Subthalamic nucleus stimulation in Parkinson disease induces apathy: A PET study
Subthalamic deep brain stimulation can improve gastric emptying in Parkinson's disease
Transcript of Subthalamic deep brain stimulation can improve gastric emptying in Parkinson's disease
BRAINA JOURNAL OF NEUROLOGY
Subthalamic deep brain stimulation can improvegastric emptying in Parkinson’s diseaseEiji Arai,1 Makoto Arai,1 Tomoyuki Uchiyama,2 Yoshinori Higuchi,3 Kyoko Aoyagi,3
Yoshitaka Yamanaka,2 Tatsuya Yamamoto,2 Osamu Nagano,3 Akihiro Shiina,4 Daisuke Maruoka,1
Tomoaki Matsumura,1 Tomoo Nakagawa,1 Tatsuro Katsuno,1 Fumio Imazeki,1 Naokatsu Saeki,3
Satoshi Kuwabara2 and Osamu Yokosuka1
1 Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan2 Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan3 Department of Neurosurgery, Graduate School of Medicine, Chiba University, Chiba, Japan4 Department of Psychiatry, Graduate School of Medicine, Chiba University, Chiba, Japan
Correspondence to: Makoto Arai MD,Department of Medicine and Clinical Oncology (K1),Graduate School of Medicine, Chiba University,Inohana 1-8-1, Chiba-City, 260-8670, JapanE-mail: [email protected]
It is established that deep brain stimulation of the subthalamic nucleus improves motor function in advanced Parkinson’s
disease, but its effects on autonomic function remain to be elucidated. The present study was undertaken to investigate the
effects of subthalamic deep brain stimulation on gastric emptying. A total of 16 patients with Parkinson’s disease who under-
went bilateral subthalamic deep brain stimulation were enrolled. Gastric emptying was expressed as the peak time of 13CO2
excretion (Tmax) in the 13C-acetate breath test and was assessed in patients with and without administration of 100–150mg
levodopa/decarboxylase inhibitor before surgery, and with and without subthalamic deep brain stimulation at 3 months
post-surgery. The pattern of 13CO2 excretion curve was analysed. To evaluate potential factors related to the effect of sub-
thalamic deep brain stimulation on gastric emptying, we also examined the association between gastric emptying, clinical
characteristics, the equivalent dose of levodopa and serum ghrelin levels. The peak time of 13CO2 excretion (Tmax) values for
gastric emptying in patients without and with levodopa/decarboxylase inhibitor treatment were 45.6 ! 22.7min and
42.5 ! 13.6min, respectively (P = not significant), thus demonstrating levodopa resistance. The peak time of 13CO2 excretion
(Tmax) values without and with subthalamic deep brain stimulation after surgery were 44.0 ! 17.5min and 30.0 ! 12.5min
(P5 0.001), respectively, which showed that subthalamic deep brain stimulation was effective. Simultaneously, the pattern of
the 13CO2 excretion curve was also significantly improved relative to surgery with no stimulation (P = 0.002), although the
difference with and without levodopa/decarboxylase inhibitor was not significant. The difference in peak time of 13CO2 excre-
tion (Tmax) values without levodopa/decarboxylase inhibitor before surgery and without levodopa/decarboxylase inhibitor and
subthalamic deep brain stimulation after surgery was not significant, although motor dysfunction improved and the levodopa
equivalent dose decreased after surgery. There was little association between changes in ghrelin levels (!ghrelin) and changes
in Tmax values (!Tmax) in the subthalamic deep brain stimulation trial after surgery (r = "0.20), and no association between
changes in other characteristics and !Tmax post-surgery in the subthalamic deep brain stimulation trial. These results showed
that levodopa/decarboxylase inhibitor did not influence gastric emptying and that subthalamic deep brain stimulation can
improve the dysfunction in patients with Parkinson’s disease possibly by altering the neural system that controls gastrointestinal
function after subthalamic deep brain stimulation. This is the first report to show the effectiveness of subthalamic deep brain
stimulation on gastrointestinal dysfunction as a non-motor symptom in Parkinson’s disease.
