REVIEW

CURRENT
OPINION Gastroparesis
Jan Tack, Florencia Carbone, and Alessandra Rotondo

Purpose of review
This review summarizes recent progress in the epidemiology, pathophysiology, and treatment of
gastroparesis.
Recent findings
The relationship between delayed gastric emptying and symptom pattern in gastroparesis and, related to it,
its separation from functional dyspepsia remains an area of controversy and uncertainty.
Pathophysiological studies have focused on the role of pyloric resistance and duodenal motility in
generation of symptoms. In diabetic patients, glycemic control did not determine short-term changes in
gastric emptying rate in type 2 diabetes, but poor glycemic control was a major risk factor for long-term
development of gastroparesis in type 1 diabetes. At the cellular level, diabetic gastroparesis is
characterized by loss of interstitial cells of Cajal (ICCs), and this is inversely correlated to the number of
CD206þ macrophages, which are thought to have a protective effect on ICCs. Treatment trials have
focused on dietary factors and a nasal spray formulation of metoclopramide. A meta-analysis of prokinetic
studies found no association between symptom improvement and enhancement of gastric emptying in
gastroparesis. Two controlled studies showed no benefit of tricyclic antidepressants (nortriptyline,
amitriptyline) in idiopathic gastroparesis and functional dyspepsia with delayed emptying.
Summary
The relationship between delay in gastric emptying, symptom pattern, and response to prokinetic therapy in
gastroparesis is poor. In diabetes, gastroparesis is characterized by loss of ICCs, and this is inversely
correlated to the number of CD206þ macrophages. Dietary interventions may help to alleviate symptoms.
Tricyclic antidepressants do not provide symptomatic benefit to patients with idiopathic gastroparesis.
Keywords
diabetes, functional dyspepsia, gastroparesis, prokinetic, tricyclic antidepressant

INTRODUCTION in gastroparesis, is expected to generate more severe

Gastroparesis is a syndrome characterized by delayed symptoms, including weight loss [1]. A single-center
gastric emptying in the absence of mechanical study analyzed symptom pattern, body weight,
obstruction and is accompanied by symptoms such energy expenditure, and caloric intake in 29 idio-
as postprandial fullness, early satiety, nausea, vomit- pathic gastroparesis patients and 39 controls. BMI
ing, and bloating [1,2]. Gastroparesis occurs in several and resting energy expenditure were similar in both
clinical settings, particularly as a complication of groups, but gastroparesis patients, as a group, had
diabetes mellitus, but also as a complication of upper lower caloric intake and lower exercise-related energy
gastrointestinal surgery, neurological disease, colla- expenditure. A subset of 12 gastroparesis patients
gen vascular disorders, viral infections, drugs, and so who experienced weight gain had lower symptom
on. In the majority of cases no underlying cause is burden and higher caloric intake compared with
found and gastroparesis is termed idiopathic [1,2].
This review summarizes recent progress in our under-
Translational Research Center for Gastrointestinal Diseases, University
standing of symptoms, pathophysiology, and treat-
of Leuven, Leuven, Belgium
ment in gastroparesis.
Correspondence to Jan Tack, Translational Research Center for Gastro-
intestinal Diseases (TARGID), University of Leuven, University Hospital
Gasthuisberg, O&N I – bus 701, Herestraat 49, B-3000 Leuven,
SYMPTOM PATTERN Belgium. Tel: +32 16 34 42 25; fax: +32 16 34 44 19;
A long-standing controversy is the differentiation e-mail: jan.tack@med.kuleuven.ac.be
between gastroparesis and functional dyspepsia [3]. Curr Opin Gastroenterol 2015, 31:499–505
The presence of worse gastric motor dysfunction, as DOI:10.1097/MOG.0000000000000220

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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Stomach and duodenum

difficulty to finish a normal sized meal, and soma-

KEY POINTS tization [6]. These findings confirm that symptoms

The role of delayed emptying in symptom generation in and psychosocial distress cannot predict the pres-
gastroparesis is unclear. ence of gastroparesis, and the majority of children
with dyspeptic symptoms have normal gastric emp-

Recent pathophysiological studies identified increased tying. In the subset with delayed emptying, similar
pyloric resistance and altered duodenal contractility as
to adults [3], nausea and vomiting best correlate
factors related to symptom pattern in gastroparesis.
with severity of delayed emptying.

