Preoperative factors of apathy in subthalamic stimulated Parkinson disease: A PET study Gabriel H. Robert, Florence Le Jeune, Clement Lozachmeur, et al. Neurology 2014;83;1620-1626 Published Online before print September 24, 2014 DOI 10.1212/WNL.0000000000000941 This information is current as of September 24, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/83/18/1620.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Preoperative factors of apathy in subthalamic stimulated Parkinson disease A PET study
Gabriel H. Robert, MD, PhD* Florence Le Jeune, MD, PhD* Clement Lozachmeur, MD Sophie Drapier, MD Thibaut Dondaine, MSc Julie Péron, PhD Jean-Francois Houvenaghel, MSc David Travers, MD Paul Sauleau, MD, PhD Bruno Millet, MD, PhD Marc Vérin, MD, PhD Dominique Drapier, MD, PhD
ABSTRACT
Objective: The current literature provides discrepant results regarding preoperative sociodemographic and clinical factors, and no information about preoperative cerebral metabolic patterns associated with apathy after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease.
Methods: To resolve this issue, we set out to identify preoperative metabolic patterns and sociodemographic and clinical factors associated with increased apathy after STN-DBS. Forty-four patients with Parkinson disease were enrolled in this study. They all underwent STN-DBS. Metabolic activity was assessed with F-18 fluorodeoxyglucose PET 3 months before surgery. Apathy was assessed on the Apathy Evaluation Scale 3 months before and after STN-DBS. We controlled for preoperative age, levodopa therapy, and overall cognitive functions.
Results: Increased apathy after STN-DBS was significantly associated with reduced preoperative metabolism within the right ventral striatum. None of the sociodemographic and clinical variables tested were associated with apathy after STN-DBS. Conclusions: Preoperative PET, but not sociodemographic or clinical factors, is associated with apathy after STN-DBS. Neurology® 2014;83:1620–1626 GLOSSARY
Correspondence to Dr. Robert: [email protected]
AES 5 Apathy Evaluation Scale; AMDP-TA 5 Association for Methodology and Documentation in Psychiatry–Trait Anxiety; A-STN-DBS 5 subthalamic nucleus deep brain stimulation postoperative apathy; DRT 5 dopamine replacement therapy; 18-FDG-PET 5 F-18 fluorodeoxyglucose PET; GLM 5 general linear model; LEDD 5 levodopa equivalent daily dose; MCST 5 Modified Card Sorting Test; MDRS 5 Mattis Dementia Rating Scale; PD 5 Parkinson disease; ROI 5 region of interest; STN-DBS 5 subthalamic nucleus deep brain stimulation; TMT 5 Trail Making Test; UPDRS-III 5 Unified Parkinson’s Disease Rating Scale–III; VS 5 ventral striatum; WFU 5 Wake Forest University.
Several nonmotor side effects, including apathy,1–4 are described following uni- and bilateral subthalamic nucleus deep brain stimulation (STN-DBS), compromising the overall surgical outcome5 and impairing quality of life.6 Some results suggest that age at surgery,3,7 wide preoperative variations in anxiety during a dopamine challenge, and the presence of preoperative nonmotor fluctuations4 are associated with greater postoperative apathy (A-STN-DBS). Identifying the clinical predictors of A-STNDBS will help clinicians to select those patients who will benefit most from STN-DBS. However, attempts have so far lacked consistency. The STN is a motor, cognitive, but also limbic structure,8 and it is suggested that A-STNDBS occurs as a result of stimulating the limbic cortico-subcortical loops,9 independently of the reduction in dopamine replacement therapy (DRT) after STN-DBS.1,10 Another hypothesis is that A-STN-DBS stems from dopamine mesolimbic pathway degeneration that is unmasked by the DRT reduction.4 Thus, A-STN-DBS appears to be a complex and multifactorial behavioral disorder, arising from the massive disruption by STN limbic stimulation and DRT reduction of a gradual degenerative process. Supplemental data at Neurology.org *These authors contributed equally to this work. From the Academic Department of Psychiatry (G.H.R., C.L., T.D., B.M., D.D.), Guillaume Régnier Hospital, Rennes; Nuclear Medicine Unit (F.L.J.), Oncology Department, Eugène Marquis Center, Rennes; Movement Disorders Unit, Neurology Department (S.D., J.-F.H., M.V.), Academic Department of Psychiatry (D.T.), and Neurophysiology Unit, Neurology Department (P.S.), Rennes University Hospital, France; and Neuroscience of Emotion and Affective Dynamics Laboratory (J.P.), Swiss Center for Affective Sciences, Geneva, Switzerland. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 1620
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We sought to pinpoint preoperative metabolic activity associated with greater A-STNDBS in Parkinson disease (PD) using F-18 fluorodeoxyglucose PET (18-FDG-PET) and a region-of-interest (ROI) approach with the Wake Forest University (WFU) PickAtlas toolbox.11 We hypothesized that preoperative metabolic activity within brain regions involved in goal-oriented behaviors is associated with greater A-STN-DBS, whereas potential clinical predictors will lack sensitivity.
The main variable is the differential score (D) between postoperative and preoperative AES (DAES 5 postoperative AES 2 preoperative AES). The DAES distribution is displayed in figure 1. Preoperative trait anxiety was assessed on the Association for Methodology and Documentation in Psychiatry–Trait Anxiety (AMDP-TA) Scale. This scale is particularly appropriate for assessing anxiety in PD because there are only a few somatic items, which can confound anxiety assessment in PD.1 Depression symptoms severity was assessed with the Montgomery and Åsberg Depression Rating Scale.e1
METHODS Participants, study design, standard protocol approvals, and patient consents. All patients were consecutively recruited at Rennes University Hospital, France, between 2005 and 2012. All 44 patients with PD (24 males) met the clinical criteria of the Parkinson’s UK Brain Bank for idiopathic PD, and exclusion criteria for STN-DBS12 were applied, including severe cognitive impairments (Mattis Dementia Rating Scale [MDRS]13 score ,130) and major depression (according to the Mini-International Neuropsychiatric Interview 50014). All patients underwent sociodemographic and clinical assessment 3 months before and after STN-DBS. All patients benefited from 18-FDG-PET 3 months before STN-DBS, under medication as prescribed by their neurologist. Patients with missing data were excluded from the study. Written informed consent was obtained from each participant and the study was approved by the local ethical standard committee on human experimentation.
