Pallidal Stimulation in Parkinson’s Disease Does Not Induce Apathy
Publication: The Journal of Neuropsychiatry and Clinical Neurosciences
Abstract
Background: Whereas apathy is known as a common consequence of subthalamic nucleus deep brain stimulation in Parkinson’s disease, few studies have investigated the psychiatric consequences of internal globus pallidus deep brain stimulation.
Method: Twenty consecutive parkinsonian patients who underwent bilateral pallidal stimulation were assessed 3 months prior to surgery (M‒3) and at both 3 (M3) and 6 months (M6) after surgery, using psychiatric, neuropsychological, and motor scales. Apathy, mood state, and anxiety state were scored using the Apathy Evaluation Scale, the Montgomery-Åsberg Depression Rating Scale, and the anxiety scale from the Association for Methodology and Documentation in Psychiatry, respectively.
Results: The mean apathy score remained stable between the preoperative M‒3 assessment (37.2±6.2) and both the postoperative M3 (36.9±7.5) and M6 (37.2±5.0) assessments. The mean depression score did not differ between the M‒3 assessment and M3 and M6 assessments. There was no difference between the preoperative mean anxiety score and both the postoperative M3 and M6 scores. The mean score for the Mattis Dementia Rating Scale remained stable at each study visit.
Conclusions: The main result of this study is the absence of deterioration in psychiatric and cognitive scores 3 months and 6 months after pallidal stimulation.
Deep brain stimulation (DBS) is now well established as an adjunct therapy for Parkinson’s disease (PD), especially for patients affected by long-term complications of levodopa therapy such as motor fluctuations and severe dyskinesias. Indeed, chronic DBS targeting the internal globus pallidus (GPi) and the subthalamic nucleus (STN) has been shown to yield a benefit both in motor function and in functional disability.1–5
Currently, the subthalamic nucleus has become the preferred target because the antiakinetic effect seems to be more robust, which allows a greater reduction of antiparkinsonian drug treatment, and requires less stimulation energy.6–10 However, an increasing number of studies have reported that STN DBS may be associated with neuropsychological, cognitive, and psychiatric dysfunction.11–13 Among these disturbances, apathy, defined as a lack of feeling, emotion, interest, concern, or motivation,14 has been largely described as a very common psychiatric STN DBS side effect.13 The STN is described as being situated in a central position in all five corticobasal ganglia-thalamocortical circuits, which each have specific motor, oculomotor, associative, and limbic functions.15 Neuroanatonomical and physiological studies in animals have demonstrated that the STN can be functionally divided into sensorimotor (dorsolateral), limbic (medial), and cognitive (ventromedial) regions.16 Because of the small size of the STN and current diffusion within the structure, STN DBS may act on different functional circuits, either activating or inhibiting different neuronal networks, including emotional and associative circuits. Apathy following STN DBS could be related to the stimulation of the STN associative circuit.
Because of all these reasons, patients with cognitive impairment or severe psychiatric disease are now excluded from subthalamic surgery. For some of them, GPi appears to be the target of choice.17 Nevertheless, only few studies have investigated the non-motor effects of GPi DBS,18–21 particularly focusing on apathy known as a common consequence of STN DBS.13
To further characterize the psychiatric symptoms that may occur in GPi DBS, we report a prospective study on the incidence of apathy, mood disorders, and anxiety consecutive to GPi DBS in disabled parkinsonian patients.
Methods
Participants
Twenty consecutive PD patients underwent bilateral GPi DBS between 2005 and 2010. There were 10 men and 10 women with a mean±standard deviation (SD) age of 60.1±9.1 years, and a mean disease duration of 13.3±5.4 years. All met the criteria of the United Kingdom Parkinson’s Disease Society brain bank for idiopathic PD.22 STN DBS was contraindicated for all patients, due to global cognitive impairment (Mattis Dementia Rating Scale ≤130), impaired executive functions, and/or dopa-resistant axial motor signs at baseline, including dysarthria, freezing, and falls.17
All patients were assessed 3 months prior to surgery (M‒3) and 3 (M3) and 6 months (M6) after GPi DBS, using psychiatric, neuropsychological, and motor scales.
