Bartzokis G, Lu PH, Stewart SB, Oluwadara B, Lucas AJ, Pantages J et al. In vivo evidence of differential impact of typical and atypical antipsychotics on intracortical myelin in adults with schizophrenia. Schizophr Res 113: 322-331

Department of Psychiatry and Biobehavioral Sciences, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-6968, USA.
Schizophrenia Research (Impact Factor: 3.92). 08/2009; 113(2-3):322-31. DOI: 10.1016/j.schres.2009.06.014
Source: PubMed


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.
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.
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).
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.
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.
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.

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    • "We do this by means of a myelinated cortical thickness technique, where we measure the thickness of lightly and heavily myelinated portions of the cortical depth separately. Separating cortical tissue into lightly and heavily myelinated portions based on MR contrast was previously suggested in 2D for studies of intracortical myelin in schizophrenia (Bartzokis et al., 2009), and here we extend it to map the entire cortex in 3D. Figure 1 shows representative 40 µm thick histological sections of human cortex stained for myelin (adapted from Braitenberg, 1962). In general, the deeper layers of the cortex (IV–VI) are typically the most heavily myelinated and will have an MR signal that is distinct from the signal in superficial gray matter, which has few myelinated fibers. "
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    ABSTRACT: Alterations in the myelination of the cerebral cortex may underlie abnormal cortical function in a variety of brain diseases. Here, we describe a technique for investigating changes in intracortical myelin in clinical populations on the basis of cortical thickness measurements with magnetic resonance imaging (MRI) at 3 Tesla. For this, we separately compute the thickness of the shallower, lightly myelinated portion of the cortex and its deeper, heavily myelinated portion (referred to herein as unmyelinated and myelinated cortex, respectively). Our expectation is that the thickness of the myelinated cortex will be a specific biomarker for disruptions in myeloarchitecture. We show representative atlases of total cortical thickness, T, unmyelinated cortical thickness, G, and myelinated cortical thickness, M, for a healthy group of 20 female subjects. We further demonstrate myelinated cortical thickness measurements in a preliminary clinical study of 10 bipolar disorder type-I subjects and 10 healthy controls, and report significant decreases in the middle frontal gyrus in T, G, and M in the disorder, with the largest percentage change occurring in M. This study highlights the potential of myelinated cortical thickness measurements for investigating intracortical myelin involvement in brain disease at clinically relevant field strengths and resolutions.
    Frontiers in Neuroscience 11/2015; 9:396. DOI:10.3389/fnins.2015.00396 · 3.66 Impact Factor
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    • "Volumes were computed by summing the cross-sectional area from each slice then multiplying by the slice thickness. Images from (Bartzokis et al., 2009), reprinted with permission. is combined with the PD image to produce a calculated T 2 image were used to delineate the brain/CSF border in subsequent analyses. Both IR and spin-echo sequences have a 256 × 192 view matrix, 24 cm field of view, to produce co-registered 3 mm thick contiguous slices. "
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    ABSTRACT: Imaging and post-mortem studies suggest that frontal lobe intracortical myelination is dysregulated in schizophrenia (SZ). Prior MRI studies suggested that early in the treatment of SZ, antipsychotic medications initially increase frontal lobe intracortical myelin (ICM) volume, which subsequently declines prematurely in chronic stages of the disease. Insofar as the trajectory of ICM decline in chronic SZ is due to medication non-adherence or pharmacokinetics, it may be modifiable by long acting injection (LAI) formulations. Assess the effect of risperidone formulation on the ICM trajectory during a six-month randomized trial of LAI (RLAI) versus oral (RisO) in first-episode SZ subjects. Two groups of SZ subjects (RLAI, N=9; and RisO, N=13) matched on pre-randomization oral medication exposure were prospectively examined at baseline and 6 months later, along with 12 healthy controls (HCs). Frontal lobe ICM volume was assessed using inversion recovery (IR) and proton density (PD) MRI images. Medication adherence was tracked. ICM volume change scores were adjusted for the change in the HCs. ICM volume increased significantly (p=.005) in RLAI and non-significantly (p=.39) in the RisO groups compared with that of the healthy controls. A differential between-group treatment effect was at a trend level (p=.093). SZ subjects receiving RLAI had better medication adherence and more ICM increases (chi-square p<.05). The results suggest that RLAI may promote ICM development in first-episode SZ patients. Better adherence and/or pharmacokinetics provided by LAI may modify the ICM trajectory. In vivo MRI myelination measures can help clarify pharmacotherapeutic mechanisms of action.
    Schizophrenia Research 07/2012; 140(1-3):122-8. DOI:10.1016/j.schres.2012.06.036 · 3.92 Impact Factor
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    • "Previous studies have indicated that the APDs, quetiapine and clozapine, but not haloperidol prevented spatial working impairment induced by CPZ (Zhang et al., 2008). These results suggest that APDs have superior effects on cognitive and negative symptoms , compared to traditional antipsychotics and this may be due, in part, to their impact on OLs (Bartzokis et al., 2009). "
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    ABSTRACT: Myelin and oligodendrocyte dysfunctions have been consistently found in patients with schizophrenia. The effect of antipsychotics on myelin disturbances is unknown. The present study examined the effects of quetiapine on oligodendrocyte regeneration and myelin repair in a demyelination animal model. C57BL/6 mice were fed with cuprizone (0.2% w/w) for 12 weeks to induce chronic demyelination and oligodendrocyte degeneration, after which cuprizone was withdrawn to allow recovery. Quetiapine (10mg/kg/day) or vehicle (water) was administrated orally to mice for 0, 2, 3, or 4 weeks after cuprizone withdrawal. Locomotor activity and Y-maze tests were used to evaluate behavioral changes in the mice. Immunohistochemical staining was used to detect morphological and biological changes in the brains. Cuprizone administration for 12 weeks resulted in severe demyelination, locomotor hyperactivity, and working memory impairment in mice. Remyelination occurred when cuprizone was withdrawn. Quetiapine treatment during the recovery period significantly improved the spatial working memory and increased myelin restoration. Quetiapine treatment also enhanced the repopulation of mature oligodendrocytes in the demyelinated lesions, which was associated with down-regulation of transcription factor olig2 in the process of cell maturation. The results of this study demonstrated that quetiapine treatment during the recovery period improves spatial working memory and promotes oligodendrocyte development and remyelination. This study supports the role of oligodendrocyte dysfunction in memory deficits in a schizophrenia mouse model and suggests that quetiapine may target oligodendrocytes and improve cognitive function.
    Schizophrenia Research 05/2012; 138(1):8-17. DOI:10.1016/j.schres.2012.04.006 · 3.92 Impact Factor
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