Motor assessment. The motor part of the Unified Parkinson’s Disease Rating Scale–III (UPDRS-III) was administered both when patients were in the off-drug condition (i.e., after a 12-hour period without their DRT) and during a dopamine challenge (usual morning dose 1 50 mg levodopa) in order to assess their motor dopamine response. A levodopa equivalent daily dose (LEDD) was calculated for each patient according to the DRT prescribed by their neurologist.17 The quantitative effect of STN-DBS was calculated as follows: pre-STN-DBSoff levodopa 2 post-STNDBSon stim & off levodopa/pre-STN-DBSoff levodopa 3 100.18 Sociodemographic and preoperative motor, psychiatric, and cognitive data are provided in the table.
Psychiatric assessment. Apathy was assessed on the Apathy Evaluation Scale (AES), Clinician Version.15 This is an 18-item scale with scores ranging from 18 to 72, the highest scores reflecting severe apathy. It is recognized as the most psychometrically robust apathy scale across all populations.16
Figure 1
DAES distribution within the sample (n 5 44)
AES 5 Apathy Evaluation Scale.
Neuropsychological assessment. Executive functions were assessed by means of a neuropsychological battery that included the Modified Card Sorting Test (MCST),e2 the Trail Making Test (TMT),e3 semantic and phonemic fluency, and the Stroop test.e4
PET imaging procedure. PET measurements were performed using a Discovery ST PET scanner (axial resolution): Y coordinates from the field of view center: 1 cm (full width at half maximum 5 5.1 mm and full width of the tenth of maximum 5 9.4 mm); Y coordinates from the field of view center: 10 cm (full width at half maximum 5 6.2 mm and full width of the tenth of maximum 5 12.6 mm; General Electric Medical Systems, Milwaukee, WI) in 2-dimensional (2D) mode, with an axial field of view of 15.2 cm. A 222- to 296-MBq injection of F-18 FDG was administered IV under standardized conditions. Stable positioning was attained using a crosshair laser system. Thirty minutes after the injection, patients were positioned at the center of the field of view and a 20-minute 2D scan was acquired. After x-ray CT-based attenuation, scatter, deadtime, and random corrections, the PET images were reconstructed with 2D filtered back-projection, yielding 47 contiguous transaxial 3.75-mm-thick slices. The data were analyzed with Statistical Parametric Mapping software19 (SPM8; Wellcome Department of Cognitive Neurology, London) written in MATLAB version 7.9.0 (MathWorks, Natick, MA). Statistical parametric maps combine the general linear model (GLM) with the random field theory to make statistical inferences about regional effects.20 All images were realigned and spatially normalized to a standard stereotactic space according to the Talairach-Tournoux atlas.21 Rigid and nonlinear transformations enable coregistering the images together. Then, images are spatially normalized onto the template space. Finally, the coregistered and normalized images are smoothed, using an isotropic 12-mm full width at half maximum isotropic gaussian kernel to ensure normal distribution and respect parametric statistics assumptions. The effects of whole-brain metabolism (i.e., global normalization) are removed by scaling proportionally the count of each voxel to the total brain count. Neurosurgery. Methodology. Quadripolar DBS electrodes (3389; Medtronic, Minneapolis, MN) were implanted bilaterally in the subthalamic nucleus.22 The exact locations of the 2 selected Neurology 83
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Table
Sociodemographic and preoperative motor, psychiatric, and cognitive variables (n 5 44)
Features
Range
Mean
SD
Pearson r with DAES
p Value
Age, y
36–68
56.3
7.5
0.2
0.9
DAES
211 to 16
0.18
5.35
—
—
Preoperative AES (18–72)
18–44
31.4
6.4
20.27
0.07
Postoperative AES (18–72)
18–51
31.6
7.1
—
—
Disease duration, y
5–21
11.4
4.1
20.09
0.55
Preoperative MADRS (0–60)
0–17
4.45
4
20.28
0.07
Preoperative AMDP-TA (0–85)
0–40
9.45
8.7
0.1
0.5
Preoperative UPDRS-III off dopamine (0–108)
10–67
32.6
12.8
0
1
Preoperative UPDRS-III on dopamine (0–108)
0–23
7.5
5.2
0.06
0.7
Postoperative UPDRS-III off dopamine–off stimulation (0–108)
8–61
29.2
12.7
—
—
Postoperative UPDRS-III off dopamine–on stimulation (0–108)
1–37
15.9
9.6
—
—
Postoperative UPDRS-III on dopamine–off stimulation (0–108)
0–27
8.8
7.1
—
—
Postoperative UPDRS-III on dopamine–on stimulation (0–108)
0–11
5.2
2.5
—
—
Preoperative motor dopamine response
5–64
25.2
11.7
20.03
0.8
Preoperative LEDD, mg/d
240–2,990
1,280.8
632.4
0.25
0.09
LEDD reduction after STN-DBS, mg/d
21,470 to 455
2390.9
2413.1
0.23
0.1
Preoperative MDRS (/144)
132–144
140.6
2.5
0.17
0.3
Preoperative stroop interference score
222.6 to 15.1
1.2
7.6
20.25
0.1
Preoperative TMT B-A
12–309
64.4
54
0.16
0.3
Preoperative semantic fluency
13–53
28.1
9.8
0.05
0.7
Preoperative phonemic fluency
12–36
22.6
6.8
0.06
0.7
Preoperative MCST–Criteria
3–6
5.7
0.7
20.18
0.26
Preoperative MCST–Errors
0–18
4.5
4.7
0.2
0.2
Preoperative MCST–Perseverations
0–10
1.4
2.2
0.2
0.2
Abbreviations: DAES 5 postoperative AES 2 preoperative AES; AES 5 Apathy Evaluation Scale; AMDP-TA 5 Association for Methodology and Documentation in Psychiatry–Trait Anxiety; LEDD 5 levodopa equivalent daily dose; MADRS 5 Montgomery and Åsberg Depression Rating Scale; MCST 5 Modified Card Sorting Test; STN-DBS 5 subthalamic nucleus deep brain stimulation; TMT 5 Trail Making Test; UPDRS-III 5 Unified Parkinson’s Disease Rating Scale–III. One patient with tremor-dominant Parkinson disease had UPDRS-III Off scores of 10.
electrode contacts (left and right) were determined using stereotactic coordinates derived from a 3-dimensional CT scan. Electrode locations and parameters. The selected contacts were located 14.2 6 1.6 mm (17.1–10.8) lateral to, 2.7 6 1.7 mm (25.3 to 21.5) posterior to, and 1.3 6 1.9 mm (3.5–3.2) below the midcommissural point on the left side, and 13.5 6 2.3 mm (10–18.1) lateral to, 2.5 6 1.4 mm (4.3 to 21.9) posterior to and 1.2 6 3.1 mm (6.9 to 26.4) below the midcommissural point on the right side. In all patients, chronic stimulation was monopolar. The stimulation characteristics are the ones that better improve motor scores: mean pulse width 60.7 ms for the right side (SD 5 4.6) and 60.7 ms (SD 5 4.6) for the left side, mean frequency 132.1 Hz (SD 5 6.2) for the right side and 131.5 Hz (SD 5 4.4) for the left side, and mean voltage 2.1 V (SD 5 0.6) for the right side and 2.1 V (SD 5 0.6) for the left side.
