0. Jama Neurol 2013; p100

ORIGINAL CONTRIBUTION

Differences in Brain Activation Between Tremor- andNontremor-Dominant Parkinson DiseaseJaney Prodoehl, PhD; Peggy J. Planetta, PhD; Ajay S. Kurani, MS; Cynthia L. Comella, MD;Daniel M. Corcos, PhD; David E. Vaillancourt, PhD

Objective: To compare differences in functional brainactivity between tremor- and nontremor-dominant sub-types of Parkinson disease (PD) using functional mag-netic resonance imaging.

Design: In our study, patients with tremor-dominant PDand thosewith nontremor-dominant PDperformed a griptask, and the results obtained were compared using vox-elwise analysis. Areas of the brain that were signifi-cantly different were then examined using a region-of-interest analysis to compare these patients with healthycontrols. Voxel-based morphometry was used to deter-mine macroscopic differences in gray and white mattervolume between patient groups.

Setting: University-affiliated research institution.

Participants:A total of 20 drug-naive patients with PD(10 with tremor-dominant PD and 10 with nontremor-dominant PD) and a total of 20 healthy controls.

Main Outcome Measures: Blood oxygenation leveldependent activation and percent signal change.

Results: Robust findings across both voxelwise and re-gion-of-interest analyses showed that, comparedwith pa-

tientswith tremor-dominant PD, patientswithnontremor-dominant PD had reduced activation in the ipsilateraldorsolateral prefrontal cortex, the globus pallidus in-terna, and the globus pallidus externa. Region-of-interest analyses confirmed that patients with nontremor-dominant PD had reduced activity in the ipsilateraldorsolateral prefrontal cortex, the globus pallidus in-terna, and the globus pallidus externa comparedwith pa-tients with tremor-dominant PD and healthy controls.Patients with tremor-dominant PD had increased activ-ity in the contralateral dorsolateral prefrontal cortex com-pared with patients with nontremor-dominant PD andhealthy controls. These results could not be explainedby differences in gray or white matter volume.

Conclusions: Reduced brain activity occurs in the pre-frontal cortex and globus pallidus of patients with non-tremor-dominant PD compared with both patients withtremor-dominant PD and healthy controls, which sug-gests that functional magnetic resonance imaging is apromising technique to understand differences in brainactivation between subtypes of PD.

JAMA Neurol. 2013;70(1):100-106. Published onlineOctober 8, 2012. doi:10.1001/jamaneurol.2013.582

T HE CARDINAL MOTOR FEA-tures of Parkinson disease(PD) are bradykinesia, ri-gidity, and tremor. Withinthe general diagnosis of PD,distinct clinical subtypes have been iden-tified based in part on the age at onset, thepredominant motor sign (eg, tremor-dominant PD and nontremor-dominant,akinetic-rigid PD), and the clinical courseof the disease.1,2 Previous studies3-5 haveshown that the tremor-dominant varianthas a slower rate of progression with lessdeterioration regardinghealth-relatedqual-ity of life.

Postmortemanalysis of the brains of pa-tients with PD further supports the clas-sification based on specific clinical fea-

tures. Postmortem confirmation of PD isbased on evidence of specific inclusionbodies that develop as spindle-like orthreadlike Lewy neurites in cellular pro-cesses and in the form of globular Lewybodies in neuronal cell bodies.6 Patientswith the nontremor-dominant pheno-type of PD have been shown to have a sig-nificantly higher mean overall Lewy bodyscore than pat ients with tremor-dominant PD, and,more specifically, theyshow significantlymore cortical Lewybod-ies in the frontal regions of the brain thando patients with tremor-dominant PD.7

Parkinson disease is also characterizedpostmortem by substantia nigra com-pacta dopamine neuronal loss and dopa-mine deficiency in specific nuclei of the

Author AffDepartmenNutrition (Corcos), Bi(Dr Corcosand PsychoUniversityChicago, anNeurologicUniversity(Drs ComeChicago, IllDepartmenPhysiology(Drs PlanetNeurologyand Bioeng(Dr VaillanFlorida, Ga

Author Affiliations:Departments of Kinesiology andNutrition (Drs Prodoehl andCorcos), Bioengineering(Dr Corcos and Mr Kurani),and Psychology (Dr Corcos),University of Illinois atChicago, and Department ofNeurological Sciences, RushUniversity Medical Center(Drs Comella and Corcos),Chicago, Illinois; andDepartments of AppliedPhysiology and Kinesiology(Drs Planetta and Vaillancourt),Neurology (Dr Vaillancourt),and Bioengineering(Dr Vaillancourt), University ofFlorida, Gainesville.