The presence of neuropathy and poor glycemic control
exacerbate gastroparesis in type 1 diabetes. PATHOPHYSIOLOGICAL MECHANISMS

The role of poor glycemic control in determining
abnormal gastric motility in type 2 diabetes is Pyloric resistance
less clear. Under physiological circumstances, the pylorus is a
key regulator of nutrient passage from the stomach

Studies with the ghrelin agonist TRP-102 in diabetic
into the duodenum [8]. Although pyloric hyper-
gastroparesis and with tricyclic antidepressants in
idiopathic gastroparesis failed to show benefit. tonicity has been implicated in the pathogenesis
of gastroparesis, evidence was limited, and technol-
ogies to measure pyloric function were cumbersome
[9]. The recently developed endoscopic functional
patients without weight gain [4]. Hence, weight loss luminal imaging probe (EndoFLIP), a catheter-
is not a typical feature of gastroparesis patients. mounted balloon with impedance sensors for
Although the distinguishing feature of gastro- measuring balloon diameter, enables measurement
paresis is the presence of delayed gastric emptying, of resistance of the pylorus to distension [10].
the relationship between symptom pattern and Malik et al. [11] used the EndoFLIP to measure
degree of delay in emptying, and the efficacy of pyloric resistance in 54 gastroparesis patients (39
prokinetic drugs for symptom relief are areas of idiopathic, 15 diabetic) during endoscopy. At a
controversy [3]. In fact, the stability of delayed 40 ml balloon volume, pyloric diameter did not
emptying over time is poor and the correlation differ between diabetic and idiopathic gastroparesis,
between delayed emptying and symptoms in gastro- and was not correlated to gastric emptying rate
paresis is at best modest. A systematic review measured by scintigraphy. Symptom intensities of
confirmed that the symptomatic response to proki- early satiety and postprandial fullness, measured
netics is variable and poorly correlates with with the Patient’s Assessment of GastroIntestinal
enhancement of gastric emptying [5]. Hence, it is Symptoms (PAGI-SYM) questionnaire [12], were
assumed that other pathophysiological mechan- inversely correlated to pyloric diameter [11]. How-
isms, such as gastric hypersensitivity or impaired ever, the lack of a control group is a limitation.
&
gastric accommodation, may also underlie symp- Gourcerol et al. [13 ] used the EndoFLIP to
toms in gastroparesis. A recent opinion article measure pyloric resistance in 21 healthy controls,
suggested a number of novel approaches to increase 27 gastroparesis patients, and five patients with
the clinical usefulness of a diagnosis of gastroparesis, esophagectomy without pyloroplasty. Fasting
including a higher threshold for diagnosing delayed pyloric compliance was significantly higher in con-
gastric emptying and selection of patients based on a trols compared with both patient groups. In the
symptom pattern that includes nausea or vomiting, patients, fasting pyloric compliance correlated with
as these are more likely to be associated with delayed symptoms as well as quality of life, measured with
emptying [3]. the Gastrointestinal Quality of Life Index (GIQLI)
Similar issues also occur in pediatric gastropa- score. These findings support a pathophysiological
resis. In a study of symptom pattern and psychoso- role for pyloric resistance in gastroparesis. The 10
cial distress in 100 children referred for gastric patients with the lowest pyloric compliance under-
emptying scintigraphy, gastroparesis was diagnosed went pneumatic pyloric dilation and reevaluation
in 25 based on a scintigraphic gastric retention value after 10 days showed improved symptoms, gastric
&
more than 10% at 4 h (abnormal for adults) [6,7]. emptying, and GIQLI score [13 ]. Limitations are the
Symptoms evaluated in 83 patients with age more small size of the treated group, short follow-up, and
than 10 did not differ between those with normal measurement of compliance in the fasting state.
and delayed emptying, and both groups had similar
anxiety and somatization ratings. In the subgroup Duodenal motility
with delayed emptying, gastric retention was inver- Wireless motility capsule (WMC, Smartpill) was
sely correlated to severity of vomiting, nausea, used to study the correlation of gastric and small