Statistics. Clinical factors. Because all the variables were normally distributed, we calculated correlations between the DAES and the sociodemographic and preoperative motor, cognitive, and 1622
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psychiatric measures. We conducted independent t tests between male and female participants to determine whether there was a sex effect. The significance threshold was set at p 5 0.05. To check for regression to the mean between preoperative apathy and DAES, we determined the so-called a(a 2 b) effect by examining the covariance between preoperative AES and DAES.23 If the preoperative AES score was found to be significantly related to DAES without any regression to the mean effect, we would also include preoperative AES as a covariate in the imaging analysis. PET data: Statistical parametric mapping. ROI definition. The ROI mask includes the cerebral bases of apathy in PD24–27 and A-STN-DBS2,4 based on previous litterature.2,4,24–27 We built our ROI mask using the automated anatomical labeling atlas11 from the WFU PickAtlas toolbox28 implemented in SPM8. The following regions were chosen as ROIs, all bilaterally: the superior frontal gyrus and its orbital part, the middle frontal gyrus and its orbital part, the inferior frontal gyrus and its orbital part, the anterior and posterior cingulate cortices, the caudate nucleus, and the putamen.
Figure 2
Decreased metabolism within the right VS is associated with greater DAES scores
dopamine motor response, LEDD reduction), cognitive (MDRS, Stroop interference score, TMT B-A, MCST criteria, MCST errors and MCST perseverative answers, semantic and phonemic fluency scores), or psychiatric (AMDP-TA scores) variables. We did not find any DAES differences between male and female participants (p 5 0.7). Mean LEDD reduction was 28.6% after STN-DBS within the whole sample. The quantitative effect of STN-DBS was equal to 51%. PET results. We found that decreased metabolism within the right ventral striatum (VS) (Talairach coordinates: x 5 18, y 5 20, z 5 28; z 5 3.12, cluster size 5 139) was associated with greater DAES (figure 2). We did not find any brain region where increased metabolism was associated with greater DAES. We found that preoperative metabolism within the identified cluster was inversely associated with DAES (r 5 20.48; p 5 0.002). Figure 3 displays the correlation between the b values within the right VS and DAES.
Results obtained using F-18 fluorodeoxyglucose PET in 44 patients with Parkinson disease without dementia and depression (p value ,0.005 uncorrected, cluster threshold k 5 100). AES 5 Apathy Evaluation Scale; VS 5 ventral striatum.
To identify the brain regions whose metabolism was significantly correlated with DAES, a multiple regression design of the GLM was tested at each voxel within the ROI, with DAES as a covariate. Age, LEDD, and MDRS score were also included in the model as covariates to control for their confounding effects. Because we found a trend toward significance between preoperative AES and DAES that was not driven by a regression to the mean (see below), we also included the preoperative AES score in the model as a covariate to control for its confounding effect. Two contrasts were performed: either increased or decreased voxel values (i.e., metabolism) associated with increased DAES. Clusters of a minimum of 100 voxels with a threshold z score of 3 (p 5 0.005, uncorrected) were deemed to be significant. We then used MarsBaR29 to extract the b values from the cluster generated by the GLM, for each individual. Results were then plotted against DAES using partial correlation controlling for age, LEDD, MDRS score, and preoperative AES score using SPSS software. RESULTS Sociodemographic and clinical factors. Pear-
son correlation coefficients and p values are displayed in the table. Because we found that preoperative AES and DAES were inversely associated with a trend toward significance, we sought for a regression to the mean effect between those 2 variables. The method23 applied shows that the correlation between the preoperative AES score and DAES is not accounted for by a regression to the mean effect. We did not find any relationship between DAES and any of the demographic (age), motor (disease duration, LEDD, UPDRS-III off and on dopamine,
DISCUSSION Our results can be interpreted in light of previous results supporting the theory of degeneration of the mesolimbic dopamine pathway (which includes the VS) in patients who develop apathy after STN-DBS.4 Mesolimbic dopamine manipulations in animals suggest that dopamine has a key role in regulating motivated behaviors, especially their rewardseeking (wanting, or anticipating).30 Wanting is associated with the anticipation phase of a reward and VS activity31; the latter has also been related to apathy in schizophrenia.32 Alternatively, our results may be attributable to broad lesions of the limbic cortico-subcortical loop. Indeed, apathy in PD is likely to be associated with decreased gray matter volumes within the anterior cingulate and the orbitofrontal cortex,25 both part of the limbic loop.33 The right-sided lateralization is consistent with a previous study that found that the right side of the brain is particularly involved in apathy’s metabolic network in PD.24,34 The predominance of the right side in apathy’s cerebral bases is also described in Alzheimer disease.35 Moreover, some researchers suggest that the reward-related dopamine system is predominantly associated with the right VS, especially in men.36 The age-related decline in dopamine transmission is suggested to be lower within the right (vs left) anterior caudate and putamen.37 These results are consistent with the decreased metabolism within the right VS and greater A-STN-DBS in our sample of patients with a mean age of 56.3 (67.5) years and a slight predominance of men (24 of 44 patients). When the present result is set against the available literature, it suggests that A-STN-DBS could be either related to Neurology 83
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Figure 3
Decreased metabolism within the right ventral striatum cluster is associated with greater DAES scores
The b values from the cluster generated by statistical parametric mapping were extracted for each individual using MarsBaR. AES 5 Apathy Evaluation Scale.