JAMA NEUROL/VOL 70 (NO. 1), JAN 2013 WWW.JAMANEURO.COM100

2013 American Medical Association. All rights reserved.

Downloaded From: http://archneur.jamanetwork.com/ by elfrida meryance on 03/27/2015

basal ganglia,8 with patients with nontremor-dominantPD having reduced dopamine levels in the globus palli-dus.9Using in vivo functionalmagnetic resonance imaging(fMRI), Spraker et al10 found that, comparedwith healthycontrols, drug-naive patients with PD have reduced ac-tivity in the thalamus, primary motor cortex, supple-mentary motor area, and in all nuclei of the basal gan-glia. Prodoehl et al11 also found that fMRI activity in nucleiof the basal ganglia correlateswith specific symptoms suchas bradykinesia and tremor in drug-naive patients withPD. However, to date, no direct comparison of brain ac-tivation in drug-naive patients with PD who have thetremor-dominant phenotype vs those who have the non-tremor-dominantphenotypehasbeenperformed.Thepres-ent study was designed to examine functional and struc-tural differences between drug-naive patients withnontremor-dominant PD and patients with tremor-dominant PD using fMRI and voxel-based morphom-etry. We hypothesized that patients with nontremor-dominant PDwould show both cortical and basal gangliaactivation deficits compared with patients with tremor-dominant PD. We further test the hypothesis that areasthat show reduced activation in patients with nontremor-dominant PD relative to patients with tremor-dominantPDwill also show reduced activation in patientswith non-tremor-dominant PD relative to healthy controls.

METHODS

A total of 20 drug-naive patients with PDwho have never beentreatedwith dopaminergicmedications participated in the study(Table1). TheMini-Mental State Examination scorewas greaterthan 26 for each participant. All patients were diagnosed withPD by a movement disorder neurologist and met the UK Par-kinsons Disease Society Brain Bank diagnostic criteria.12,13 Agroup diagnosis approach was used such that the diagnosis ofeach patient was confirmed by 7 othermovement disorder neu-rologists (who looked at videotapes of the patients) in prac-tice at Rush University Medical Center in Chicago, Illinois. Ofthese 20 patients, 10 were in the tremor-dominant group, and10 were in the nontremor-dominant group. The criterion forinclusion in the tremor-dominant group was the presence of atremor at rest in either the head-neck region or in at least 1upper or lower extremity that was given a score of 2 from themotor examination section of the Unified Parkinsons DiseaseRating Scale (UPDRS). The criterion for inclusion in the non-tremor-dominant group was the absence of a tremor at rest inthe head-neck region or in any upper extremity. The diagno-ses of all the patients were reconfirmed 2 years after MRI test-ing by reviewing the patientsmedical records, whichwere docu-mented by the movement disorder neurologists. A consistentdiagnosis was maintained over 2 years for each patient. Twoyears following testing, all but 3 patients with PD (1 patientwith nontremor-dominant PD and 2 patients with tremor-dominant PD) had started either dopamine agonists or le-

Table 1. Characteristics of 20 Patients With Either Nontremor- or Tremor-Dominant Parkinson Disease

Patient No./Sex Age, y

Time SinceDiagnosis,

mo HandednessHandTested

HYStage

Motor UPDRS Scores

Total

Rest Tremor Action Tremor

H/N LUE RUE LLE RLE Total LUE RUE

Nontremor-Dominant Parkinson Disease1/F 47 1 R R 1 10 0 0 0 0 0 0 12/M 57 4 L R 2 25 0 0 0 0 0 0 0 13/M 69 2 R L 2 18 0 0 0 0 0 0 1 04/F 45 19 R L 2 18 0 0 0 0 0 0 1 05/M 57 18 R L 2 18 0 0 0 0 0 0 1 16/F 55 9 R R 2 11 0 0 0 0 1 1 0 07/M 50 3 R R 2 10 0 0 0 0 0 0 0 18/M 44 1 L L 1 7 0 0 0 0 0 0 2 09/F 66 10 R R 2 27 0 0 0 0 0 0 0 110/M 47 5 R R 1 9 0 0 0 0 0 0 0 0Mean

(1 SD)53.7(8.7)

7.2(6.7)

15.3(6.9)

0(0)

0(0)

0(0)

0(0)

0.1(0.31)

0.1(0.31)

0.5(0.7)