Standard Protocol Approval, Registration, and Patient Consent
Written informed consent was obtained from each participant and the study met the ethical standards of the responsible committee on human experimentation.
Psychiatric Evaluation
Apathy was scored using the Apathy Evaluation Scale (Clinician version, C-AES).23 This is an 18-item scale with scores ranging from 18 to 72, the highest score reflecting severe apathy. It is recognized as the most psychometrically robust apathy scale across any population and was given “suggested scale” status for PD in a recent review.24 A cut-off score of 42 or above is chosen to define clinical apathy.23 Mood state was scored using Montgomery-Åsberg Depression Rating Scale (MADRS).25 Anxiety state was scored using the AMDP-AT (Association for Methodology and Documentation in Psychiatry).26 Patients were assessed by trained psychiatrists sensitized to psychiatric disorders in PD.
Neuropsychological Evaluation
The neuropsychological battery included the Mattis Dementia Rating Scale (MDRS)27 for the global cognitive assessment and a battery of tests assessing frontal executive functions, including Nelson’s simplified version of the Wisconsin Card Sorting Test (WCST),28 the Trail Making Test (TMT),29 the Categorical and Literal Fluency (F),30 and the Stroop Test.31
Motor Evaluations
Medical Treatment
Total levodopa equivalent dose (LED) was calculated on the bases of the Deuschl et al.’s method.35 Drug doses and electrical parameters for stimulation were adjusted at follow-up visits during the ensuing months until the best possible clinical conditions were achieved.
Surgical Procedure
Quadripolar DBS electrodes (3387 Medtronic, Minneapolis, MN) were implanted in the posteroventral part of the two GPis in a single operating session.36 Antiparkinsonian treatment was stopped the evening before surgery. The patient was awake throughout the procedure and the effect of stimulation on rigidity was assessed by passive movement of the contralateral wrist. The ventral contact was kept above the optic tract, as evidenced by the induction of visual flashes by stimulation. During surgery, the electrodes were connected to an external pulse generator for stimulation testing. Programmable pulse generators (Soletra, Medtronic) were implanted in the subclavicular region 2 days later and connected to the electrodes. The electrode contacts were selected and the electrical parameters (voltage, pulse width, and frequency) adjusted to bring about the greatest improvement in motor symptoms with the fewest side effects. The exact location of the two selected electrode contacts (one on the left and one on the right) was determined using stereotactic coordinates derived from a 3D CT scan performed a few days after surgery.
Statistical Analysis
Statistical analysis was performed using Statistica 8.0 (StatSoft, Tulsa, OK). Data are presented as means±standard deviation (SD). The scores of the different scales rated before surgery, 3 months and 6 months afterward were compared using nonparametric repeated-measures analysis of variance (Friedman test) because these variables were non-normally distributed. If of significant difference, pairwise comparisons were performed between the different times of evaluation using the Wilcoxon rank sum test. For all analyses, a p value of <0.05 was considered significant. All reported p values are two-sided.
Results
Psychiatric and Neuropsychological Results (Tables 1 and 2)
| Baseline (M–3) | DBS (M+3) | DBS (M+6) | ||
|---|---|---|---|---|
| Rating Scales | Mean±SD | Mean±SD | Mean±SD | p |
| AES | 37.2±6.2 | 36.9±7.5 | 37.2±5.0 | 0.36 |
| MADRS | 9.1±8.3 | 8.4±8.5 | 8.4±8.6 | 0.76 |
| AMDPAT | 8.7±7.7 | 10.5±8.9 | 9.3±8.0 | 0.22 |
AES: Apathy Evaluation Scale; AMDP-AT: Association for Methodology and Documentation In Psychiatry-Anxiety; DBS: deep brain stimulation; GPi: internal globus pallidus; MADRS: Montgomery-Åsberg Depression Rating Scale.