abnormal preoperative limbic dopamine secretion4 or dysfunctional cortico-subcortical limbic loop in combination with the stimulation of the limbic and associative parts of the STN.2,9 In the context of the gradual degeneration of motor and limbic dopamine neurons in PD,38 it suggests that STN-DBS brutally disrupts a precarious preoperative balance among brain plasticity, residual dopamine resources, and dopaminergic medication. The clinical and sociodemographic factors associated with increased apathy after STN-DBS are inconsistent across studies. Middle-aged (vs older) patients are found to experience a steeper increase in apathy in unilateral stimulation,3 whereas age is found to magnify apathy after bilateral STN-DBS.7 Our results do not highlight age as an associated factor for increased apathy after bilateral STN-DBS. However, our sample included patients who were younger (mean age 56.3 6 7.5 years) than those of the latter study7 (mean 5 60.1 6 8.7 years), and our follow-up time point was 3 months after surgery, as opposed to 12 months in their study.7 These differences may account for the discrepant results. The presence of nonmotor fluctuations and a greater variation in Beck Anxiety Inventory scores during a dopamine challenge in the off-drug state may be associated with apathy after STN-DBS.4 There was, however, no 1624
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significant association between trait anxiety and apathy after STN-DBS in our study, possibly because we used a different anxiety scale. We also failed to find an association between motor score variations during a dopamine challenge and higher apathy scores after STN-DBS. This is in line with the absence of reports of significant links between motor structure metabolism and A-STN-DBS both here and in previous research.2 We failed to find association between preoperative AES and DAES scores. Instead, we found an inverse relationship between the 2, with a trend toward significance that was not accounted for by a regression to the mean effect. However, had the correlation between preoperative AES and DAES been clearly significant, there might have been a regression to the mean effect. Further studies with larger samples are needed to test this hypothesis. The LEDD reduction observed here was smaller than that in other reports,18 but we found a similar effect of the stimulation on the UPDRS-III scores18 and we attribute this to the neurologists’ sensitization toward the nonmotor effect of LEDD reduction after STN-DBS, such as apathy. Our negative results regarding the sociodemographic and clinical factors are in line with the discrepant results in the literature. We suggest that these inconsistencies can be ascribed to a lack of homogeneity in the studies conducted thus far, combined with the absence of specific tools for spotting altered limbic functions. Several limitations must be borne in mind when interpreting these results. First, our research focus on apathy scores 3 months after STN-DBS, and some results, suggest that apathy scores may continue to increase beyond the 3-month mark.1,3,4 Even so, the literature suggests that 3 months is a reasonable point at which to study the chronic effects of bilateral STNDBS, because any motor, cognitive, or psychiatric complications arising from the surgery itself are unlikely to occur after 3 months.1 Second, the mean DAES score is 0.18, suggesting minimal variation in apathy across the group as a whole, whereas our sample displays a relatively wide range of DAES scores (211 to 116) that yields stronger results at the metabolic level. Further studies are warranted to replicate this result with larger samples and 2 measurement points after surgery. They should also specifically address the predictive value of individual preoperative imaging patterns in patients candidate to STN-DBS combining a 1-vs-many 2-sample t-test univariate39 and multivariate pattern analysis.40 This study suggests that only metabolic activity within the right VS is associated with apathy after STN-DBS in patients with PD without depression and dementia. By contrast, none of the sociodemographic and clinical factors tested were found to be related to apathy. This suggests that, if replicated,
preoperative activity within the right VS will be a candidate biomarker for predicting apathy after STNDBS at an individual level and result in a major improvement in the care of patients with PD.
8.
9.
AUTHOR CONTRIBUTIONS G.H. Robert: psychiatric assessment, statistical analyses, SPM analyses, writing of the first draft. F. Le Jeune: PET acquisition, SPM analyses, conception of the study, writing of the first draft. C. Lozachmeur: psychiatric assessment, revision of the manuscript. S. Drapier: neurologic assessment, revision of the manuscript. T. Dondaine: neuropsychological assessment, revision of the manuscript. J. Péron: neuropsychological assessment, revision of the manuscript. J.-F. Houvenaghel: neuropsychological assessment, revision of the manuscript. D. Travers: conception of the study, revision of the manuscript. P. Sauleau: conception of the study, revision of the manuscript. B. Millet: conception of the study, revision of the manuscript. M. Vérin: conception of the study, revision of the manuscript. D. Drapier: conception of the study, revision of the manuscript.
ACKNOWLEDGMENT The authors thank Dr. Mitul Mehta from the Institute of Psychiatry (King’s College, London) for his help with the statistical analyses of the clinical data, and all members of the nuclear medicine and neurology staff at Rennes University Hospital.
STUDY FUNDING This study was supported by the University of Rennes 1, “Innovating Project” grants 2011 and 2012. The funding source had no involvement in the study design, collection, analysis, and interpretation of the data.
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DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
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Skidmore FM, Yang M, Baxyer L, et al. Apathy, depression, and motor symptoms have distinct and separable resting activity patterns in idiopathic Parkinson disease. Neuroimage 2013;81:484–495. Lawrence AD, Goerendt IK, Brooks DJ. Apathy blunts neural response to money in Parkinson’s disease. Soc Neurosci 2011;6:653–662. Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH. An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 2003;19:1233–1239. Brett M, Anton J, Valabrègue R, Poline JB. Region of interest analysis using the MarsBaR toolbox for SPM 99. Neuroimage 2002;16:S497. Salamone JD, Correa M. The mysterious motivational functions of mesolimbic dopamine. Neuron 2012;76: 470–485. Knutson B, Westdorp A, Kaiser E, Hommer D. FMRI visualization of brain activity during a monetary incentive delay task. Neuroimage 2000;12:20–27. Simon JJ, Biller A, Walther S, et al. Neural correlates of reward processing in schizophrenia: relationship to apathy and depression. Schizophr Res 2010;118:154–161. Alexander GE, Crutcher MD, DeLong MR. Basal gangliathalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Prog Brain Res 1990;85:119–146.
