Faculty Bibliography

Based on reports of increased platelet serotonin in 30 to 50% of autistic subjects, abnormal serotonergic neurotransmission may be important in the pathogenesis of autism. However, serotonin metabolite measurements in cerebrospinal fluid of autistic subjects have failed to demonstrate consistent abnormalities. Using alpha-[11C]methyl-L-tryptophan as a tracer for serotonin synthesis with positron emission tomography, we now report unilateral alterations of serotonin synthesis in the dentatothalamocortical pathway in autistic boys. Asymmetries of serotonin synthesis were found in frontal cortex, thalamus, and dentate nucleus of the cerebellum in all 7 boys, but not in the 1 autistic girl studied. Decreased serotonin synthesis was found in the left frontal cortex and thalamus in 5 of the 7 boys and in the right frontal cortex and thalamus in the 2 remaining autistic boys. In all 7 cases, elevated serotonin synthesis in the contralateral dentate nucleus was observed. Statistically significant differences between autistic boys and their nonautistic siblings (n = 5) were obtained when comparing asymmetry indices for frontal cortex, thalamus, and dentate nucleus combined as well as individually for frontal cortex and thalamus. These serotonergic abnormalities in a brain pathway, important for language production and sensory integration, may represent one mechanism underlying the pathophysiology of autism.

We explored the effects of maturational plasticity on motor activations for the affected hand in patients with unilateral lesion involving the rolandic cortex. Ten patients with early lesion (onset < 4 years), seven patients with late lesion (onset > or = 10 years) and eight normal adults underwent [15O]-water positron emission tomography (PET). Rolandic activations in the contralesional hemisphere were enhanced in both patient groups when compared to normal adults. Secondary motor and frontoparietal nonmotor cortices were more activated in the early than in the late lesion group, suggesting a greater potential for reorganization during early development than later in life. Cerebellar activations were similar in late lesion patients and normal adults, but significantly weaker in early lesion patients.

We describe the tracer kinetic analysis of [C-11]-labeled alpha-methyl-tryptophan (AMT), an analogue of tryptophan, which has been developed as a tracer for serotonin synthesis using positron emission tomography (PET) in human brain. Dynamic PET data were acquired from young healthy volunteers (n = 10) as a series of 22 scans covering a total of 60 minutes and analyzed by means of a three-compartment, four-parameter model. In addition, functional images of the K-complex were created using the Patlak-plot approach. The application of a three-compartment model resulted in low identifiability of individual k-values, especially that of k3. Model identifiability analysis using a singular value decomposition of the final sensitivity matrix showed parameter identifiability to increase by 50% when the Patlak-plot approach was used. K-complex values derived by the Patlak-plot approach overestimated the compartmental values by 10 to 20%, because of the violation of the dynamic equilibrium assumption. However, this bias was fairly constant in all structures of the brain. The rank order of K-complex values from different brain regions corresponded well to the regional concentrations of serotonin in human brain (P < 0.0001). These results indicate that the Patlak-plot method can be readily applied to [C-11]AMT data in order to create functional images of the K-complex, reflecting serotonin synthesis rate, within an acceptable error margin.