991). In the human brain, the nigrostriatal dopaminergic system originates in the midbrain (substantia nigra) and terminates in the caudate nucleus and putamen. Radiolabeled

-CIT and nor--CIT have high binding to the dopamine transporter system

(Kuikka et al., 1995) and can also be used as radioligands in the

investigation of the dopamine system. In our study, regression analysis between DAT specific binding and normalized striatal volume showed a nonsignificant correlation (r  .39). Similarly, there was a significant negative correlation between internalization and DAT specific binding (r  .65; p  .02).

Dougherty et al. (Dougherty et al., 2025) and Krause et al. (2000) (Krause, Dresel, Krause, Kung, & Tatsch, 2000) have reported increased DAT

densities in the basal ganglia of adults with ADHD studied by SPECT. Vies et al (Vles et al., 2003) have shown that there is a 74.7% down-regulation of DAT in striatum after 4 weeks methylphenidate medication in children. All the FAS children in our study had ADHD. The characteristic deficits of ADHD, namely impaired attention, excessive motor activity, and

impulsivity, may therefore result from the selective deficiency in the avail- ability of dopamine at the synaptic level.

Type 2 alcoholism is characterized by antisocial personality traits from teenage and persistent seeking of alcohol and other substances for their euphoric effects. There is early onset of instability to abstain entirely from alcohol, impulsiveness, fighting, and arrests when drinking and antisociality (Cloninger et al., 1988). Type 1 alcoholism is characterized by anxious (passive-dependent) personality traits and rapid development of tolerance and dependence on the antianxiety effects of alcohol. This type includes 80% of all alcoholics. Type 2 alcoholics have apparently higher and type 1 alcoholics lower DAT densities than healthy control subjects (Tiihonen et al., 1995). Type 2 alcoholics have also a serotonergic defect (Cloninger, 1987; Virkkunen & Linnoila, 1990).

Our patients clearly had a decreased SERT and increased DAT binding, both characteristic of type 2 alcoholics. It is unknown whether it is a reflection of genetic background or due to a deficit in the balance of DA and

serotonergic neuroregulation. Impaired serotonergic function in FAS children might partly explain why the FAS children cannot respond

appropriately to stress or other stimuli or modulate their affective states.

Serotonin agonists can prevent some of the adverse effects of ethanol on the development of the serotonin system (Eriksen, Gillespie, & Druse,

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2000). Some behavioral aspects of FAS might be preventable by early intervention and treatment.

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9 OPTICAL COHERENCE TOMOGRAPHY SHOWS