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Robert G, Le Jeune F, Dondaine T, et al. Apathy and impaired emotional facial recognition networks overlap in Parkinson’s disease: a PET study with conjunction analyses. J Neurol Neurosurg Psychiatry Epub 2014 Jan 8. Bruen PD, McGeown WJ, Shanks MF, Venneri A. Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer’s disease. Brain 2008;131:2455–2463. Martin-Soelch C, Szczepanik J, Nugent A, et al. Lateralization and gender differences in the dopaminergic response to unpredictable reward in the human ventral striatum. Eur J Neurosci 2011;33:1706–1715. Van Dyck CH, Seybil JP, Malison RT, et al. Age-related decline in dopamine transporters: analysis of striatal subregions, nonlinear effects, and hemispheric asymmetries. Am J Geriatr Psychiatry 2002;10:36–43. Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K. Stages in the development of Parkinson’s diseaserelated pathology. Cell Tissue Res 2004;318:121–134. Maumet C, Maurel P, Ferré JC, Carsin B, Barillot C. Patient-specific detection of perfusion abnormalities combining within-subject and between-subject variances in arterial spin labeling. Neuroimage 2013;81:121–130. Orrù G, Pettersson-Yeo W, Marquand AF, Sartori G, Mechelli A. Using Support Vector Machine to identify imaging biomarkers of neurological and psychiatric disease: a critical review. Neurosci Biobehav Rev 2012;36: 1140–1152.
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Preoperative factors of apathy in subthalamic stimulated Parkinson disease: A PET study Gabriel H. Robert, Florence Le Jeune, Clement Lozachmeur, et al. Neurology 2014;83;1620-1626 Published Online before print September 24, 2014 DOI 10.1212/WNL.0000000000000941 This information is current as of September 24, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/18/1620.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/09/24/WNL.00000 00000000941.DC1.html
References
This article cites 37 articles, 6 of which you can access for free at: http://www.neurology.org/content/83/18/1620.full.html##ref-list1
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This article, along with others on similar topics, appears in the following collection(s): All Neuropsychology/Behavior http://www.neurology.org//cgi/collection/all_neuropsychology_b ehavior Parkinson's disease/Parkinsonism http://www.neurology.org//cgi/collection/parkinsons_disease_par kinsonism PET http://www.neurology.org//cgi/collection/pet
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Preoperative factors of apathy in subthalamic stimulated Parkinson disease A PET study
Gabriel H. Robert, MD, PhD* Florence Le Jeune, MD, PhD* Clement Lozachmeur, MD Sophie Drapier, MD Thibaut Dondaine, MSc Julie Péron, PhD Jean-Francois Houvenaghel, MSc David Travers, MD Paul Sauleau, MD, PhD Bruno Millet, MD, PhD Marc Vérin, MD, PhD Dominique Drapier, MD, PhD
ABSTRACT
Objective: The current literature provides discrepant results regarding preoperative sociodemographic and clinical factors, and no information about preoperative cerebral metabolic patterns associated with apathy after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease.
Methods: To resolve this issue, we set out to identify preoperative metabolic patterns and sociodemographic and clinical factors associated with increased apathy after STN-DBS. Forty-four patients with Parkinson disease were enrolled in this study. They all underwent STN-DBS. Metabolic activity was assessed with F-18 fluorodeoxyglucose PET 3 months before surgery. Apathy was assessed on the Apathy Evaluation Scale 3 months before and after STN-DBS. We controlled for preoperative age, levodopa therapy, and overall cognitive functions.
Results: Increased apathy after STN-DBS was significantly associated with reduced preoperative metabolism within the right ventral striatum. None of the sociodemographic and clinical variables tested were associated with apathy after STN-DBS. Conclusions: Preoperative PET, but not sociodemographic or clinical factors, is associated with apathy after STN-DBS. Neurology® 2014;83:1620–1626 GLOSSARY
Correspondence to Dr. Robert: [email protected]
AES 5 Apathy Evaluation Scale; AMDP-TA 5 Association for Methodology and Documentation in Psychiatry–Trait Anxiety; A-STN-DBS 5 subthalamic nucleus deep brain stimulation postoperative apathy; DRT 5 dopamine replacement therapy; 18-FDG-PET 5 F-18 fluorodeoxyglucose PET; GLM 5 general linear model; LEDD 5 levodopa equivalent daily dose; MCST 5 Modified Card Sorting Test; MDRS 5 Mattis Dementia Rating Scale; PD 5 Parkinson disease; ROI 5 region of interest; STN-DBS 5 subthalamic nucleus deep brain stimulation; TMT 5 Trail Making Test; UPDRS-III 5 Unified Parkinson’s Disease Rating Scale–III; VS 5 ventral striatum; WFU 5 Wake Forest University.
Several nonmotor side effects, including apathy,1–4 are described following uni- and bilateral subthalamic nucleus deep brain stimulation (STN-DBS), compromising the overall surgical outcome5 and impairing quality of life.6 Some results suggest that age at surgery,3,7 wide preoperative variations in anxiety during a dopamine challenge, and the presence of preoperative nonmotor fluctuations4 are associated with greater postoperative apathy (A-STN-DBS). Identifying the clinical predictors of A-STNDBS will help clinicians to select those patients who will benefit most from STN-DBS. However, attempts have so far lacked consistency. The STN is a motor, cognitive, but also limbic structure,8 and it is suggested that A-STNDBS occurs as a result of stimulating the limbic cortico-subcortical loops,9 independently of the reduction in dopamine replacement therapy (DRT) after STN-DBS.1,10 Another hypothesis is that A-STN-DBS stems from dopamine mesolimbic pathway degeneration that is unmasked by the DRT reduction.4 Thus, A-STN-DBS appears to be a complex and multifactorial behavioral disorder, arising from the massive disruption by STN limbic stimulation and DRT reduction of a gradual degenerative process. Supplemental data at Neurology.org *These authors contributed equally to this work. From the Academic Department of Psychiatry (G.H.R., C.L., T.D., B.M., D.D.), Guillaume Régnier Hospital, Rennes; Nuclear Medicine Unit (F.L.J.), Oncology Department, Eugène Marquis Center, Rennes; Movement Disorders Unit, Neurology Department (S.D., J.-F.H., M.V.), Academic Department of Psychiatry (D.T.), and Neurophysiology Unit, Neurology Department (P.S.), Rennes University Hospital, France; and Neuroscience of Emotion and Affective Dynamics Laboratory (J.P.), Swiss Center for Affective Sciences, Geneva, Switzerland. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 1620
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We sought to pinpoint preoperative metabolic activity associated with greater A-STNDBS in Parkinson disease (PD) using F-18 fluorodeoxyglucose PET (18-FDG-PET) and a region-of-interest (ROI) approach with the Wake Forest University (WFU) PickAtlas toolbox.11 We hypothesized that preoperative metabolic activity within brain regions involved in goal-oriented behaviors is associated with greater A-STN-DBS, whereas potential clinical predictors will lack sensitivity.
