In vivo evidence of differential impact of typical and atypical antipsychotics on intracortical myelin in adults with schizophrenia

Abstract

Context: Imaging and post-mortem studies provide converging evidence that patients with schizophrenia have a dysregulated developmental trajectory of frontal lobe myelination. The hypothesis that typical and atypical medications may differentially impact brain myelination in adults with schizophrenia was previously assessed with inversion recovery (IR) images. Increased white matter (WM) volume suggestive of increased myelination was detected in the patient group treated with an atypical antipsychotic compared to a typical one.

Objective: In a follow-up reanalysis of MRI images from the original study, we used a novel method to assess whether the difference in WM volumes could be caused by a differential effect of medications on the intracortical myelination process.

Design, setting, and participants: Two different male cohorts of healthy controls ranging in age from 18-35 years were compared to cohorts of subjects with schizophrenia who were treated with either oral risperidone (Ris) or fluphenazine decanoate (Fd).

Main outcome measure: A novel MRI method that combines the distinct tissue contrasts provided by IR and proton density (PD) images was used to estimate intracortical myelin (ICM) volume.

Results: When compared with their pooled healthy control comparison group, the two groups of schizophrenic patients differed in the frontal lobe ICM measure with the Ris group having significantly higher volume.

Conclusions: The data suggest that in adults with schizophrenia antipsychotic treatment choice may be specifically and differentially impacting later-myelinating intracortical circuitry. In vivo MRI can be used to dissect subtle differences in brain tissue characteristics and thus help clarify the effect of pharmacologic treatments on developmental and pathologic processes.

Figure 1. Quadratic (inverted U) trajectories of human brain myelination over the lifespan

Myelination (Y axis) versus age (X axis) in frontal lobes of normal individuals. Left panel is in vivo data from Bartzokis et al (2001). Right panel shows post-mortem intracortical myelin stain data from Kaes (1907) adapted and reproduced in Kemper (1994) depicting the heavy myelination of the lower cortical layers. Used with permission. The data were acquired 100 years apart yet the two samples of normal individuals show remarkably similar frontal lobe myelination trajectories, both reaching a peak at age 45.

Figure 2. In Vivo Measure of Frontal Lobe Intracortical Myelin Volume

Left: Proton density (PD) image that is not sensitive to the cholesterol in myelin. The black region of interest (ROI) line depicts the border between the gray and white matter (WM). This same gray/white separation line is depicted in the image on the right as the gray line inside the white line. Right: Inversion recovery (IR) Image of the same slice of brain as in the PD image on the left (both images obtained sequentially in the same imaging session). The IR image optimally detects the high cholesterol in myelin and is used to obtain the “myelinated WM volume” that includes heavily myelinated parts of the deeper portions of gray matter (see Figure 1). The white ROI line separates myelinated WM and unmyelinated portion of gray matter. The difference between the gray and white lines is the measure of intracortical myelination.

Figure 3. Frontal Lobe Volume Residual z-scores in Male Subjects with Schizophrenia Receiving Either a Typical or Atypical Antipsychotic Medication

Frontal lobe = total frontal lobe (white plus gray matter), WMIR = frontal lobe white matter volume measured on IR images, GMIR = frontal lobe gray matter volume measured on IR images, WMPD = frontal lobe white matter volume measured on PD images, GMPD = frontal lobe gray matter volume measured on PD images; ICM = intracortical myelination. Between group tests (risperidone vs. fluphenazine): *p<0.05. Within group tests (schizophrenic vs. healthy controls, standardized to mean = 0 and SD = 1): +p < 0.05, ++p < 0.01, +++p < 0.001.