doi:10.1093/brain/aws086 Brain 2012: Page 1 of 8 | 1
Received December 19, 2011. Revised February 14, 2012. Accepted February 19, 2012.! The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.For Permissions, please email: [email protected]
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Keywords: deep brain stimulation; ghrelin; gastric emptying; Parkinson’s disease; body weight
Abbreviations: DCI = decarboxylase inhibitor; STN-DBS = subthalamic deep brain stimulation; Tmax = peak time of 13CO2 excretion
IntroductionParkinson’s disease is a progressive neurodegenerative disease,
mainly characterized by the loss of dopamine neurons in the sub-
stantia nigra pars compacta, culminating in motor symptoms.
Furthermore, long-term treatment with anti-parkinsonian medica-
tions produces motor fluctuation and motor complications
at advanced stages of Parkinson’s disease. In addition to motor
dysfunction, there are a variety of non-motor symptoms asso-
ciated with Parkinson’s disease. Gastrointestinal dysfunction such
as dysphagia, reflux and constipation, is a common non-motor
dysfunction of Parkinson’s disease. Patients with Parkinson’s dis-
ease also complain of early satiety, abdominal discomfort, post-
prandial bloating and weight loss. Impaired gastric emptying
(gastroparesis) and abnormal gastric motility occur both in
untreated and treated Parkinson’s disease and might be one of
the causes of gastrointestinal symptoms. The gastrointestinal dys-
function likely results from degeneration of extranigral lesions
related to neural control of gastrointestinal tract function such as
in the dorsal vagal nucleus and the intramural plexus of the whole
intestine prior to degeneration of the substantia nigra (Del Tredici
et al., 2002; Cersosimo and Benarroch, 2008; Jost, 2010) and
occur secondarily to unstable absorption of levodopa (Hardoff
et al., 2001). The ideal strategy for the management of gastro-
intestinal dysfunction remains uncertain.
Previous reports have shown that gastric emptying time is
slower in levodopa-treated patients with Parkinson’s disease com-
pared with untreated control subjects (Djaldetti et al., 1996;
Hardoff et al., 2001; Thomaides et al., 2005), and that delayed
gastric emptying of solids is associated with greater disease sever-
ity (Goetze et al., 2005). In addition, delayed gastric emptying is
evident in patients with early stage Parkinson’s disease, which
suggests that it may be a marker for the preclinical stage of
Parkinson’s disease (Krygowska-Wajs et al., 2009; Tanaka et al.,
2011). The effect of anti-parkinsonian medication on gastric
emptying is not clear. Levodopa treatment has been shown to
slow gastric emptying in normal volunteers (Berkowitz et al.,
1980; Carrio et al., 1982; Robertson et al., 1990, 1992; Casellas
et al., 1999). Gastric emptying time is slower in levodopa-treated
patients with Parkinson’s disease compared with untreated control
subjects (Djaldetti et al., 1996; Hardoff et al., 2001; Thomaides
et al., 2005). Indeed, drugs that block dopamine receptors also
accelerate gastric emptying, presumably via an effect on gastric
dopamine receptors (McCallum et al., 1985; Soykan et al., 1997).
However, to our knowledge, there have been no reports about
the features of gastric emptying in patients with Parkinson’s
disease when fasting and just after levodopa intake.