The main variable is the differential score (D) between postoperative and preoperative AES (DAES 5 postoperative AES 2 preoperative AES). The DAES distribution is displayed in figure 1. Preoperative trait anxiety was assessed on the Association for Methodology and Documentation in Psychiatry–Trait Anxiety (AMDP-TA) Scale. This scale is particularly appropriate for assessing anxiety in PD because there are only a few somatic items, which can confound anxiety assessment in PD.1 Depression symptoms severity was assessed with the Montgomery and Åsberg Depression Rating Scale.e1
METHODS Participants, study design, standard protocol approvals, and patient consents. All patients were consecutively recruited at Rennes University Hospital, France, between 2005 and 2012. All 44 patients with PD (24 males) met the clinical criteria of the Parkinson’s UK Brain Bank for idiopathic PD, and exclusion criteria for STN-DBS12 were applied, including severe cognitive impairments (Mattis Dementia Rating Scale [MDRS]13 score ,130) and major depression (according to the Mini-International Neuropsychiatric Interview 50014). All patients underwent sociodemographic and clinical assessment 3 months before and after STN-DBS. All patients benefited from 18-FDG-PET 3 months before STN-DBS, under medication as prescribed by their neurologist. Patients with missing data were excluded from the study. Written informed consent was obtained from each participant and the study was approved by the local ethical standard committee on human experimentation.
Motor assessment. The motor part of the Unified Parkinson’s Disease Rating Scale–III (UPDRS-III) was administered both when patients were in the off-drug condition (i.e., after a 12-hour period without their DRT) and during a dopamine challenge (usual morning dose 1 50 mg levodopa) in order to assess their motor dopamine response. A levodopa equivalent daily dose (LEDD) was calculated for each patient according to the DRT prescribed by their neurologist.17 The quantitative effect of STN-DBS was calculated as follows: pre-STN-DBSoff levodopa 2 post-STNDBSon stim & off levodopa/pre-STN-DBSoff levodopa 3 100.18 Sociodemographic and preoperative motor, psychiatric, and cognitive data are provided in the table.
Psychiatric assessment. Apathy was assessed on the Apathy Evaluation Scale (AES), Clinician Version.15 This is an 18-item scale with scores ranging from 18 to 72, the highest scores reflecting severe apathy. It is recognized as the most psychometrically robust apathy scale across all populations.16
Figure 1
DAES distribution within the sample (n 5 44)
AES 5 Apathy Evaluation Scale.
Neuropsychological assessment. Executive functions were assessed by means of a neuropsychological battery that included the Modified Card Sorting Test (MCST),e2 the Trail Making Test (TMT),e3 semantic and phonemic fluency, and the Stroop test.e4
PET imaging procedure. PET measurements were performed using a Discovery ST PET scanner (axial resolution): Y coordinates from the field of view center: 1 cm (full width at half maximum 5 5.1 mm and full width of the tenth of maximum 5 9.4 mm); Y coordinates from the field of view center: 10 cm (full width at half maximum 5 6.2 mm and full width of the tenth of maximum 5 12.6 mm; General Electric Medical Systems, Milwaukee, WI) in 2-dimensional (2D) mode, with an axial field of view of 15.2 cm. A 222- to 296-MBq injection of F-18 FDG was administered IV under standardized conditions. Stable positioning was attained using a crosshair laser system. Thirty minutes after the injection, patients were positioned at the center of the field of view and a 20-minute 2D scan was acquired. After x-ray CT-based attenuation, scatter, deadtime, and random corrections, the PET images were reconstructed with 2D filtered back-projection, yielding 47 contiguous transaxial 3.75-mm-thick slices. The data were analyzed with Statistical Parametric Mapping software19 (SPM8; Wellcome Department of Cognitive Neurology, London) written in MATLAB version 7.9.0 (MathWorks, Natick, MA). Statistical parametric maps combine the general linear model (GLM) with the random field theory to make statistical inferences about regional effects.20 All images were realigned and spatially normalized to a standard stereotactic space according to the Talairach-Tournoux atlas.21 Rigid and nonlinear transformations enable coregistering the images together. Then, images are spatially normalized onto the template space. Finally, the coregistered and normalized images are smoothed, using an isotropic 12-mm full width at half maximum isotropic gaussian kernel to ensure normal distribution and respect parametric statistics assumptions. The effects of whole-brain metabolism (i.e., global normalization) are removed by scaling proportionally the count of each voxel to the total brain count. Neurosurgery. Methodology. Quadripolar DBS electrodes (3389; Medtronic, Minneapolis, MN) were implanted bilaterally in the subthalamic nucleus.22 The exact locations of the 2 selected Neurology 83
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Table
Sociodemographic and preoperative motor, psychiatric, and cognitive variables (n 5 44)
Features
Range
Mean
SD
Pearson r with DAES
p Value
Age, y
36–68
56.3
7.5
0.2
0.9
DAES
211 to 16
0.18
5.35
—
—
Preoperative AES (18–72)
18–44
31.4
6.4
20.27
0.07
Postoperative AES (18–72)
18–51
31.6
7.1
—
—
Disease duration, y
5–21
11.4
4.1
20.09
0.55
Preoperative MADRS (0–60)
0–17
4.45
4
20.28
0.07
Preoperative AMDP-TA (0–85)
0–40
9.45
8.7
0.1
0.5
Preoperative UPDRS-III off dopamine (0–108)
10–67
32.6
12.8
0
1
Preoperative UPDRS-III on dopamine (0–108)
0–23
7.5
5.2
0.06
0.7
Postoperative UPDRS-III off dopamine–off stimulation (0–108)
8–61
29.2
12.7
—
—
Postoperative UPDRS-III off dopamine–on stimulation (0–108)
1–37
15.9
9.6
—
—
Postoperative UPDRS-III on dopamine–off stimulation (0–108)
0–27
8.8
7.1
—
—
Postoperative UPDRS-III on dopamine–on stimulation (0–108)
0–11
5.2
2.5
—
—
Preoperative motor dopamine response
5–64
25.2
11.7
20.03
0.8
Preoperative LEDD, mg/d
240–2,990
1,280.8
632.4
0.25
0.09
LEDD reduction after STN-DBS, mg/d
21,470 to 455
2390.9
2413.1
0.23
0.1
Preoperative MDRS (/144)
132–144
140.6
2.5
0.17
0.3
Preoperative stroop interference score
222.6 to 15.1
1.2
7.6
20.25
0.1
Preoperative TMT B-A
12–309
64.4
54
0.16
0.3
Preoperative semantic fluency
13–53
28.1
9.8
0.05
0.7
Preoperative phonemic fluency
12–36
22.6
6.8
0.06
0.7
Preoperative MCST–Criteria
3–6
5.7
0.7
20.18
0.26
Preoperative MCST–Errors
0–18
4.5
4.7
0.2
0.2
Preoperative MCST–Perseverations
0–10
1.4
2.2
0.2
0.2
Abbreviations: DAES 5 postoperative AES 2 preoperative AES; AES 5 Apathy Evaluation Scale; AMDP-TA 5 Association for Methodology and Documentation in Psychiatry–Trait Anxiety; LEDD 5 levodopa equivalent daily dose; MADRS 5 Montgomery and Åsberg Depression Rating Scale; MCST 5 Modified Card Sorting Test; STN-DBS 5 subthalamic nucleus deep brain stimulation; TMT 5 Trail Making Test; UPDRS-III 5 Unified Parkinson’s Disease Rating Scale–III. One patient with tremor-dominant Parkinson disease had UPDRS-III Off scores of 10.