0.5(0.52)

Tremor-Dominant Parkinson Disease1/M 72 4 R L 2 32 1 2 1 2 0 6 1 12/F 55 19 R L 1 12 0 2 0 1 0 3 2 03/M 55 33 L R 2 31 0 0 2 0 0 2 0 14/F 58 8 R R 2 16 0 0 2 0 0 2 1 15/M 64 3 R L 2 25 0 2 0 1 0 3 0 06/F 70 2 R L 2 9 0 2 0 0 0 2 1 07/F 56 2 R R 2 12 0 0 2 0 0 2 0 08/M 47 14 R R 2 28 0 0 2 0 0 2 1 29/F 47 18 R R 2 10 0 1 2 0 0 3 0 010/M 49 8 R R 2 21 1 1 2 0 0 4 1 2Mean

(1 SD)57.3(8.9)

11.1(9.99)

19.6(8.9)

0.2(0.42)

1.0(0.94)

1.3(0.94)

0.4(0.67)

0(0)

2.9(1.2)

0.7(0.67)

0.7(0.82)

P valuea .37 .31 .24 .15 .005 .001 .08 .33 .001 .52 .52

Abbreviations: H/N, head and neck; HY, Hoehn and Yahr; L, left; LLE, left lower extremity; LUE, left upper extremity; R, right; RLE, right lower extremity; RUE,right upper extremity; UPDRS, Unified Parkinsons Disease Rating Scale.

aDetermined by use of the t test.




vodopa, and each of these patients had a positive response todrug therapy. Twenty healthy aged-matched controls also par-ticipated in our study (mean age, 58 years; 10men and 10wom-en). The controls were healthy volunteers from the Chicago-land area who did not have a prior history of neurological orpsychiatric disease. The UPDRS motor scores for all controlswere 0. The first patient was enrolled on March 22, 2007, andthe last patientwas enrolled onOctober 2, 2010. The first healthycontrol was enrolled onMay 7, 2007, and the last healthy con-trol was enrolled in October 19, 2010. All participants pro-vided written informed consent consistent with the Declara-tion of Helsinki, whichwas approved by the institutional reviewboards at Rush University Medical Center and the Universityof Illinois at Chicago.

The grip task consisted of each participant applying forceto a fiber-optic force transducer (Aither Engineering), with pa-tients using theirmost affected hand and controls using the handthat allowed us to maintain a similar left hand to right handdominance ratio as the patient groups (Figure 1A). Imageswere collected using a quadrature volume head coil inside a3-T MR scanner (GE Healthcare 3T94 Excite 2.0). Each par-ticipants headwas stabilized using adjustable padding. The func-tional images were obtained using a T2*-sensitive, single-shot, gradient-echo echo-planar pulse sequence (echo time, 25milliseconds; repetition time, 2500milliseconds; flip angle, 90;field of view, 200mm2; imagingmatrix, 64 64; 42 axial slicesat 3 mm thickness; 0-mm gap). The anatomical images wereobtained using a T1-weighted, fast spoiled gradient-echo pulsesequence (echo time, 1.98milliseconds; repetition time, 9mil-liseconds; flip angle, 25; field of view, 240 mm2; imaging ma-trix, 256 256; 120 axial slices at 1.5 mm thickness; 0-mmgap).

The fMRI methods are consistent with previous work.10,11

The fMRI experiment was a block-design paradigm of four 30-second task blocks and five 30-second rest blocks. During restblocks, the participants fixated on a stationary red target with-

out producing force. During task blocks, the participants per-formed 2-second pulse-hold contractions followed by 1 sec-ond of rest (Figure 1B).10 The target bar represented 15% ofthe maximum voluntary contraction. A white cursor that wasdisplayed on the screenmoved vertically and was related to theforce produced by the participant. Each force pulse began asthe target bar turned green and remained green for 2 seconds.The force pulse ended when the target bar turned red for 1 sec-ond, indicating rest. There were 10 pulses per task block.

After the force output data were collected, 4 points weremarked for each pulse: onset of force, beginning and end of thesustained force period, and offset of force.14 Based on thesemarked points, 4 force variables were calculated: (1)mean forceamplitude, (2) duration of force, (3) rate of change of increas-ing force, and (4) rate of change of decreasing force. Force datawere analyzed in order to compare behavioral performance be-tween groups. The difference in the groupmean valueswas ana-lyzed using a 1-way between-subjects analysis of variance foreach dependent measure. All tests were evaluated as signifi-cant at P .05.