p values calculated by Friedman test.
| Baseline DBS (M–3) | DBS (M+3) | DBS (M+6) | ||
|---|---|---|---|---|
| Rating Scales | Mean±SD | Mean±SD | Mean±SD | p |
| MDRS (/144) | 133.1±7.2 | 132.9±8.6 | 133.2±9.5 | 0.69 |
| TMT (B-A) | 109.9±46.1 | 122.7±99.4 | 128.1±92.3 | 0.84 |
| Stroop test | –2.4±8.9 | –0.9±9.7 | –2.3±8.4 | 0.52 |
| Categorical Fluency | 22.1±11.5 | 19.3±8.0 | 21.2±9.8 | 0.22 |
| Literal Fluency | 15.7±7.7 | 13.1±7.3 | 14.6±7.5 | 0.15 |
| WCST errors | 9.0±7.1 | 9.3±9.0 | 8.3±6.5 | 0.75 |
Neuropsychological data are presented as raw scores.
DBS: deep brain stimulation; GPi: internal globus pallidus; MDRS: Mattis Dementia Rating Scale; TMT (B-A): difference between the time scores of part B and part A of the Trail Making Test (seconds); WCST: Wisconsin Card Sorting Test.
Stroop test: Interference index.
p values calculated by Friedman test.
There was no significant difference between preoperative assessment and both postoperative M3 and M6 assessments for apathy, depression, anxiety, and neuropsychological evaluations
Motor Results (Table 3)
| Off-Dopa | On-Dopa | |||||
|---|---|---|---|---|---|---|
| Rating Scales | Baseline (M–3) | DBS (M+3) | DBS (M+6) | Baseline (M–3) | DBS (M+3) | DBS (M+6) |
| Mean±SD | Mean±SD | Mean±SD | Mean±SD | Mean±SD | Mean±SD | |
| UPDRS II (/52) | 22.4±8.1 | 17.1±7.9a | 17.3±7.0b | 9.7±7.2 | 6.7±4.5c | 9.3±5.3d |
| UPDRS III (/108) | 40.7±15.9 | 25.2±13.5e | 24.2±12.0f | 10.9±4.8 | 9.2±4.2 | 9.7±5.2 |
| Schwab and England (/100%) | 48.0±20.8 | 59.3±28.1 | 66.0±19.6g | 80.1±13.4 | 84.1±23.2 | 85.3±7.2 |
| Hoehn and Yahr (/5) | 3.4±0.9 | 2.7±1.0 | 2.8±0.9 | 2.0±1.1 | 1.3±1.0 | 1.9±0.8 |
| LED | — | — | — | 1348.7±510.2h | 1368.3±428.2h | 1341.3±367.4h |
GPi: internal globus pallidus; LED: L-dopa equivalent dose (mg/24 h); UPDRS: United PD Rating Scale.
p values calculated two-tailed Wilcoxon test.
a
M+3 versus M+6, p=0.005.
b
M–3 versus M+6, p=0.003.
c
M+3 versus M+6, p=0.003.
d
M–3 versus M+6, p=0.005.
e
M–3 versus M+3, p=0.0005.
f
M–3 versus M+6, p=0.004.
g
M–3 versus M+6, p=0.006.
h
p=0.94 (Friedman test).
There was an improvement in the scores for the main motor manifestations of the disease between the preoperative off-dopa and postoperative off-dopa/on-stim conditions. The effect was significant for the UPDRS III between the preoperative and both the postoperative M3 and M6 scores in the off-dopa condition. There was a significant improvement in S&E scores in the off-dopa condition between the preoperative score and the postoperative M6 score. Although not significant, there was the same tendency for H&Y score in the off-dopa.
Medical Treatment (Table 2)
The L-dopa equivalent dose remained unchanged at every evaluation.
