Holiga, Š.

Jech, R.

Moeller, H.

Mueller, K.

Roth, J.

Růžička, F.

Schroeter, M.

English

MPG.PuRe

Levodopa-induced pattern of putamen activity in Parkinson's diseaseKarsten Mueller1, Štefan Holiga1, Harald E Möller1, Filip Růžička2,3, Jan Roth2, Matthias L Schroeter1,4, Evzen Růžička2, Robert Jech2,31Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; 2Department of Neurology and Center of Clinical Neuroscience,Charles University, First Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic; 3Na Homolce Hospital, Prague, Czech Republic; 4Clinic for Cognitive Neurology, University Hospital Leipzig, Leipzig, Germanykarstenm@cbs.mpg.de, jech@cesnet.czIntroduction Methods Recent research is aimed at investigating brainactivity change with levodopa treatment inParkinson’s disease (PD) using functional magneticresonance imaging (fMRI). Current findings are controversial in the context ofthe role of the putamen. While some papers report an increase of putamenactivity with levodopa medication (Kraft 2009,Holiga 2012, 2014, Martinu 2014), other studiesshow a decrease after treatment (Kwak 2012,Maillet 2012). We hypothesize a differential role of the putamendepending on the experimental context. Clinical assessment and fMRI were performed afteran overnight withdrawal of levodopa (at least 12hours), and one hour after administration of 250mg levodopa. 32 PD patients: equivalent akinetic/rigid type, Hoehn-Yahr stages II-III, 26 males, age 56.1±7.7 y, diseaseduration 12.2±2.5 y, levodopa treatment duration9.0±3.0 y. MRI: 1.5-T MAGNETOM Symphony scanner (Siemens,Germany) using a birdcage head coil and T2*-weighted gradient-echo echo-planar imaging (EPI)(repetition time, TR=1 s; echo time, TE=54 ms, 500repetitions). Ten oblique slices (thickness 3 mm; 1 mm sliceseparation; nominal in-plane resolution 3×3 mm2)were acquired along the central sulcus, covering theprimary sensorimotor cortex and the basal ganglia. Paradigm: Consecutive tapping (TAP) and rest epochs(REST), each lasting 10 s and recurring 25 times,resulting in 50 blocks with a total length of 500 s. 4 sessions per subject: OFF/ON levodopa medicationand LEFT/RIGHT hand finger tapping.FiguresResults and Discussion Data pre-processing and analysis was performedusing SPM12. First-level statistics was performed for every sessionseparately using a GLM including two experimentalconditions (TAP/REST). For all patients and all sessions, both resultingparameter images were fed into a second-levelanalysis using a flexible factorial design including 4factors: SUBJECT, OFF/ON, LEFT/RIGHT, andTAP/REST. We analyzed the interaction between the factorsOFF/ON and TAP/REST. Using smaller models, we also analyzed OFF/ONdifferences for the TAP and the REST phaseseparately. Significant results were found with family-wise error(FWE) correction at the voxel-level with p<0.05(using the SPM’s “FWE-button”). We obtained a divergent pattern of brain activityincrease and decrease with dopaminergic medicationin PD patients depending on the experimental context. Our findings suggest a differential role of the putamenduring TAP and REST depending on the state oflevodopa treatment. Putamen at REST was underactive in the ON comparedto OFF medication state but its activity increased withlevodopa challenge with the TAP condition. This suggests a fundamental difference of involvementof resting and active motor network in PD dependingon actual dopamine level in basal ganglia. In the TAP phase, we observed an increase of putamenactivity with levodopa (Fig 1, left column, red color),while in the REST phase, we observed a decrease withlevodopa (Fig 1, middle column, blue color). The interaction analysis between both factors OFF/ONand TAP/REST showed a significant effect (Fig 1, rightcolumn) reflecting the inverse pattern of levodopa-induced putamen activity change in the TAP and REST. Note that only the left and right putamen appeared inall analyses (see Fig 1). The inverse contrasts did notyield any significant result.1Figure 1. Cross-sectional brain slices showing the differential pattern of brain activity changewith levodopa treatment in Parkinson’s disease during finger tapping and rest. Using anexperimental design with consecutive blocks of finger tapping (TAP) and rest (REST) in both treatmentstates with (ON) and without (OFF) levodopa medication, we observed a differential pattern of brainactivity change in both left and right putamen. During TAP phases, an increased brain activity wasobtained with levodopa medication (left column, color-coded in red). In contrast, during RESTperiods, putamen activity was decreased with levodopa (middle column, color-coded in blue). Asignificant interaction between both factors of experimental condition (TAP/REST) and levodopatreatment (OFF/ON) was observed in the left and right putamen (right column). All results wereobtained with p<0.05 with family-wise error (FWE) correction at the voxel-level.2Figure 2. Contrast estimates of a factorial model containing both experimental conditions offinger tapping and rest in both treatment states without and with levodopa medication.Contrast estimates of the putamen showed a differential pattern of brain activity change afterlevodopa treatment during finger tapping (TAP) and rest (REST). With the TAP condition, we observeda putamen activity increase with levodopa treatment while we found an activity decrease during REST(see left column for the left and right putamen, p<0.05 family-wise error (FWE) corrected). In contrastto the differential pattern of brain activity in the left and right putamen, we did not observe any brainactivity differences between the OFF and the ON state in the left or right motor cortex, neither in theTAP nor in the REST condition (see right column for the left and right motor cortex).[1] Holiga et al. (2012). Accounting for movement increases sensitivity indetecting brain activity in Parkinson's disease. PLoS One. 2012;7(5):e36271.[2] Holiga et al. (2014). Motor matters: tackling heterogeneity ofParkinson's disease in functional MRI studies. PLoS One. 2013;8(2):e56133.[3] Martinu et al. (2014). Asymmetrical effect of levodopa on the neuralactivity of motor regions in PD. PLoS One. 2014 Nov 4;9(11):e111600.[4] Kraft et al. (2009). Levodopa-induced striatal activation in Parkinson'sdisease: a functional MRI study. Parkinsonism Relat Disord. 2009 Sep;15(8):558-63.[5] Kwak et al. (2012). l-DOPA changes ventral striatum recruitmentduring motor sequence learning in Parkinson's disease. Behav Brain Res.2012 Apr 21;230(1):116-24.[6] Maillet et al. (2012). Levodopa effects on hand and speechmovements in patients with Parkinson's disease: a FMRI study. PLoSOne. 2012; 7(10):e46541.ReferencesSupported by the Czech Science Foundation (grant 16-13323S), the Parkinson's Disease Foundation (PDF-IRG-1307), and the Michael J. Fox Foundation (MJFF-11362).RR LA: TAP: ON>OFFR L LB: REST: ON<OFF A – By = -1                            z = 10p < 0.05 FWE

Levodopa-induced pattern of putamen activity in Parkinson's disease

Levodopa-induced pattern of putamen activity in Parkinson's disease

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