AFNI, the public domain software (http://afni.nimh.nih.gov/afni/), was used to analyze fMRI data. Before analysis, fMRIdata were transposed for those participants who used their lefthand, so that the left and right hemispheres in all data sets werecontralateral and ipsilateral to the tested hand, respectively.Headmotion was less than 1 mm in x, y, and z directions for all par-ticipants. A voxelwise analysis was performed on the fMRI datato identify group differences in blood oxygenation leveldependent (BOLD) activation between the nontremor- andtremor-dominant patient groups. Motion-corrected indi-vidual data sets were normalized by dividing the instanta-neous signal in each voxel at each point in the time series bythe mean signal in that voxel across the scan. A Gaussian filterwas applied to the resultant data sets (full-width at half-maximum, 3.3 mm). Then, the time series data were regressedto a simulated hemodynamic response function for the task se-quence. Before group analysis, each participants anatomical andfunctional data set was transformed to standardized space usingthe normalized anatomical data set as a template. The outputdata for the tasks were analyzed using a mixed-effects, 2-wayanalysis of covariancewith patient group (patients with tremor-dominant PD and those with nontremor-dominant PD) as thefixed factor and participant as the random factor. We analyzedthe tremor-dominant vs nontremor-dominant comparisonwithandwithout covariates.We included action tremor scores fromTable 1 as one covariate and bradykinesia minus tremor at restas the other covariate. For the bradykinesia covariate, wesummed bradykinesia items from the UPDRS (questions 23,24, 25, 26, 29, and 31) and subtracted summed tremor at rest(question 20) values for both tremor- and nontremor-dominant groups. Adding the covariates to the model did notalter the findings, and the same areaswere identified using eitherapproach. Following the analysis of covariance, this yielded theestimated difference in the patient group mean values for taskminus rest. These data were corrected for type I error using aMonteCarlo simulationmodel (AFNI, Alphasim).Data setswerethresholded at t 3.8 (P .005) with a minimum activationcluster volume of 205 L (P .05, corrected). Because nucleiin the basal ganglia are small, an uncorrected threshold of t 3.8(P .005) was used.

Brain regions with activation differences between the non-tremor- and tremor-dominant groups were compared with thebrain regions of healthy controls using a region-of-interest analy-sis. Percent signal change (PSC) data were acquired, consis-tent with previous work.10 The regions of interest were deter-mined based on the voxelwise analysis. One-way analyses ofvariance were performed to compare PSCs within regions ofinterest in patientswith tremor-dominant PD, patientswith non-

A

B

Grip force transducer Rest Force

MVC

, %

White cursormoves with

applied force

15TD NTD

2 s

0

30 s

Figure 1. A, Grip force transducer used to produce isometric force andvisual display seen by the participant at rest (red bar) and during forceproduction (green bar). B, Representative force traces from a patient withtremor-dominant PD (TD; left) and a patient with nontremor-dominant PD(NTD; right).The functional magnetic resonance imaging experiment was ablock-design paradigm of four 30-second task blocks and five 30-secondrest blocks. During rest blocks, the participants fixated on a stationary redtarget without producing force. During task blocks, the participantsperformed 2-second pulse-hold contractions followed by 1 second of rest.The target bar represented 15% of the maximum voluntary contraction(MVC). A white cursor on the screen moved vertically and was related to theforce produced by the participant.




tremor-dominant PD, and healthy controls. Significant maineffects were examined using Tukey honestly significant differ-ence post hoc tests.

To ensure that any differences in voxelwise functional ac-tivation betweennontremor- and tremor-dominant patientswithPD were not due to changes in brain structure between pa-tient groups, voxel-based morphometry analyses were imple-mented using SPM8 in MATLAB version 7.10 (The Math-Works Inc) and FreeSurfer version 5.0.0 (http://surfer.nmr.mgh.harvard.edu). The New Segment procedure described inthe SPM8 manual, with enhanced preprocessing methods andmodeling parameters based on the voxel-based morphometrystudy of Pereira et al,15 was used as the model for analysis. Avoxelwise statistical analysis was performed by implementingthe general linear model with comparison between the tremor-and nontremor-dominant groups using a 2-sample t test. Areasof volumetric variation had to meet a statistical threshold ofP .05, corrected formultiple comparisons using the false dis-covery rate method, and a minimum cluster size of 10 voxels.