Deep brain stimulation of the subthalamic nucleus (STN-DBS)
is a surgical treatment for motor dysfunction in advanced
Parkinson’s disease. Since its introduction into clinical practice,
many studies have reported on its benefits and limitations (Krack
et al., 2003; Ford et al., 2004; Rodriguez-Oroz et al., 2004, 2005;
Schupbach et al., 2005; Fraix et al., 2006; Derost et al., 2007;
Stefani et al., 2007; Benabid et al., 2009). It has previously been
shown that non-motor symptoms (i.e. sensory, mood/psychosis,
cognition, sleep, abnormal sweating and cardiovascular symptom/
falls) may be improved by STN-DBS and reduction of anti-
parkinsonian drugs (Holmberg et al., 2005; Witjas et al., 2007;
Zibetti et al., 2007; Hwynn et al., 2011). Non-motor dysfunction
such as altered sleep patterns, urinary disturbance, sympathetic
skin responses, cutaneous sympathetic vasoconstriction and ortho-
static regulation differs between the off and on states of STN-DBS,
and subthalamic nucleus stimulation has been shown to have
influence on cardiovascular function. However, it remains unclear
as to whether STN-DBS would be effective in improving gastro-
intestinal dysfunction. Thus, we evaluated the effect of STN-DBS
on gastric emptying.
Subjects and methods
Subjects and bilateral subthalamicnucleus deep brain stimulationFrom December 2009 to October 2011, 16 patients underwent bilat-
eral STN-DBS implantation at Chiba Cardiovascular Centre and were
followed at Chiba University Hospital. They were diagnosed with
Parkinson’s disease on the basis of the UK Parkinson’s Disease
Society Brain Bank Clinical diagnostic criteria (Hughes et al., 1992),
as well as the results of cardiac I-metaiodobenzylguanidine (MIBG)
testing, and had complained about medication resistant motor fluctu-
ation and motor complications. All 16 patients with Parkinson’s disease
that underwent STN-DBS implantation were enrolled in the study. The
clinical background of the patients is listed in Table 1. Levodopa/de-
carboxylase inhibitor (DCI) was administered to patients after they had
fasted for 1 h before the start of the ‘ON medication’ study to ensure
drug efficacy. The interval and the dose of levodopa/DCI were set
based on the dose that we usually used, which is a safety limited
dose in Japan. Prior to enrolment in the study, patients had
been treated long term with anti-parkinsonian medications and were
taking levodopa/DCI and dopamine agonists, but none were taking
anti-cholinergics just before and during this study. They had no history
of previous gastrointestinal surgery and no change of medication
affecting gastric motility for at least 4 weeks. None of the patients
had general diseases such as severe liver dysfunction, renal failure,
cardiopulmonary disease, uncontrolled diabetes mellitus or gastrointes-
tinal disease. The levodopa equivalent dose of anti-parkinsonian medi-
cations in all patients with Parkinson’s disease was converted as
described previously (Herzog et al., 2003; Ford et al., 2004). The
study was approved by Chiba University Hospital Institutional
Review Board and all patients gave informed consent.
Gastric emptying studyThe gastric emptying study was carried out using the 13C-acetate
breath test with a slight modification (Sanaka et al., 2008; Sanaka
and Nakada, 2010; Tanaka et al., 2011). Gastric emptying can also
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be evaluated using the acetaminophen absorption test and by techne-
tium-99m scintigraphy. However, the acetaminophen absorption test
requires repeated blood sample collection, and scintigraphy requires
specialized instrumentation. In contrast, the 13C-acetate breath test
can be performed at the patient’s bedside and the results have been
shown to correlate well with those obtained using scintigraphy
(Chapman et al., 2011). Therefore, we chose the 13C-acetate breath
test to determine the prevalence of delayed gastric emptying in patients
with Parkinson’s disease. 13C-sodium acetate administrated orally with
a test meal moves from the stomach and is absorbed from the digestive
tract, where it is then metabolized to 13CO2, and finally expired by the
lungs. Thus, measurement of 13CO2 in expired breath is an indirect
measure of gastric emptying. Patients with Parkinson’s disease were
tested after an overnight 12-h fast. First, a breath sample was obtained
following the ingestion of a liquid test meal (Racol, 200 kcal/200ml;
Otsuka Pharmaceutical Co., Ltd) containing 100mg of 13C-sodium
acetate (Sigma-Aldrich). The test meal was consumed in 55min and
breath samples were then collected at 5, 10, 15, 20, 30, 40, 50, 60, 75
and 90min after consuming the test meal. Patients remained in a seated
position throughout the examination. All breath samples were analysed
by infrared isotope spectrometry (UBit-IR200; Otsuka Electronics Co.,
Ltd). Gastric emptying time was expressed as the peak time of 13CO2
excretion (Tmax) and the gastric emptying rate curve was determined
from the pattern of the 13CO2 excretion curve. Prior to performing
STN-DBS implantation, gastric emptying studies were conducted
twice with (ON medication) or without (OFF medication) administration
of 100–150mg levodopa/DCI in the early morning on the different
days. All medications were withheld starting the night before the
study day to ensure a drug-free interval of at least 12 h. At 3 months
after STN-DBS implantation, gastric emptying studies were performed
twice on different days with (‘on stimulation’) or without (‘off stimula-
tion’) overnight STN-DBS after medications had been withheld for at
least 12 h. In the off stimulation condition, STN-DBS was stopped at
least 12 h before gastric emptying testing.