electrode contacts (left and right) were determined using stereotactic coordinates derived from a 3-dimensional CT scan. Electrode locations and parameters. The selected contacts were located 14.2 6 1.6 mm (17.1–10.8) lateral to, 2.7 6 1.7 mm (25.3 to 21.5) posterior to, and 1.3 6 1.9 mm (3.5–3.2) below the midcommissural point on the left side, and 13.5 6 2.3 mm (10–18.1) lateral to, 2.5 6 1.4 mm (4.3 to 21.9) posterior to and 1.2 6 3.1 mm (6.9 to 26.4) below the midcommissural point on the right side. In all patients, chronic stimulation was monopolar. The stimulation characteristics are the ones that better improve motor scores: mean pulse width 60.7 ms for the right side (SD 5 4.6) and 60.7 ms (SD 5 4.6) for the left side, mean frequency 132.1 Hz (SD 5 6.2) for the right side and 131.5 Hz (SD 5 4.4) for the left side, and mean voltage 2.1 V (SD 5 0.6) for the right side and 2.1 V (SD 5 0.6) for the left side.
Statistics. Clinical factors. Because all the variables were normally distributed, we calculated correlations between the DAES and the sociodemographic and preoperative motor, cognitive, and 1622
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psychiatric measures. We conducted independent t tests between male and female participants to determine whether there was a sex effect. The significance threshold was set at p 5 0.05. To check for regression to the mean between preoperative apathy and DAES, we determined the so-called a(a 2 b) effect by examining the covariance between preoperative AES and DAES.23 If the preoperative AES score was found to be significantly related to DAES without any regression to the mean effect, we would also include preoperative AES as a covariate in the imaging analysis. PET data: Statistical parametric mapping. ROI definition. The ROI mask includes the cerebral bases of apathy in PD24–27 and A-STN-DBS2,4 based on previous litterature.2,4,24–27 We built our ROI mask using the automated anatomical labeling atlas11 from the WFU PickAtlas toolbox28 implemented in SPM8. The following regions were chosen as ROIs, all bilaterally: the superior frontal gyrus and its orbital part, the middle frontal gyrus and its orbital part, the inferior frontal gyrus and its orbital part, the anterior and posterior cingulate cortices, the caudate nucleus, and the putamen.
Figure 2
Decreased metabolism within the right VS is associated with greater DAES scores
dopamine motor response, LEDD reduction), cognitive (MDRS, Stroop interference score, TMT B-A, MCST criteria, MCST errors and MCST perseverative answers, semantic and phonemic fluency scores), or psychiatric (AMDP-TA scores) variables. We did not find any DAES differences between male and female participants (p 5 0.7). Mean LEDD reduction was 28.6% after STN-DBS within the whole sample. The quantitative effect of STN-DBS was equal to 51%. PET results. We found that decreased metabolism within the right ventral striatum (VS) (Talairach coordinates: x 5 18, y 5 20, z 5 28; z 5 3.12, cluster size 5 139) was associated with greater DAES (figure 2). We did not find any brain region where increased metabolism was associated with greater DAES. We found that preoperative metabolism within the identified cluster was inversely associated with DAES (r 5 20.48; p 5 0.002). Figure 3 displays the correlation between the b values within the right VS and DAES.
Results obtained using F-18 fluorodeoxyglucose PET in 44 patients with Parkinson disease without dementia and depression (p value ,0.005 uncorrected, cluster threshold k 5 100). AES 5 Apathy Evaluation Scale; VS 5 ventral striatum.
To identify the brain regions whose metabolism was significantly correlated with DAES, a multiple regression design of the GLM was tested at each voxel within the ROI, with DAES as a covariate. Age, LEDD, and MDRS score were also included in the model as covariates to control for their confounding effects. Because we found a trend toward significance between preoperative AES and DAES that was not driven by a regression to the mean (see below), we also included the preoperative AES score in the model as a covariate to control for its confounding effect. Two contrasts were performed: either increased or decreased voxel values (i.e., metabolism) associated with increased DAES. Clusters of a minimum of 100 voxels with a threshold z score of 3 (p 5 0.005, uncorrected) were deemed to be significant. We then used MarsBaR29 to extract the b values from the cluster generated by the GLM, for each individual. Results were then plotted against DAES using partial correlation controlling for age, LEDD, MDRS score, and preoperative AES score using SPSS software. RESULTS Sociodemographic and clinical factors. Pear-
son correlation coefficients and p values are displayed in the table. Because we found that preoperative AES and DAES were inversely associated with a trend toward significance, we sought for a regression to the mean effect between those 2 variables. The method23 applied shows that the correlation between the preoperative AES score and DAES is not accounted for by a regression to the mean effect. We did not find any relationship between DAES and any of the demographic (age), motor (disease duration, LEDD, UPDRS-III off and on dopamine,
DISCUSSION Our results can be interpreted in light of previous results supporting the theory of degeneration of the mesolimbic dopamine pathway (which includes the VS) in patients who develop apathy after STN-DBS.4 Mesolimbic dopamine manipulations in animals suggest that dopamine has a key role in regulating motivated behaviors, especially their rewardseeking (wanting, or anticipating).30 Wanting is associated with the anticipation phase of a reward and VS activity31; the latter has also been related to apathy in schizophrenia.32 Alternatively, our results may be attributable to broad lesions of the limbic cortico-subcortical loop. Indeed, apathy in PD is likely to be associated with decreased gray matter volumes within the anterior cingulate and the orbitofrontal cortex,25 both part of the limbic loop.33 The right-sided lateralization is consistent with a previous study that found that the right side of the brain is particularly involved in apathy’s metabolic network in PD.24,34 The predominance of the right side in apathy’s cerebral bases is also described in Alzheimer disease.35 Moreover, some researchers suggest that the reward-related dopamine system is predominantly associated with the right VS, especially in men.36 The age-related decline in dopamine transmission is suggested to be lower within the right (vs left) anterior caudate and putamen.37 These results are consistent with the decreased metabolism within the right VS and greater A-STN-DBS in our sample of patients with a mean age of 56.3 (67.5) years and a slight predominance of men (24 of 44 patients). When the present result is set against the available literature, it suggests that A-STN-DBS could be either related to Neurology 83
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Figure 3
Decreased metabolism within the right ventral striatum cluster is associated with greater DAES scores
The b values from the cluster generated by statistical parametric mapping were extracted for each individual using MarsBaR. AES 5 Apathy Evaluation Scale.