RESULTS

Table 1 shows the characteristics of patients from bothgroups. There were no significant differences between pa-tientgroupswith regard toage (t18 = 0.91,P = .37)orUPDRSmotor score (t18 = 1.03, P = .32). Figure 1B shows a forcetrace fromrepresentative patientswithPD from the tremor-dominant (left) and nontremor-dominant (right) groups.Despite having a visible tremor at rest, the patient withtremor-dominant PD was able to perform the task as wellas the patient with nontremor-dominant PD. At the grouplevel, the results of a 1-way analysis of variance showed nodifferences among nontremor-dominant, tremor-dominant, and control groups with regard to mean force(F2,37 = 0.32, P = .73), rate of change of increasing force(F2,37 = 2.38, P = .11), or rate of change of decreasing force(F2,37 = 0.60, P = .55). There was a main group effect forduration of force (F2,37 = 5.22, P = .010). Post hoc tests re-vealed that this was due to the longer duration of force inthe tremor-dominant group compared with controls(P = .013), but there was no significant difference be-tween nontremor- and tremor-dominant groups. Overall,these data suggest that behavioral performance is not driv-ing any differences observed in the fMRI data.

Voxelwise analysis of the BOLD signal revealed re-duced activation in the nontremor-dominant group com-pared with the tremor-dominant group in several corti-cal and subcortical areas: the bilateral dorsolateralprefrontal cortex (DLPFC), the contralateral presupplementary motor area, the ipsilateral inferior pari-etal lobule, the ipsilateral precuneus, the contralateral lin-gual gyrus, the contralateral caudate, the contralateralglobus pallidus interna (GPi), the contralateral globuspallidus externa (GPe), and the ipsilateral thalamus(Table 2; Figure 2A and B). There were no areas thatshowed increased activity in the nontremor-dominantgroup comparedwith the tremor-dominant group. Table 1shows that one of the patients with nontremor-dominant PD had a tremor at rest score of 1 on the rightlower extremity. Removing this patient from our studydid not alter our findings.

The results of voxel-based morphometry analysisshowed no differences in gray or white matter volume

either cortically or subcortically between nontremor- andtremor-dominant groups that could have accounted forthe between-group differences found in the functionalvoxelwise analysis. An uncorrected threshold at P .001did not reveal any differences between groups for the re-gions shown in Table 2.

Follow-up region-of-interest analysis of the areas listedin Table 2 confirmed findings from the voxelwise analy-sis for the nontremor- and tremor-dominant compari-son in the bilateral DLPFC, the contralateral GPi andGPe,the ipsilateral thalamus, the inferior parietal lobule, andthe precuneus (Table 3). In each of these areas, the PSCwas lower in patients with nontremor-dominant PD thanin patients with tremor-dominant PD. Patients with non-tremor-dominant PD showed lower PSCs in the ipsilat-eral DLPFC, the GPi, and the GPe than did controls(Figure 2C). Patientswith tremor-dominant PDwere onlydifferent from controls in 1 area, the contralateral DLPFC,where the PSC was higher in patients with tremor-dominant PD than in controls (Figure 2C, Table 3). Thus,the bilateral DLPFC, the contralateral GPi and GPe, theipsilateral thalamus, the inferior parietal lobule, and theprecuneus are areas that show robust differences be-tween tremor- and nontremor-dominant patient groupsacross both voxelwise and region-of-interest analyses.

COMMENT

The present study examined functional and structuraldifferences in the brains of drug-naive patients with eithertremor- or nontremor-dominant PD, using fMRI andvoxel-basedmorphometry. Follow-up analysis using a re-gion-of-interest approach was performed to confirm be-tween-group differences and to examine how these be-tween-group differences related to a healthy controlgroup. Robust findings across both analysis methodsshowed significant differences both cortically (prefrontalcortex) and subcortically (globus pallidus) between pa-tients with nontremor-dominant PD and patients with

Table 2. Talairach Coordinates for Significant Regionsin Voxelwise Comparison Between PatientsWith Tremor-Dominant PD and ThoseWith Nontremor-Dominant PD

Region

Center of Mass

x y z

DLPFCIpsilateral 33.1 40.8 31.3Contralateral 40.8 39.3 22.9

Contralateral pre-SMA 14.1 6.8 64.7Contralateral caudate 12.0 21.4 2.2Contralateral GPi 18.3 11.3 4.3Contralateral GPe 26.1 15.1 3.6Ipsilateral thalamus 1.8 22.6 7.7Ipsilateral supramarginal gyrus/IPL 49.3 43.1 34.9Contralateral lingual gyrus 21.7 65.0 2.6Ipsilateral precuneus 7.9 73.4 28.1