Measurement of serum ghrelin levelsBlood samples were collected from fasted subjects, not treated with
typical anti-parkinsonian medications, with and without stimulation
3 months after STN-DBS implantation. The samples were immediately
centrifuged at 1500g for 15min at 4#C, and HCl was added at a ratio
of 1:10 (v/v). The samples were then stored at "80#C until analysis.
The levels of ghrelin in serum were measured according to the manu-
facturer’s instructions (Matsumura et al., 2010; Arai et al., 2012).
Statistical analysisAll data values are expressed as the mean ! standard error
(SE). Commercially available SPSS software was used for the statistical
analysis. Parameters before and after administration of levodopa,
STN-DBS and surgery were compared within subjects by paired
t-test and chi-square test. The level for significance was P5 0.05.
The association between gastric emptying, clinical backgrounds, levo-
dopa equivalent dose and serum ghrelin levels was established statis-
tically using Pearson’s correlation coefficient test or Spearman’s
correlation coefficient by rank test.
Results
The effect of subthalamic deep brainstimulationAll the procedures were performed without complications in all
cases. Results of the clinical evaluation of the effects of STN-
DBS are listed in Table 1. There were significant improvements
in the Unified Parkinson’s Disease Rating Scale III and Hoehn
and Yahr scores in the ON compared with OFF medication con-
dition before STN-DBS implantation (P50.001), and on stimula-
tion compared with the off stimulation condition 3 months after
surgery (P50.001). Furthermore, there were also significant
improvements in these scores in the OFF medication–off stimula-
tion condition after surgery compared with OFF medication con-
dition before surgery (P50.05). The levodopa equivalent dose of
anti-parkinsonian drugs was reduced by 43.3% from baseline after
surgery (P50.001). There was a significant 3.8 ! 1.0 kg increase
Table 1 Clinical evaluation of the effects of STN-DBS implantation
Before DBS 3 months after DBS P-value
Age (years) 64 ! 6.9 (49–76)
Gender (male/female) 7/9
Body weight (kg) 20.6 ! 3.6 (18.7–25.3) 21.9 ! 3.4 (18.0–26.8) 50.01*
Duration of Parkinson’s disease (years) 13.7 ! 4.6 (7–21)
Levodopa (mg)a 789 ! 196 (525–1200) 478 ! 146 (175–665) 50.01*
Unified Parkinson’s Disease Rating Scale-III
ON medication 26.1 ! 5.2 50.01**
OFF medication 55.1 ! 11.8
On stimulation – 30.1 ! 6.1 50.01**
Off stimulation – 46.4 ! 10.7
Hoehn and Yahr staging
ON medication 2.6 ! 0.4 50.01**
OFF medication 4.4 ! 0.5
On stimulation – 2.7 ! 0.4 50.01**
Off stimulation – 3.9 ! 0.5
a The levodopa equivalent dose expressed in mg/day represented the sum of the doses of levodopa and dopamine agonist. Dopamine agonist equivalentdoses were calculated with the following equivalences: 100 mg levodopa = 10mg apomorphine = 1mg pergolide = 2mg cabergoline = 1mg pramipex-ole = 10mg bromocriptine = 5mg ropinirole (Herzog et al., 2003). *Paired t-test; **Wilcoxon signed-rank test.