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 Gastroparesis Tack et al.

intestinal motility to the symptom pattern in gastro- emptying. These findings argue, at least in type 2
paresis [14]. In addition to the traditional WMC diabetes, against the widely held belief that better
parameters of gastric retention time and small glycemic control will improve gastric emptying.
bowel/colonic transit time, the authors also quanti- However, as the patients in this study did not report
fied antral and duodenal contractions from the major gastrointestinal symptoms, the implications
manometry tracing as area under the curve (AUC) for treatment of gastroparesis symptoms remain
&
as well as motility index and contraction frequency, unclear [19 ].
respectively, 1 h before and 1 h after emptying from
the stomach. The authors found a moderate corre- Neuropathy and glycemic control in type 1
lation between symptom severity and duodenal, diabetes
but not antral AUC (Pearson correlation R ¼ -0.42, Softeland et al. [20] studied gastric emptying (using
P ¼ 0.02). The gastroparesis cardinal symptom index radiopaque markers), rectal multimodal sensitivity
(GCSI) [15] also correlated with the duodenal con- (heat, mechanical distension, and electrical stimu-
traction frequency and the motility index (all lation), and autonomic cardiac innervation in 20
R < -0.55, all P < 0.01), indicating that duodenal, diabetic patients with gastroparesis symptoms and
rather than antral motility, correlates with symp- 16 healthy controls. Delayed gastric emptying was
toms [14]. found in 60% of the patients, and this was inversely
associated with symptoms of nausea and vomiting
(i.e., less symptoms with more delayed emptying).
PATHOGENESIS Compared with controls, patients were hyposensi-
tive to thermal, mechanical, and electrical rectal
Autoantibodies stimulation, and showed signs of autonomic neuro-
The mechanisms through which gastric motor con- pathy (reduced heart-rate variability). Rectal ther-
trol processes are affected in diabetic and idiopathic mal hyposensitivity was correlated to gastric
gastroparesis are incompletely elucidated. Autoim- retention and to reduced heart-rate variability.
munity is a key feature in the pathogenesis of type 1 These observations indicate that diabetic patients
diabetes, but may also be involved in type 2 diabetes have a widespread neuropathy, involving both auto-
as shown by the presence of autoantibodies. Singla nomic and sensory neuropathy, and including vis-
et al. [16] report antiglutamic acid decarboxylase but ceral hyposensitivity [20].
no antiislet cell or antiinsulin antibodies in six (five &
Bharucha et al. [21 ] also studied a cohort of type
type 1 diabetes) out of 16 diabetic gastroparesis 1 diabetes patients who were enrolled in multicenter
patients (12 with type 1 diabetes). There was no long-term follow-up studies of effects of improved
association with severity of symptoms or delay in glycemic control. Seventy four type 1 diabetes
gastric emptying, suggesting, therefore, that auto- patients from seven centers, with a diabetes history
antibodies are probably not key factors in the patho- of more than 400 months, underwent gastric emp-
genesis of diabetic gastroparesis. tying testing, and results were correlated to
parameters of glycemic control, diabetes compli-
Glycemic control in type 2 diabetes cations, and gastrointestinal symptom question-
Altered glycemic control has been implicated in the naires. Delayed emptying was present in 47% and,
pathogenesis of dysmotility in diabetes [17,18], and in multivariate analysis, this was associated with the
this is the basis to recommend improved glycemic presence of retinopathy, the duration of diabetes,
control for treating diabetic gastroparesis [2,3]. and glycosylated hemoglobin levels before and
&
Bharucha et al. [19 ] studied the impact of improved during the follow-up study. Gastrointestinal symp-
glycemic control on gastric emptying rate in 30 tom scores, assessed with PAGI-SYM and GCSI ques-
patients with poorly controlled type 2 diabetes (gly- tionnaires [12,14], did not differ between normal or
cosylated hemoglobin levels >9%). Baseline gastric &
delayed emptying [21 ]. This study shows that long-
emptying was abnormal in two-thirds of the term poor glycemic control is a risk factor for the
patients (delayed in 14, rapid in six), and higher development of gastroparesis, and was associated
fasting glucose was associated with more rapid emp- with increased prevalence of other diabetic compli-
tying. Patients were randomized to a repeat empty- cations, but the impact on gastrointestinal symp-
ing test one week later with administration of saline &
toms is limited [21 ].
or insulin. Although insulin improved glycemia,
gastric emptying rate did not differ from the saline Interstitial cells of Cajal and macrophages
group. All patients underwent 6 months intensive The studies discussed above have focused on func-
diabetes therapy, which significantly improved tional changes at the organ level in diabetic gastro-
glycosylated hemoglobin levels but not gastric paresis. Histological studies utilizing gastric resection

