Intracortical Myelination Within The Frontal Lobe As A Potential Biomarker For Therapeutic Effectiveness In Antipsychotics Using Mri With Selective Myelin-Lipid Suppression At 1.5 And 3 T

Abstract Converging evidence suggests that the degree of intracortical myelination (ICM), which is thought to be responsible for high-frequency synchronization of electrical activity across the cerebral cortex, is dysregulated in schizophrenia (SZ) and that consistent treatment with antipsychotic medications can increase ICM or stabilize loss of ICM during the course of the disease. The current research demonstrates the use of a novel MRI approach to selectively discriminate lipids involved in myelinated tissues in order to quantify changes in frontal lobe ICM at both 1.5 and 3 T as a result of antipsychotic therapy. This research involved 3 phases: (1) quantification of frontal lobe ICM at 1.5 T in SZ patients treated with oral second-generation antipsychotics at a single institution; (2) calibration of frontal lobe ICM measures between 1.5 and 3 T (Calibration); and (3) initial ICM results obtained at 3 T from a prospective, multicenter trial in recent-onset SZ patients comparing paliperidone palmitate long-acting injection vs oral antipsychotics (DREaM trial, NCT02431702). Coronal oblique proton density and inversion recovery spin echo images (0.94 × 0.94 × 3 mm voxel size, 24-cm FOV) were obtained at 1.5 and/or 3 T MRI, segmented, and the volume of ICM was quantified for all subjects. (1) At 1.5 T, frontal lobe ICM of SZ patients was higher as a function of duration of second-generation antipsychotic medication exposure over the first year of treatment but declined thereafter. A quadratic polynomial regression model between ICM and logged medication exposure fit the data (overall model  = 13.47, df = 2,89, < .0001; linear effect:  = 4.19, < .0001; quadratic effect:  = −4.85, < .0001), with peak ICM volume corresponding to 12.6 months of treatment. Frontal lobe ICM was substantially lower as a function of increasing age in SZ patients ( = −0.345, < .001), but not in healthy controls. (2) Slight modifications of inversion times and other parameters, along with homogeneity corrections, allowed for close correlation of frontal lobe ICM between 1.5 and 3 T. (3) Consistent with what was found at lower (1.5 T) field strengths, ICM of SZ patients at 3 T was higher as a function of duration of antipsychotic medication exposure over the first year of treatment ( = 0.68,  = .03). The inverted U-shaped function of ICM with duration of lifetime oral antipsychotic exposure is consistent with initial clinical response followed by increasing medication nonadherence and increased clinical symptoms. Preliminary results from the DREaM trial at 3 T demonstrate feasibility for obtaining multicenter measurements of frontal lobe ICM and indicate a similar initial increase in ICM as a function of antipsychotic exposure duration. Frontal lobe ICM measured using a specialized MRI sequence shows promise as a potential biomarker for multicenter evaluation of therapeutic effectiveness.