Allelic variation within the putative autism spectrum disorder risk gene homeobox A1 and cerebellar maturation in typically developing children and adolescents.

Homeobox A1 (HOXA1) has been proposed as a candidate gene for autism spectrum disorder (ASD) as it regulates embryological patterning of hind-brain structures implicated in autism neurobiology. In line with this notion, a nonsynonymous single nucleotide polymorphism within a highly conserved domain of HOXA1--A218G (rs10951154)--has been linked to both ASD risk, and cross-sectional differences in superior posterior lobar cerebellar anatomy in late adulthood. Despite evidence for early onset and developmentally dynamic cerebellar involvement in ASD, little is known of the relationship between A218G genotype and maturation of the cerebellum over early development. We addressed this issue using 296 longitudinally acquired structural magnetic resonance imaging brain scans from 116 healthy individuals between 5 and 23 years of age. Mixed models were used to compare the relationship between age and semi-automated measures of cerebellar volume in A-homozygotes (AA) and carriers of the G allele (Gcar). Total cerebellar volume increased between ages of 5 and 23 years in both groups. However, this was accelerated in the Gcar relative to the AA group (Genotype-by-age interaction term, P = 0.03), and driven by genotype-dependent differences in the rate of bilateral superior posterior lobar volume change with age (P = 0.002). Resultantly, although superior posterior lobar volume did not differ significantly between genotype groups at age 5 (P = 0.9), by age 23 it was 12% greater in Gcar than AA (P = 0.002). Our results suggest that common genetic variation within this putative ASD risk gene has the capacity to modify the development of cerebellar systems implicated in ASD neurobiology.

Metabolic correlates of antidepressant and antipsychotic response in patients with psychotic depression undergoing electroconvulsive therapy.

OBJECTIVES: Although electroconvulsive therapy (ECT) is a very effective treatment of depression and psychosis, the mechanisms by which this occurs are not fully delineated. The objective of this study was to investigate the functional alterations in brain metabolism in response to ECT through the use of positron emission tomography assessment of cerebral glucose metabolism before and after a course of ECT. METHODS: Ten subjects with psychotic depression were studied with positron emission tomography using [F]fluorodeoxyglucose before and between 2 and 3 weeks after a course of ECT. Statistical parametric mapping and region of interest analyses of the anterior cingulate cortex (ACC) subregions (dorsal, rostral, subcallosal, and subgenual) and hippocampus were used to determine glucose metabolic changes from ECT. The Hamilton Depression Rating Scale and the Scale for Assessing Positive Symptoms were the primary measures used for assessing clinical changes from ECT. RESULTS: Electroconvulsive therapy led to significant increases in the left subgenual ACC and hippocampal metabolism, which were directly correlated with each other and to a reduction in depression as measured by total Hamilton Depression Rating Scale scores. Better antidepressant responders had increased, whereas poorer responders had a decreased left subgenual ACC and hippocampal metabolism. The decrease in positive symptoms was also correlated with increased left hippocampal metabolism. CONCLUSIONS: The antidepressant effect of ECT was correlated with increased metabolism in the left subgenual ACC and hippocampus, whereas the antipsychotic effect of ECT was only correlated with increased left hippocampal metabolism. This finding has implications to better understand the mechanism of antidepressant and antipsychotic effects of ECT.

Cerebellar development and clinical outcome in attention deficit hyperactivity disorder.

OBJECTIVE: Anatomic magnetic resonance imaging (MRI) studies have detected smaller cerebellar volumes in children with attention deficit hyperactivity disorder (ADHD) than in comparison subjects. However, the regional specificity and longitudinal progression of these differences remain to be determined. The authors compared the volumes of each lobe of the cerebellar hemispheres and vermis in children with ADHD and comparison subjects and used a new regional cerebellar volume measurement to characterize the developmental trajectory of these differences. METHOD: In a longitudinal case-control study, 36 children with ADHD were divided into a group of 18 with better outcomes and a group of 18 with worse outcomes and were compared with 36 matched healthy comparison subjects. The volumes of six cerebellar hemispheric lobes, the central white matter, and three vermal subdivisions were determined from MR images acquired at baseline and two or more follow-up scans conducted at 2-year intervals. A measure of global clinical outcome and DSM-IV criteria were used to define clinical outcome. RESULTS: In the ADHD groups, a nonprogressive loss of volume was observed in the superior cerebellar vermis; the volume loss persisted regardless of clinical outcome. ADHD subjects with a worse clinical outcome exhibited a downward trajectory in volumes of the right and left inferior-posterior cerebellar lobes, which became progressively smaller during adolescence relative to both comparison subjects and ADHD subjects with a better outcome. CONCLUSIONS: Decreased volume of the superior cerebellar vermis appears to represent an important substrate of the fixed, nonprogressive anatomical changes that underlie ADHD. The cerebellar hemispheres constitute a more plastic, state-specific marker that may prove to be a target for clinical intervention.