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Stomach and duodenum

specimens show alterations of myenteric neurons, a to 4 h after meal ingestion [26]. Both high-fat meals
low-grade inflammatory infiltrate and, most consist- as well as low-fat solid meal were associated with
ently, loss of interstitial cells of Cajal (ICC) in human higher symptom burden. The total symptom score
gastroparesis [22]. Recent studies in mice models of was significantly elevated after the high-fat solid
type 1 diabetes demonstrate a protective effect of meal compared with all other meals. Nausea was
CD206-positive heme oxygenase-1 expressing M2 highest with the high-fat solid meal and lowest with
macrophages against the development of gastropa- the low-fat liquid meal. This provides support for
&
resis [23]. Bernard et al. [24 ] studied transmural recommending low-fat and more liquid meals in
gastric corpus biopsies from diabetic patients with gastroparesis to reduce symptoms, but longer term
and without gastroparesis, idiopathic gastroparesis diet studies are needed [26].
patients, and controls (n ¼ 10 age-matched females In a longer term dietary intervention study, 56
each). The number of ICCs was significantly lower in diabetic gastroparesis patients were randomized to a
idiopathic and diabetic gastroparesis specimens. The 20-week treatment with an intervention diet (small
&
number of CD45-positive immune cells, CD206- particle size) or a control diet (diabetes diet) [27 ]. All
positive macrophages, and inducible nitric oxide symptoms, measured by the PAGI-SYM question-
synthase-positive cells did not differ significantly naire [12] except for upper abdominal pain,
between groups, but a significant correlation was improved significantly with the intervention diet
found between the number of CD206-positive but not the control diet. The improvement in the
macrophages and ICC in diabetic patients with or three PAGI-SYM subscales that constitute the GCSI
without gastroparesis. These observations confirm [15] was significantly higher after the intervention
the finding of ICC depletion in gastroparesis, and diet, and the same was true for the heartburn/regur-
&
suggest that, similar to mice, CD206-positive cells gitation scale [27 ]. Based on this study, a diet with
may serve a protective role in preserving ICC. Other small particle size should be incorporated in the
pathways may be involved in idiopathic gastroparesis dietary management of patients with diabetic gas-
&
[24 ]. troparesis.