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in body weight at 3 months after surgery, equivalent to a mean
increase of 6.5 ! 7.3% (P = 0.0054). An increase or decrease of
40.5 kg was designated as ‘weight gain’ or ‘weight loss’, respect-
ively. Twelve cases showed significant weight gain at 3 months
after surgery and four cases showed no change.
Gastric emptying studyBefore surgery, the Tmax values in the OFF and ON medication
conditions were 45.6 ! 22.7min and 42.5 ! 13.6min, respect-
ively, indicating that administration of levodopa/DCI did not cor-
rect the delayed gastric emptying (Fig. 1A). Individually, six
patients showed deterioration and three patients showed no
change in gastric emptying. At 3 months after surgery and with-
out the use of anti-parkinsonian medication, the Tmax values in the
off and on stimulation conditions were 44.0 ! 17.5min and
30.0 ! 12.5min, respectively; the improvement in the on stimula-
tion condition was significant (P5 0.001; Fig. 1B). Individually, 12
patients showed significant improvement of gastric emptying,
while three patients showed no change. However, the difference
between the Tmax values in the OFF medication condition before
surgery and in the OFF medication–off stimulation conditions after
surgery, was not significant. There were no significant associations
between body weight and clinical background features such as
age, gender, disease duration, gastric emptying (Tmax), ghrelin
levels, levodopa equivalent dose (mg) or motor scores. There
was also no association between the rate of change in Tmax
(!Tmax) and changes in other characteristics.
The 13CO2 excretion curve showed two patterns: a steep curve
with an obvious peak, or a flattened curve without an obvious
peak, designated as peak and non-peak patterns, respectively.
Before surgery, there were 10 patients with peak pattern and six
patients with non-peak pattern in the OFF medication condition,
and seven with peak and three with non-peak pattern in the ON
medication condition. There were no significant differences in the
curve patterns between the OFF and ON medication conditions.
After surgery, there were nine patients with peak pattern and six
patients with non-peak pattern in the off stimulation condition,
and 15 with peak and one with non-peak pattern in the on stimu-
lation condition. The increase in the number of patients with peak
pattern in the on stimulation condition was statistically significant
compared with the off stimulation condition (P = 0.002). The dif-
ference between the pattern of the 13CO2 excretion curve in the
OFF medication condition before and in the OFF medication–off
stimulation condition after surgery was not significant (Table 2).
Changes in ghrelin levelsThe ghrelin levels, before surgery, in the OFF and ON medication
conditions were 18.0 ! 14.1 fmol/ml and 13.9 ! 11.3 fmol/ml,
respectively, and these values did not differ significantly. The ghre-
lin levels were increased in three cases, decreased in five cases and
unchanged in one case in the ON medication condition.
The ghrelin levels, 3 months after surgery, in the off and on
stimulation conditions without anti-parkinsonian medication were
15.8 ! 10.6 fmol/ml and 14.3 ! 12.1 fmol/ml, respectively, which
also did not differ significantly. Ghrelin levels were increased in
seven cases, decreased in five cases and unchanged in one case
in the on stimulation condition. There was little association be-
tween changes in ghrelin levels (!ghrelin) and changes in Tmax
values (!Tmax) in the OFF versus ON medication conditions before
surgery (r = 0.475) and in the off versus on stimulation conditions
3 months after surgery (r = "0.198) (Fig. 2A and B).
DiscussionSTN-DBS is the preferred surgical treatment for advanced
Parkinson’s disease. Despite limited evidence-based data, STN-
DBS has been shown to produce improvements in dopaminergic
100
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OFF medication ON medication
80BAP < 0.01†
60
70
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50
30
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in)
Tm
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in)
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Figure 1 The peak time of 13CO2 excretion (Tmax) in patients with Parkinson’s disease. (A) ON versus OFF medication before STN-DBSand (B) on versus off stimulation after STN-DBS. Medication = administration of 100–150mg levodopa/DCI early in the morning beforeDBS implantation. Bars represent mean ! SD. †Paired t-test.
