ASYMMETRY OF CORTICAL FUNCTION

Asymmetry of Cortical Function

Asymmetry of Cortical Function

Introduction

The role of serotonin in prenatal and postnatal brain development is well documented in the animal literature. In earlier studies using positron emission tomography (PET) with the tracer alpha[11C]methyl-l-tryptophan (AMT), they reported global and focal abnormalities of serotonin synthesis in children with autism. In the present study, they measured brain serotonin synthesis in a large group of autistic children (n = 117) with AMT PET and related these neuroimaging data to handedness and language function. Cortical AMT uptake abnormalities were objectively derived from small homotopic cortical regions using a predefined cutoff asymmetry threshold (>2 S.D. of normal asymmetry). Autistic children demonstrated several patterns of abnormal cortical involvement, including right cortical, left cortical, and absence of abnormal asymmetry. Global brain values for serotonin synthesis capacity (unidirectional uptake rate constant, K-complex) values were plotted as a function of age. K-complex values of autistic children with asymmetry or no asymmetry in cortical AMT uptake followed different developmental patterns, compared to that of a control group of non-autistic children. The autism groups, defined by presence or absence and side of cortical asymmetry, differed on a measure of language as well as handedness. Autistic children with left cortical AMT decreases showed a higher prevalence of severe language impairment, whereas those with right cortical decreases showed a higher prevalence of left and mixed handedness. Global as well as focal abnormally asymmetric development in the serotonergic system could lead to miswiring of the neural circuits specifying hemispheric specialization.

Discussion

Abnormalities of serotonergic function in autism were first recognized in 1961 when Schain and Freedman reported hyperserotonemia in autistic and mentally retarded children. This result has been replicated by several groups (Hoshino et al., 1984, Anderson et al., 1987 and Cook et al., 1990), and extended with the recognition that blood serotonin is also elevated in their first degree relatives (Leventhal et al., 1990, Piven and Palmer, 1999, Cook et al., 1994 and Leboyer et al., 1999).

AMT model for measurement of serotonin synthesis capacity

AMT, which was developed as a tracer for serotonin synthesis with PET (Diksic et al., 1991), is an analogue of tryptophan, the precursor for serotonin synthesis. Following the intravenous administration, AMT in plasma competes with tryptophan and other large neutral amino acids for transport across the blood brain barrier. Partial conversion of AMT to a-methyl-serotonin (AM-5HT) in brain has been demonstrated in animals (Missala and Sourkes, 1988, Diksic et al., 1990, Gharib et al., 1999, Shoaf et al., 1998 and Shoaf et al., 2000). [H-3]a-methyl-serotonin synthesized in brain was localized to serotonergic neurons and nerve terminals by combined autoradiography and tryptophan hydroxylase immunocytochemistry at the electron microscopic level (Cohen et al., 1995). However, Shoaf et al., 1998 and Shoaf et al., 2000 and Gharib et al. (1999) argued that AMT cannot be used to measure serotonin synthesis since only a fraction of the AMT taken up into the tissue is converted to serotonin. These two groups of investigators concluded that AMT is primarily a measure of brain uptake ...