Abbreviations: DLPFC, orsolateral prefrontal cortex; GPe, globus pallidusexterna; GPi, globus pallidus interna; IPL, inferior parietal lobule; PD,Parkinson disease; SMA, supplementary motor area.




tremor-dominant PD, with the nontremor-dominant pa-tients showing reduced activation. Compared with con-trols, the patients with nontremor-dominant PD alwaysshowed reduced activation, whereas the patients withtremor-dominant PD either had brain activity thatwas notsignificantly different from that of controls or, in the caseof the contralateral DLPFC, showed increased activation.These results could not be explained by differences in grayor white matter volume. Therefore, BOLD changes in theprefrontal cortex and basal ganglia differ in patients withearly-stage PD who are clustered into nontremor- andtremor-dominant groups.

In the cortex, the patients with nontremor-dominantPD showed reduced activity in the bilateral DLPFC com-pared with the patients with tremor-dominant PD. The

patients with nontremor-dominant PD also had lowerPSCs in the ipsilateral DLPFC compared with controls.One possibility is that the presence of resting tremors inthe tremor-dominant group could not explain these find-ings because increased resting activity in the tremor-dominant group could reduce the task-related BOLD sig-nal change in the tremor-dominant group, thusminimizing any between-group differences. Another pos-sibility is that DLPFC activity was higher in the tremor-dominant group to suppress tremor because the DLPFChas been related to inhibiting force output.14 We com-pared the BOLD activity with andwithout covariates thatincluded action tremor and bradykinesia minus restingtremor, and the findings were similar for the DLPFC andall other areas with and without the covariates. Thus, al-though the presence of a tremor at rest in the tremor-dominant group and the absence of a tremor at rest inthe nontremor-dominant group led to between-group dif-ferences in the BOLD signal, these group findings are ro-bust to the UPDRS scores as covariates.

A prior postmortem analysis7 of brain structure in PDhas shown a significantly highermean overall Lewy bodyscore for patients with nontremor-dominant PD than forpatientswith tremor-dominant PD, particularly in the pre-frontal regions of the cortex. Patients with nontremor-dominant PD show signs of bradykinesia more fre-quently than patientswith tremor-dominant PD, and theyalso showminimal tremor at disease onset.7 It is not clearwhether this is due to pathological differences in brainstructure between phenotypes at the outset of the dis-ease orwhether this is due to adaptive changes from symp-tomdifferences between phenotypes. To resolve this ques-tion, it would be necessary to perform correlationalanalyses between Lewy body deposition and measuresof bradykinesia. Nevertheless, brain changes observedpostmortem seem to support clinical subtyping of pa-tients into either nontremor- or tremor-dominant PDphe-notypes. Because the present study examined tremor- andnontremor-dominant patients relatively early in the dis-ease process, prior to starting dopaminergic medica-tion, our findings suggest that grouping patients intotremor- and nontremor-dominant groups based on mo-toric features reveals changes in the BOLD signal in areassuch as the DLPFC.Whether these changes in the BOLDsignal in the DLPFC have any relation to cortical Lewybody deposition is beyond the scope of the present study,and caution should be taken in attempting to relate thesefindings without further inquiry.

The task used in the present study was chosen be-cause it requires robust activation of frontal cortical re-gions and parietal cortical regions, including the pri-mary motor cortex, the dorsal and ventral premotorcortices, the supplementary motor area, the DLPFC, theinferior parietal lobule, the superior parietal lobule, andthe anterior cingulate cortex.17,18 However, in the pre-sent study, only the DLPFC in the prefrontal cortex wasdifferent between patient groups in both voxelwise andregion-of-interest analysis, which suggests that this pre-frontal area is robustly sensitive to differences in pa-tients clustered into tremor- and nontremor-dominantgroups. The DLPFC has been suggested to play an im-portant role in working memory and executive func-