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drug-sensitive symptoms as well as reductions in subsequent drug
dose and motor complication such as dyskinesias and dystonias
(Vingerhoets et al., 2002; Arai et al., 2008; Benabid et al.,
2009), although STN-DBS implantation can lead to severe surgi-
cal complications. In our cases, STN-DBS improved motor dys-
function in patients with Parkinson’s disease measured using
Unified Parkinson’s Disease Rating Scale-III and Hoehn and Yahr
staging criteria, as reported in previous studies (Herzog et al.,
2003; Krack et al., 2003; Rodriguez-Oroz et al., 2004, 2005;
Schupbach et al., 2005; Fraix et al., 2006; Derost et al., 2007).
Therefore, physicians should assess the risk and benefit of
STN-DBS for each patient. The levodopa equivalent dose of
anti-parkinsonian drug was also reduced by 43.3% with respect
to baseline, in agreement with previous reports (Schupbach et al.,
2005; Fraix et al., 2006). In addition, some studies have reported
rapid weight gain and increased body mass index in subjects fol-
lowing STN-DBS (Ford et al., 2004), which were also observed in
the present study.
There have been few previous reports about the association
between STN-DBS and gastrointestinal dysfunction, a common
non-motor symptom of Parkinson’s disease. Recently, the13C-acetate breath test has been widely recognized as a useful
method for evaluating gastric emptying because 13C is less inva-
sive than other isotopes or acetaminophen-based methods
(Tanaka et al., 2011). In this study, by using the 13C-acetate
breath test, we showed that STN-DBS improved gastric emptying
in patients with Parkinson’s disease. To the best of our knowledge,
this is the first published investigation of the effect of STN-DBS on
gastric emptying in patients with Parkinson’s disease. Although it
is controversial as to whether or not levodopa treatment can im-
prove gastric emptying in patients with Parkinson’s disease
(Hardoff et al., 2001; Thomaides et al., 2005; Tanaka et al.,
2011), we found that early morning treatment with levodopa/
DCI at typical doses did not alter the Tmax value, indicating that
gastric emptying was resistant to levodopa therapy. In contrast,
STN-DBS produced a significant improvement in gastric emptying,
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15
-15
-5
!Ghr
elin
seru
m le
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(pg/
ml)
-80 -60 -40 -20 0 20 40
5
10BA
0
-5
-15
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!Ghr
elin
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m le
vels
(pg/
ml)
-50 -40 -30 -20 -10 0
!Tmax (min)!Tmax (min)
Figure 2 Correlation between changes in Tmax (!Tmax) and serum ghrelin levels (!ghrelin) in patients with Parkinson’s disease (A) withor without levodopa/DCI before surgery (n = 10, r = 0.475) and (B) with or without STN-DBS after surgery (n = 14, r = "0.198). Thevalues for !Tmax and !ghrelin are expressed as the difference subtraction of that after DBS surgery from that before it. There was nocorrelation between !Tmax and !ghrelin before or after DBS implantation, or with and without stimulation (based on Pearson’scorrelation coefficients).
Table 2 The pattern of 13CO2 excretion curves
DBS implantation Medicationa DBS stimulation Pattern of 13CO2 excretion(Peak / non-peak)
*P-value
Before ON – 7/3 n.s.
0.03Before OFF – 10/6
After OFF On 15/1 0.002
After OFF Off 9/6
The 13CO2 excretion value showed an obvious peak (peak pattern), or gentle climb and descent without an obvious peak (non-peak pattern).a The gastric emptying study was performed twice with (ON) or without (OFF) administration of 100–150mg levodopa/decarboxylase-inhibitorearly in the morning. *!2 test; n.s. = not significant.