Discussion
Few studies have been performed with the objective to evaluate the non-motor effects of GPi DBS in PD. Okun et al.19 in the COMPARE study, a prospective blinded randomized trial comparing the cognitive and mood effects of unilateral STN DBS versus unilateral GPi DBS in patients with PD, did not find any significant mood differences between STN and GPi DBS groups on the Visual Analog Mood Scale from pre-DBS to post-DBS performance at 7 months. Nevertheless, more patients in the STN group had experienced postsurgical mood and cognitive adverse events (e.g., anxiety, confusion, irritability, aggressiveness, obsessive compulsive or manic symptoms, decreased confidence/motivation) than in the GPi group. Anderson et al,20 in a randomized, blinded comparison of the safety and efficacy of STN and GPi DBS in patients with advanced PD also reported more cognitive and behavioral changes after STN than GPi implantation, though they did not use any validated psychiatric scale. In the same line but not in PD, Hälbig et al.18 did not find any change in neuropsychiatric measures of 15 patients with dystonia after GPi DBS. Recently, Kirsch-Darrow et al.21 assessed apathy prior to DBS and 6 months post-DBS (STN and GPi). They showed an increase of apathy after surgery but did not find any relationship between apathy and DBS site.
Our results are in line with most of these previous studies, showing that there is no depression or anxiety after GPi DBS. Furthermore, we confirm the results of our previous study,17 indicating that GPi DBS in advanced Parkinsonian patients with contraindications for STN DBS is effective in reducing cardinal and axial motor symptoms in the off-dopa condition and also preserves cognitive functions, even for patients at high risk (i.e., displaying cognitive decline at baseline). When focusing on apathy assessment, we showed that GPi DBS may be safe for parkinsonian patients, which constitutes a main difference with our previous report concerning apathy post-STN DBS,13 using exactly the same design in the same center. Our results support the idea that there is a clear relationship between apathy and DBS site. Several hypotheses can be made to explain this difference.
We did not find any levodopa reduction before and after surgery, which could explain that there was no postoperative apathy score increase. There are mixed findings regarding whether apathy after DBS is related to reductions in levodopa dosage. Therefore, several studies did not find any relationship between apathy and reduction in levodopa, despite substantial reductions in LED.21, 37–41 In the light of these results, we can assume that the absence of apathy after GPi DBS is not linked with the stability of LED after surgery.
The territories of basal ganglia have been anatomically divided into sensorimotor, associative, and limbic regions.42 Because the GPi (∼478 mm3) is a bigger nucleus than the STN (∼158 mm3),42,43 we can assume that either the lesion itself or stimulation effect of STN would be more likely to affect non-motor pathways potentially involved in apathy than would the GPi. Thus, changes in mood, cognitions, and motivation after STN DBS could be the result of the current spread to non-motor portions of the nuclei.19,42,43
At last, cortical-subcortical neuronal pathways involved in GPi DBS may be different from STN DBS. Concerning STN DBS, correlations have been observed between variation in apathy scores and changes in glucose metabolism, using fluorodeoxyglucose-positron emission tomography (FDG-TEP). These correlations were positive in the right frontal middle gyrus [Brodmann area (BA) 10] and right inferior frontal gyrus (BA 46 and BA 47), and negative in the right posterior cingulated gyrus (BA 31) and left medial frontal lobe (BA 9).44 These results confirmed the role of the subthalamic nucleus in associative and limbic circuitry in humans and suggest that it is a key basal ganglia structure in motivation circuitry. The stability of apathy scores after GPi DBS support the hypothesis that GPi has a lesser influence on the limbic circuit. Further studies using FDG-PET are needed to confirm this hypothesis.
As a conclusion, while evidence is provided for the safety of the pallidal target regarding neuropsychiatric functions, we believe that GPi should be considered as the target of choice for advanced PD patients who are refractory to adjustments in medication and cannot benefit from STN surgery because of axial motor or cognitive contraindications.
References
1.
Limousin P, Krack P, Pollak P, et al.: Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1998; 339:1105–1111
2.
Kumar R, Lozano AM, Kim YJ, et al.: Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson’s disease. Neurology 1998; 51:850–855
3.
