A major neurochemical regulator of the thalamocortical network is GABA. We used J-edited MRS with compartment correction to evaluate the pharmacological effect of Dopamine agonist (DAA) therapy on thalamic GABA in patients with Parkinson’s disease (PD). Our findings suggest that DAA alters GABA release in PD patients, and that medication-induced changes may be associated to the presence of impulsive behaviors. These results provide evidence that J-edited MRS can be used to measure subcortical neurotransmitter concentration non-invasively, allowing the investigation of the pharmacological effects in GABAergic activity in humans.
Participants: We examined 18 patients with PD that were taking DAA medication. A neurologic exam was performed on all participants, and they all completed the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS), a rating scale designed to measure severity of ICBs symptoms. Demographic and clinical data are shown in Table 1.
Image Acquisition: Patients were scanned in the Off- and On-DAA state using a 3T MRI scanner (Achieva, Philips Healthcare, the Netherlands) with body coil transmit and 32-channel head coil reception. Scanning included a 3D structural T1-weighted whole brain image, (MPRAGE, TR/TE=8.9/4.6 ms; turbo gradient echo factor=131; spatial resolution=1x1x1 mm3), and single-voxel J-edited MRS using MEGA-PRESS (TR/TE=3000/68 ms; 320 transients; 2048 data points at a spectra width of 2 kHz; voxel dimensions=30x22x28 mm3). The spectroscopy voxel was placed in the right thalamic area. Editing pulses (14 ms, 140 Hz bandwidth) were applied at 1.9 ppm and 8 ppm on alternate scans. An unedited MRS scan without water suppression was also acquired for normalization.
Image Analysis: MRS analysis was performed using Gannet 3.0. 1 Frequency and phase correction and outlier rejection was applied. The corrected spectrum was processed to obtain the area under the edited GABA+ (i.e. GABA + macromolecules) signal at 3 ppm (Figure 1a), and the unsuppressed water spectra was processed to obtain the area under the water peak (Figure 1b), which were then used to estimate GABA+ concentration relative to water. To account for the underlying tissue composition, we applied the a-correction 2,3; GannetCoRegister was used to register the MRS voxel to the T1-weighted image, and tissue segmentation was performed by merging the results obtained from FSL FAST and FSL FIRST (Figure 2a). The MRS voxel mask was then applied to the tissue segmentation to determine the tissue voxel fractions for gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) (Figure 2b). The compartment correction (using a=0.5, Wanasapura values for relaxation parameters, and 36.1 mol/dm3, 43.3 mol/dm3, and 53.8 mol/ dm3 for MR-visible water concentrations for WM, GM, and CSF, respectively), and tissue normalization (equation (5) from 2) were then applied to account for differences in GABA+/H2O concentration between GM and WM. Finally, the MRS voxel fraction corresponding to the thalamus (fthal) was calculated using the right thalamic mask from FSL FIRST (Figure 2c), and it was preserved for statistical analysis.
Statistical Analysis: The effect of DAAs on thalamic GABA was estimated as ΔGABA=(GABA+ON – GABA+OFF)/GABA+OFF, where GABA+ON,OFF represent the GABA+ estimate in the On- and Off-DAA conditions. To understand whether GABA responses were related to a quantitative marker of impulsivity, we performed a regression analysis specifying ΔGABA as dependent variable, QUIP-RS score as independent variable, and age and fthal as covariates.
This study was supported by the NIH/NINDS R01 NS097783 and K23 NS080988.
We thank all the volunteers who participated in this study, Grace Tipps for her support in patient recruitment, and Kristen George-Durrett, Leslie McIntosh, Clair Jones, and Christopher Thompson for their assistance with the data acquisition.
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