0.02

0.00

0.02

0.04

0.06

0.08

Control

IPL Pre-SMA

+1.0

1.0

IpsilateralDLPFC

CaudatePutamen

GPeGPi

STN

Thalamus

z = 1 z = 4

ContralateralDLPFC

TD

Contralateral DLPFC

NTD

PSC,

%

C

0.02

0.00

0.02

0.04

0.06

0.08

Control TD

Ipsilateral DLPFC

NTD

PSC,

%

0.02

0.00

0.02

0.04

0.06

0.08

Control TD

GPi

NTD

PSC,

%

0.02

0.00

0.02

0.04

0.06

0.08

Control TD

GPe

NTD

PSC,

%

A

B

Figure 2. Brain activation in tremor-dominant (TD) and nontremor-dominant(NTD) groups of patients with Parkinson disease (PD). Voxelwise analysis ofTD minus NTD groups was performed using AFNI software. A, Reducedactivity in the inferior parietal lobule (IPL), the bilateral dorsolateral prefrontalcortex (DLPFC), and the presupplementary motor area (pre-SMA) in NTDpatients with PD compared with TD patients with PD. B, Color-coded BasalGanglia Human Area Template16 that was used to identify the location ofbasal ganglia activation (top panel). Reduced activation is shown for thecontralateral caudate (green circle), the globus pallidus externa (GPe; redcircle), the globus pallidus interna (GPi; orange circle), and the ipsilateralthalamus in NTD patients with PD compared with TD patients with PD.C, Percent signal change (PSC) in controls, TD patients, and NTD patients inthe contralateral and ipsilateral DLPFC (top) and in the GPi and GPe(bottom). STN indicates subthalamic nucleus.




tion. Indeed, the DLPFC activation has previously beenshown to be sensitive to changes in learning in early-stage PD, with activation being normal at baseline butdecreasing to subnormal levels after 2 years.19 Kikuchiet al20 used single-photon emission computed tomogra-phy to show hypoperfusion in the DLPFC, the supple-mentary motor area, and the insular cortex in PD. How-ever, only hypoperfusion in the DLPFC and the insularcortex was correlated with disease severity, leading Ki-kuchi et al20 to suggest that the DLPFC and the insularcortex may play key roles in specific symptoms of im-pairment at advanced stages, such as impaired workingmemory, postural instability, and autonomic dysfunc-tion. The results of the present study suggest that dis-ease severity alone may not be the main feature of thisdifference and that symptom-specific differences couldbe another factor that should be considered. That is, pa-tients with a nontremor-dominant subtype of PD, evenin the earliest stages of the disease,may show greater defi-cits in frontal cortical areas compared with patients witha tremor-dominant subtype.

Subcortically, the present study showed reduced BOLDactivity in the GPi, the GPe, and the thalamus in pa-tients with nontremor-dominant PD compared with pa-tients with tremor-dominant PD (Tables 2 and 3). Be-cause the basal ganglia have established connectionswiththe DLPFC, it could be that the cortical findings are dueto changes in the basal ganglia, or it could be that thesecortical and subcortical findings are not directly related.The reduced activity in the GPi in the nontremor-dominant group was in the ventral part of the GPi, andthis location and pattern of findings for the BOLD sig-nal are consistent with previous postmortem findings ofreduced dopamine levels in the ventral part of the GPiin patients with nontremor-dominant PD comparedwithpatients with tremor-dominant PD.9 It is also consistentwith the previous finding of Prodoehl et al11 in which agroup of drug-naive patients with PD with a mixed phe-notype had higher tremor scores on the UPDRS that wereassociated with higher PSCs in the GPi. In this study,11

there was a negative correlation between disease sever-

ity and PSC in all other nuclei of the basal ganglia and inthe thalamus, and bradykinesia was the symptom thatmost consistently predicted BOLD activation in these re-gions. In a different study,21 patients with moderate PDwere tested following a 12-hour withdrawal from medi-cation, and it was found that pallidal dopamine deple-tion correlated with clinical tremor severity and that theGPi, the GPe, and the putamen were transiently activeduring the onset of tremor episodes. Our findings ex-tend this work by showing that early-stage, drug-naivepatients clustered into a nontremor-dominant group hadreduced BOLD signals in specific nuclei of the basal gan-glia (the GPi and GPe) and in the thalamus comparedwith early-stage, drug-naive patients clustered into atremor-dominant group. Furthermore, our findings sug-gest that group differences in basal ganglia activation be-tweenpatientswithPDandhealthy controlsmaybedrivenin part by patients with motoric features consistent withthe nontremor-dominant group rather than the tremor-dominant group.