Durif F, Lemaire JJ, Debilly B, et al.: Long-term follow-up of globus pallidus chronic stimulation in advanced Parkinson’s disease. Mov Disord 2002; 17:803–807
4.
Loher TJ, Burgunder JM, Pohle T, et al.: Long-term pallidal deep brain stimulation in patients with advanced Parkinson disease: 1-year follow-up study. J Neurosurg 2002; 96:844–853
5.
Volkmann J, Allert N, Voges J, et al.: Long-term results of bilateral pallidal stimulation in Parkinson’s disease. Ann Neurol 2004; 55:871–875
6.
Krack P, Pollak P, Limousin P, et al.: Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson’s disease. Brain 1998; 121:451–457
7.
Burchiel KJ, Anderson VC, Favre J, et al.: Comparison of pallidal and subthalamic nucleus deep brain stimulation for advanced Parkinson’s disease: results of a randomized, blinded pilot study. Neurosurgery 1999; 45:1375–1382, discussion 1382–1384
8.
Krause M, Fogel W, Heck A, et al.: Deep brain stimulation for the treatment of Parkinson’s disease: subthalamic nucleus versus globus pallidus internus. J Neurol Neurosurg Psychiatry 2001; 70:464–470
9.
Volkmann J, Allert N, Voges J, et al.: Safety and efficacy of pallidal or subthalamic nucleus stimulation in advanced PD. Neurology 2001; 56:548–551
10.
Katayama Y, Kasai M, Oshima H, et al.: Double blinded evaluation of the effects of pallidal and subthalamic nucleus stimulation on daytime activity in advanced Parkinson’s disease. Parkinsonism Relat Disord 2000; 7:35–40
11.
Allert N, Volkmann J, Dotse S, et al.: Effects of bilateral pallidal or subthalamic stimulation on gait in advanced Parkinson’s disease. Mov Disord 2001; 16:1076–1085
12.
Funkiewiez A, Ardouin C, Caputo E, et al.: Long term effects of bilateral subthalamic nucleus stimulation on cognitive function, mood, and behaviour in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2004; 75:834–839
13.
Drapier D, Drapier S, Sauleau P, et al.: Does subthalamic nucleus stimulation induce apathy in Parkinson’s disease? J Neurol 2006; 253:1083–1091
14.
Marin RS: Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 1991; 3:243–254 [Review]
15.
Alexander GE, Crutcher MD, DeLong MR: Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Prog Brain Res 1990; 85:119–146
16.
Parent A, Hazrati LN: Functional anatomy of the basal ganglia. II. The place of subthalamic nucleus and external pallidum in basal ganglia circuitry. Brain Res Brain Res Rev 1995; 20:128–154 [Review]
17.
Rouaud T, Dondaine T, Drapier S, et al.: Pallidal stimulation in advanced Parkinson’s patients with contraindications for subthalamic stimulation. Mov Disord 2010; 25:1839–1846
18.
Hälbig TD, Gruber D, Kopp UA, et al.: Pallidal stimulation in dystonia: effects on cognition, mood, and quality of life. J Neurol Neurosurg Psychiatry 2005; 76:1713–1716
19.
Okun MS, Fernandez HH, Wu SS, et al.: Cognition and mood in Parkinson’s disease in subthalamic nucleus versus globus pallidus interna deep brain stimulation: the COMPARE trial. Ann Neurol 2009; 65:586–595
20.
Anderson VC, Burchiel KJ, Hogarth P, et al.: Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease. Arch Neurol 2005; 62:554–560
21.
Kirsch-Darrow L, Zahodne LB, Marsiske M, et al.: The trajectory of apathy after deep brain stimulation: from pre-surgery to 6 months post-surgery in Parkinson’s disease. Parkinsonism Relat Disord 2011; 17:182–188
22.
Gibb WRG, Lees AJ: The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 1988; 51:745–752
23.
Marin RS, Biedrzycki RC, Firinciogullari S: Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res 1991; 38:143–162
24.