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which could not be improved by the administration of levodopa/
DCI before surgery. The ability of levodopa/DCI to influence gas-
tric emptying in patients with Parkinson’s disease is unclear since
few studies have investigated the effect of levodopa on gastric
emptying in patients with Parkinson’s disease. It has been estab-
lished experimentally that orally administered levodopa induces
gastric relaxation (Valenzuela et al., 1976), decreases gastric
motility (Nagahata et al., 1995) and inhibits gastric emptying in
normal humans (Berkowitz, 1980; Carrio et al., 1982; Robertson
et al., 1990, 1992; Casellas et al., 1999). In our study, by using
the 13C-acetate breath test, we found that early morning treat-
ment with levodopa/DCI at typical doses improved motor dys-
function, but did not improve the Tmax value and individually
some slight deterioration was shown in 66.7% of patients. Our
results are similar to those of previous studies, which showed that
levodopa could cause deterioration of gastric emptying. These
findings indicate that gastric emptying may be resistant to levo-
dopa therapy, although we did not assess the effects of higher
doses of levodopa/DCI on gastric emptying. Therefore, to achieve
consensus regarding the effect of levodopa/DCI on gastric empty-
ing, further studies are required.
The pattern of the 13CO2 excretion curve changed to show an
obvious peak in almost all cases in the on stimulation condition
after surgery. We surmised that the peak in the early phase was
associated with the coordinated movement and efficiency of gas-
tric emptying, because almost all of our cases with obvious peaks
had low gastric emptying (Tmax) compared with cases without an
obvious peak. Thus, not only can STN-DBS improve the rate of
gastric emptying, it also causes it to become more dynamic and to
empty more smoothly (Sanaka and Nakada, 2010).
In this study, body weight slightly increased 3 months after
surgery. Other studies have reported that weight gain after
STN-DBS cannot be inadequately explained by motor improve-
ment or reduced dopaminergic drug dosage (Sauleau et al.,
2009). The mechanism of body weight increase after STN-DBS is
complex and influenced by various factors that are thought to be
associated with increased appetite and food intake, reduction of
energy output related to amelioration of parkinsonism and dyskin-
esias, improved alimentation and the direct influence on function
of homeostatic control centres such as the lateral hypothalamus
(Barichella et al., 2003; Montaurier et al., 2007; Novakova et al.,
2007); however, some studies investigating these processes have
general conflicting results. After STN-DBS, unpredictable motor
fluctuations such as ‘delayed-on’ and ‘no-on’ phenomena dramat-
ically improve. It has been suggested that this is mainly due to
improvement in OFF medication motor symptoms. Delayed gastric
emptying can delay the absorption of levodopa by interfering with
its accessibility to the duodenum, and this might lead to non-
motor fluctuations. Therefore, improvement of abnormal gastric
emptying mediated by SNT-DBS could contribute partly to the
improvement of unpredictable motor fluctuations, although it is
mainly mediated by improvement in OFF medication.
The mechanism by which STN-DBS might alter gastric emptying
time and the 13CO2 excretion curve pattern is unknown. Although
Mann et al. (2009) reported that STN-DBS is associated with a
lead implantation effect on motor dysfunction after surgery, Tmax
values in the OFF medication condition before and in the OFF
medication–off stimulation condition after surgery did not show
any difference. In contrast, motor dysfunction improved, the levo-
dopa equivalent dose decreased, and body weight increased after
surgery. Thus, our results suggest that lead implantation and other
changes after STN-DBS, such as improvement of motor dysfunc-
tion, decrease in anti-parkinsonian drug dose, and increase in body
weight may not affect post-surgical gastric emptying.