Comparing patients with PDwith healthy controls, wefound that only one area in the region-of-interest analysisshowed significantly increased activation in PD. The con-tralateral DLPFC showed a significantly greater PSC in pa-tients with tremor-dominant PD compared with con-trols. Although a tremor at rest in PD has been associatedwith increased metabolism in the thalamus, subthala-mus, pons, and premotor-cortical network, suggesting anincreased functional activity of thalamo-motor projec-tions,22 what underlies increased DLPFC activation inpatientswith tremor-dominant PDdeserves further study.In addition, the future study of symptom-specific dif-ferences in patients with amore advanced stage of the dis-ease should examine cognitive changes thatmight accom-pany the functional activation deficits found in the presentstudy. Because the patients included in our study weredrug-naive patients, it could be argued that patients withatypical parkinsonism were included, particularly in thenontremor-dominant group. To minimize this possibil-ity, reconfirmation of the diagnosis was made 2 years af-ter MRI testing was performed. Also, after 2 years, all but

Table 3. One-Way ANOVA Results From the Region-of-Interest Analysis

Region of Interest

ANOVA P Valuea

F Value P ValueControls vs

NTDControls vs

TDNTD vsTD

DLPFCContralateral 7.68 .005 .19 .05 .005Ipsilateral 6.58 .005 .05 .35 .005

Contralateral pre-SMA 2.04 .15Contralateral caudate 2.77 .08Contralateral GPi 4.19 .05 .05 .90 .05Contralateral GPe 11.68 .001 .001 .58 .005Ipsilateral thalamus 3.83 .05 .08 .69 .05Ipsilateral supramarginal gyrus/IPL 3.32 .05 .49 .19 .05Contralateral lingual gyrus 1.65 .21Ipsilateral precuneus 4.61 .05 .09 .44 .05

Abbreviations: ANOVA, analysis of variance; DLPFC, dorsolateral prefrontal cortex; GPe, globus pallidus externa; GPi, globus pallidus interna; IPL, inferiorparietal lobule; NTD, patients with nontremor-dominant Parkinson disease; SMA, supplementary motor area; TD, patients with tremor-dominant Parkinsondisease.

aDetermined by use of the Tukey honestly significant difference post hoc test.




3 patients had started dopamine therapy, and each of theother17patients respondedpositively tomedication,whichgave us confidence in the findings.

In conclusion, the present study confirmed that func-tional differences in the basal ganglia and cortex be-tween patients with PD and healthy controls are primar-ily due to patients with the nontremor-dominant subtypeof PD rather than the tremor-dominant subtype. Thesefindings suggest that objective measures of brain func-tion may be useful in future genotype-phenotype analy-ses and in targeted therapeutic trials focused on PD sub-types.

Accepted for Publication: April 13, 2012.Published Online: October 8, 2012. doi:10.1001/jamaneurol.2013.582Correspondence: David E. Vaillancourt, PhD, Depart-ment of Applied Physiology and Kinesiology, Univer-sity of Florida, PO Box 118205, Gainesville, FL 32611([email protected]).Author Contributions: Study concept and design: Pro-doehl, Comella, Corcos, and Vaillancourt. Acquisition ofdata: Prodoehl, Planetta, and Vaillancourt. Analysis andinterpretation of data:Prodoehl, Planetta, Kurani, andVail-lancourt. Drafting of the manuscript: Prodoehl, Corcos,and Vaillancourt. Critical revision of the manuscript forimportant intellectual content: Prodoehl, Planetta, Kurani,Comella, and Vaillancourt. Statistical analysis: Pro-doehl, Planetta, Kurani, and Vaillancourt.Obtained fund-ing: Corcos and Vaillancourt. Administrative, technical,and material support: Prodoehl and Vaillancourt. Studysupervision: Vaillancourt.Conflict of Interest Disclosures:Dr Comella has servedas a consultant for Allergan,Merz, Ipsen, Esai, and Boeh-ringer; has received royalties fromKluwer Publishing andCambridge University Press; and has received researchgrants that go to her institution from Boehringer, Ipsen,Merz, and the National Institutes of Health, and her in-stitution has also received support from a Parkinson Re-search Center grant from the Parkinsons Disease Foun-dation.DrsVaillancourt andCorcos have received fundingfrom the National Institutes of Health (grants R01-NS-52318, R01-NS-58487, R01-NS-40902, and R01-NS-28127) and the Michael J. Fox Foundation for Parkin-son Research.Funding/Support: This work was supported by the Na-tional Institutes of Health (grants R01-NS-52318, R01-NS-58487, R01-NS-40902, and R01-NS-28127), theMichael J. Fox Foundation for Parkinson Research, anda Parkinson Research Center grant from the ParkinsonsDisease Foundation.Additional Contributions:We thank the staff at the Sec-tion for Movement Disorders in the Department of Neu-rological Sciences at RushUniversityMedical Center, Chi-cago, Illinois, and the patients for their time andcommitment to this research.

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