Leentjens AF, Dujardin K, Marsh L, et al.: Apathy and anhedonia rating scales in Parkinson’s disease: critique and recommendations. Mov Disord 2008; 23:2004–2014
25.
Montgomery SA, Asberg M: A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134:382–389
26.
Bobon D: [Contribution of the AMDP scale to quantitative psychopathology]. Acta Psychiatr Belg 1985; 85:5–249
27.
Mattis S: Dementia Rating Scale. Odessa, FL, Psychological Assessment Resources Inc, 1988
28.
Nelson HE: A modified card sorting test sensitive to frontal lobe defects. Cortex 1976; 12:313–324
29.
Reitan RM: Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills 1958; 8:271–276
30.
Cardebat D, Doyon B, Puel M, et al.: [Formal and semantic lexical evocation in normal subjects. Performance and dynamics of production as a function of sex, age and educational level]. Acta Neurol Belg 1990; 90:207–217
31.
Stroop JR: Studies of interference in serial verbal reactions. J Exp Psychol 1953; 18:643–662
32.
Langston JW, Widner H, Goetz CG, et al.: Core assessment program for intracerebral transplantations (CAPIT). Mov Disord 1992; 7:2–13
33.
Fahn S, Elton RL; Members of UPDRS Development Committee: Unified Parkinson's Disease Rating Scale, in Recent Developments in Parkinson's Disease, vol 2. Edited by Fahn S, Marsden CD, Calne DB. London, Macmillan Health Care Information, Florham Park Macmillan, 1987; pp 153–163
34.
Hoehn MM, Yahr MD: Parkinsonism: onset, progression and mortality. Neurology 1967; 17:427–442
35.
Deuschl G, Schade-Brittinger C, Krack P, et al.; German Parkinson Study Group, Neurostimulation Section: A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006; 355:896–908
36.
Laitinen LV, Bergenheim AT, Hariz MI: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992; 76:53–61
37.
Czernecki V, Schüpbach M, Yaici S, et al.: Apathy following subthalamic stimulation in Parkinson disease: a dopamine responsive symptom. Mov Disord 2008; 23:964–969
38.
Denheyer M, Kiss ZH, Haffenden AM: Behavioral effects of subthalamic deep brain stimulation in Parkinson’s disease. Neuropsychologia 2009; 47:3203–3209
39.
Thobois S, Ardouin C, Lhommée E, et al.: Non-motor dopamine withdrawal syndrome after surgery for Parkinson’s disease: predictors and underlying mesolimbic denervation. Brain 2010; 133:1111–1127
40.
Porat O, Cohen OS, Schwartz R, et al.: Association of preoperative symptom profile with psychiatric symptoms following subthalamic nucleus stimulation in patients with Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2009; 21:398–405
41.
Castelli L, Lanotte M, Zibetti M, et al.: Apathy and verbal fluency in STN-stimulated PD patients. An observational follow-up study. J Neurol 2007; 254:1238–1243
42.
Sudhyadhom A, Bova FJ, Foote KD, et al.: Limbic, associative, and motor territories within the targets for deep brain stimulation: potential clinical implications. Curr Neurol Neurosci Rep 2007; 7:278–289
43.
Yelnik J: Functional anatomy of the basal ganglia. Mov Disord 2002; 17(Suppl 3):S15–S21
44.
Le Jeune F, Drapier D, Bourguignon A, et al.: Subthalamic nucleus stimulation in Parkinson disease induces apathy: a PET study. Neurology 2009; 73:1746–1751
Information & Authors
Information
Published In
History
Received: 21 February 2013
Revision received: 7 May 2013
Accepted: 8 May 2014
Published online: 1 July 2014
Published in print: Summer 2014
Authors
Funding Information
The authors report no financial relationships with commercial interests.
Metrics & Citations
Metrics
Citations
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
View Options
View options
PDF/EPUB
View PDF/EPUBGet Access
Login options
Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.
Personal login Institutional Login Open Athens loginNot a subscriber?
PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.
Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).