abnormal preoperative limbic dopamine secretion4 or dysfunctional cortico-subcortical limbic loop in combination with the stimulation of the limbic and associative parts of the STN.2,9 In the context of the gradual degeneration of motor and limbic dopamine neurons in PD,38 it suggests that STN-DBS brutally disrupts a precarious preoperative balance among brain plasticity, residual dopamine resources, and dopaminergic medication. The clinical and sociodemographic factors associated with increased apathy after STN-DBS are inconsistent across studies. Middle-aged (vs older) patients are found to experience a steeper increase in apathy in unilateral stimulation,3 whereas age is found to magnify apathy after bilateral STN-DBS.7 Our results do not highlight age as an associated factor for increased apathy after bilateral STN-DBS. However, our sample included patients who were younger (mean age 56.3 6 7.5 years) than those of the latter study7 (mean 5 60.1 6 8.7 years), and our follow-up time point was 3 months after surgery, as opposed to 12 months in their study.7 These differences may account for the discrepant results. The presence of nonmotor fluctuations and a greater variation in Beck Anxiety Inventory scores during a dopamine challenge in the off-drug state may be associated with apathy after STN-DBS.4 There was, however, no 1624
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significant association between trait anxiety and apathy after STN-DBS in our study, possibly because we used a different anxiety scale. We also failed to find an association between motor score variations during a dopamine challenge and higher apathy scores after STN-DBS. This is in line with the absence of reports of significant links between motor structure metabolism and A-STN-DBS both here and in previous research.2 We failed to find association between preoperative AES and DAES scores. Instead, we found an inverse relationship between the 2, with a trend toward significance that was not accounted for by a regression to the mean effect. However, had the correlation between preoperative AES and DAES been clearly significant, there might have been a regression to the mean effect. Further studies with larger samples are needed to test this hypothesis. The LEDD reduction observed here was smaller than that in other reports,18 but we found a similar effect of the stimulation on the UPDRS-III scores18 and we attribute this to the neurologists’ sensitization toward the nonmotor effect of LEDD reduction after STN-DBS, such as apathy. Our negative results regarding the sociodemographic and clinical factors are in line with the discrepant results in the literature. We suggest that these inconsistencies can be ascribed to a lack of homogeneity in the studies conducted thus far, combined with the absence of specific tools for spotting altered limbic functions. Several limitations must be borne in mind when interpreting these results. First, our research focus on apathy scores 3 months after STN-DBS, and some results, suggest that apathy scores may continue to increase beyond the 3-month mark.1,3,4 Even so, the literature suggests that 3 months is a reasonable point at which to study the chronic effects of bilateral STNDBS, because any motor, cognitive, or psychiatric complications arising from the surgery itself are unlikely to occur after 3 months.1 Second, the mean DAES score is 0.18, suggesting minimal variation in apathy across the group as a whole, whereas our sample displays a relatively wide range of DAES scores (211 to 116) that yields stronger results at the metabolic level. Further studies are warranted to replicate this result with larger samples and 2 measurement points after surgery. They should also specifically address the predictive value of individual preoperative imaging patterns in patients candidate to STN-DBS combining a 1-vs-many 2-sample t-test univariate39 and multivariate pattern analysis.40 This study suggests that only metabolic activity within the right VS is associated with apathy after STN-DBS in patients with PD without depression and dementia. By contrast, none of the sociodemographic and clinical factors tested were found to be related to apathy. This suggests that, if replicated,
preoperative activity within the right VS will be a candidate biomarker for predicting apathy after STNDBS at an individual level and result in a major improvement in the care of patients with PD.
8.
9.
AUTHOR CONTRIBUTIONS G.H. Robert: psychiatric assessment, statistical analyses, SPM analyses, writing of the first draft. F. Le Jeune: PET acquisition, SPM analyses, conception of the study, writing of the first draft. C. Lozachmeur: psychiatric assessment, revision of the manuscript. S. Drapier: neurologic assessment, revision of the manuscript. T. Dondaine: neuropsychological assessment, revision of the manuscript. J. Péron: neuropsychological assessment, revision of the manuscript. J.-F. Houvenaghel: neuropsychological assessment, revision of the manuscript. D. Travers: conception of the study, revision of the manuscript. P. Sauleau: conception of the study, revision of the manuscript. B. Millet: conception of the study, revision of the manuscript. M. Vérin: conception of the study, revision of the manuscript. D. Drapier: conception of the study, revision of the manuscript.
ACKNOWLEDGMENT The authors thank Dr. Mitul Mehta from the Institute of Psychiatry (King’s College, London) for his help with the statistical analyses of the clinical data, and all members of the nuclear medicine and neurology staff at Rennes University Hospital.
STUDY FUNDING This study was supported by the University of Rennes 1, “Innovating Project” grants 2011 and 2012. The funding source had no involvement in the study design, collection, analysis, and interpretation of the data.
10.
11.
12.
13. 14.
15.
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DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
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Preoperative factors of apathy in subthalamic stimulated Parkinson disease: A PET study Gabriel H. Robert, Florence Le Jeune, Clement Lozachmeur, et al. Neurology 2014;83;1620-1626 Published Online before print September 24, 2014 DOI 10.1212/WNL.0000000000000941 This information is current as of September 24, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/18/1620.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/09/24/WNL.00000 00000000941.DC1.html
References
This article cites 37 articles, 6 of which you can access for free at: http://www.neurology.org/content/83/18/1620.full.html##ref-list1
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