To determine the underlying mechanism, we assessed the serum
levels of ghrelin, which are strongly correlated with appetite and
gastric emptying (Kojima et al., 1999; Murray et al., 2005; Corcuff
et al., 2006; Fiszer et al., 2010; Matsumura et al., 2010). We
found little association between changes in ghrelin levels
(!ghrelin) and changes in Tmax values (!Tmax) induced by
administration of levodopa/DCI and STN-DBS. Ghrelin is a peptide
hormone produced and secreted in the stomach. The effect of
ghrelin is driven largely by the high expression of the ghrelin
receptors in the CNS, e.g. in the hypothalamus and pituitary
gland. There have been no reports on the relationship between
serum ghrelin levels and gastric emptying in patients with
Parkinson’s disease during treatment with levodopa, or after
STN-DBS. Some previous reports showed that serum levels of
ghrelin were unchanged before and after STN-DBS and that
changes in ghrelin levels did not appear to cause appetite and
weight gain in Parkinson’s disease (Corcuff et al., 2006;
Novakova et al., 2011). The mechanisms of action of STN-DBS
are not well understood. STN-DBS has been shown to activate
various brain areas including some of the centres of autonomic
control (Limousin et al., 1997; Schulte et al., 2006; Klein et al.,
2011). The subthalamic nucleus, basal ganglia and various centres
of autonomic control are interconnected (Canteras et al., 1990)
and there are neurons in the subthalamic nucleus that are related
to urinary storage/voiding cycles (Sakakibara et al., 2003).
Autonomic centres such as the frontal cortex, cingulate cortex,
insula, thalami, basal ganglia and periaqueductal grey matter are
also associated with gastric motility (Ladabaum et al., 2001;
Stephan et al., 2003; Vandenbergh et al., 2005). Stimulation of
the ventral and dorsal-most region can produce autonomic
responses (Benedetti et al., 2004). In fact, STN-DBS has been
shown to affect sympathetic skin responses (Priori et al., 2001),
bladder function (Seif et al., 2004; Herzog et al., 2006, 2008), and
cutaneous sympathetic vasoconstriction (Ludwig et al., 2007).
Although other autonomic symptoms were not evaluated in the
present study, some patients experienced autonomic symptoms
such as insomnia, frequent urination, constipation and excessive
sweating (data not shown). Non-motor dysfunctions such as sleep
disruption, urinary disturbance, sympathetic skin responses, cuta-
neous sympathetic vasoconstriction and orthostatic regulation dif-
fered between the off and on states of STN-DBS. These findings
indicate that STN-DBS may influence and improve some non-
motor functions. Although direct spread to the hypothalamus
nevertheless seems unlikely, activation of nerve fibres projecting
from or to the hypothalamus and crossing the subthalamic nucleus
might be a possibility of the autonomic and homeostatic effects on
gastrointestinal movement induced by STN-DBS. Thus, an effect
of STN-DBS on neural regulation of gastric emptying is possible.
Our study has some limitations, namely, the absence of a con-
trol group, a small number of patients and a short period of
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follow-up. Although the study included only a small number
of patients, the cohort comprised all of the patients treated with
STN-DBS in our hospital, which precludes selection bias. Although,
our study used only a 3 month follow-up period, several prior
studies have shown that improvements in clinical and motor
scores following STN-DBS persist considerably longer (Herzog
et al., 2003; Rodriguez-Oroz et al., 2004, 2005; Schupbach
et al., 2005). Additional studies with longer follow-up intervals
are needed to confirm our findings.
This study demonstrated improvement of gastric emptying and
the results suggest that improvement of gastric emptying can
improve upper gastrointestinal symptoms such as heavy feeling
in the stomach, bloating, nausea or feeling sick and belching. A
previous report showed that these symptoms could be influenced
by placebo effect (Moayyedi et al., 2004). As mentioned above, it
was not feasible to use a control group in this study; therefore, we
did not evaluate clinical symptoms before and after STN-DBS
implantation. Further studies involving a larger patient cohort are
needed to rule out the possibility of the placebo effect.
In conclusion, we demonstrated that STN-DBS improved anti-
parkinsonian drug resistant gastric emptying dysfunction in pa-
tients with Parkinson’s disease, possibly by altering neural control
systems regulating gastrointestinal function. To our knowledge,
this is the first report to demonstrate the effectiveness of
STN-DBS treatment for gastric emptying dysfunction, a common
non-motor dysfunction associated with Parkinson’s disease.
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