TREATMENT OPTIONS Prokinetics

Prokinetics are considered the first pharmacother-
Dietary interventions apeutic option for gastroparesis, although evidence
Although dietary measures (smaller more frequent of efficacy is limited [2,28]. In a meta-regression
meals low in fat and nondigestible residue) are a first analysis of the association between improvement
management step in gastroparesis and related severe in symptoms and in emptying rate across multiple
upper gastrointestinal motility disorders, their effi- gastroparesis studies, no significant correlation was
cacy is not proven. Wytiaz et al. [25] studied self- found between both aspects [5]. Ghrelin agonists are
reported aggravation or alleviation by nutrients in a novel class of prokinetics [29,30]. TZP-102, an
45 patients with gastroparesis (39 idiopathic), using orally administered ghrelin agonist, was evaluated
food toleration and aversion rating questionnaires. in two phase 2b controlled trials in patients with
Patients reported food substances, which they con- type 1 or type 2 diabetes with gastroparesis symp-
sidered to aggravate (orange juice, fried chicken, toms and delayed gastric emptying [31]. In one
cabbage, oranges, sausage, pizza, peppers, onions, study, a total of 201 patients were randomized to
tomato juice, lettuce, coffee, salsa, broccoli, bacon, once-daily treatment with placebo or TZP-102 (10 or
and roast beef) or improve (saltine crackers, jello, 20 mg) for 12 weeks. The second study randomized
and graham crackers) symptoms, and indicated patients to placebo or TZP-102 (10 mg t.i.d.) for
good tolerance for a number of food items (ginger 12 weeks. In both studies, symptoms showed similar
ale, gluten-free foods, tea, sweet potatoes, pretzels, improvement in all treatment arms [31]. Gastric
white fish, clear soup, salmon, potatoes, white rice, emptying at baseline and week 12 in the first study
popsicles, and applesauce) [25]. These data can be also showed no difference between groups. An
used as a basis for designing dietary interventions accompanying editorial outlined some limitations
in gastroparesis. of these negative studies, including allowed con-
The same group studied 12 gastroparesis comitant use of antiemetics and opioid analgesics
patients who received one of four meals (high-fat and discordance between symptom responses and
solid, high-fat liquid, low-fat liquid, and low-fat gastric emptying results in previous studies with
solid meal) in a randomized crossover fashion on TZP-102 [32]. Relamorelin, a subcutaneously admin-
four separate days. The severity of eight symptoms istered ghrelin receptor agonist, shown to enhance
was rated on a 0–4 scale every 15 min, before and up gastric emptying and to reduce symptoms in a pilot

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 Gastroparesis Tack et al.

trial in 10 type 1 diabetes patients, is currently and interruption rate for adverse events was greater
undergoing phase 2 testing [33]. with nortriptyline [36].
It has been argued that efficacy of traditional The efficacy of antidepressants in patients with
prokinetics administered orally may be limited due dyspeptic symptoms, including those with delayed
to poor emptying from the stomach resulting in emptying, was also addressed in a placebo-con-
poor absorption from the duodenum. Parkman trolled multicenter trial using amitriptyline and
&
et al. [34] evaluated a metoclopramide nasal spray escitalopram [37 ]. In this study, 292 functional
(10 or 20 mg) and tablets (20 mg) q.i.d. in 89 diabetic dyspepsia patients were recruited from eight US
patients with symptoms suggestive of gastroparesis. centers and randomized to 12 weeks treatment in
Total symptom score improved with all three treat- the evening with placebo, amitriptyline 50 mg, or
ment modalities with the nasal spray showing better escitalopram 10 mg. Gastric emptying rate was
tolerance and similar or higher efficacy compared obtained at baseline and the study evaluated
with the tablet. In a placebo-controlled follow-up adequate relief of functional dyspepsia symptoms
trial, the metoclopramide nasal spray was studied in at weekly intervals. Responder rates, defined as
diabetic patients with a clinical diagnosis of ‘gastro- adequate relief during at least 5 of the last 10 weeks
paresis’, based on scores on a gastroparesis daily in the trial, were 40% for placebo, 53% for amitripty-
diary. In this US multicenter study, 285 diabetic line, and 38% for escitalopram (P ¼ 0.05). In the
gastroparesis patients (82.5% type 2 diabetes) were subgroup with ulcer-like dyspepsia symptoms (pain
randomized to 4 weeks of placebo, metoclopramide as the most bothersome symptom), amitriptyline
10 mg or 14 mg sprays t.i.d., 30 min before meals resulted in more adequate relief compared with
[35]. Symptom assessment used a modified Gastro- placebo and escitalopram (67% versus, respectively,
paresis Cardinal Symptom Index Daily Diary, which 39 and 27%, P ¼ 0.06), whereas no significant
assessed the severity of four symptoms (nausea, benefit was seen in motility-like dyspepsia (pain is
bloating, early satiety, and upper abdominal pain) not the most bothersome symptom) (46, 41, and
on a 0–5 scale. Both metoclopramide doses and 43%). Delayed gastric emptying at baseline was
placebo generated similar symptom improvement. found in 21% of the patients. In the group with
In a prespecified analysis by sex, female patients normal emptying, responses were similar to the
showed significantly greater symptom relief to total group, with higher response rates for amitripty-
metoclopramide than placebo nasal spray. Metoclo- line. In contrast, no difference in response between
pramide was generally well tolerated, although dys- the three treatment arms was seen in those with
&
geusia, headache, and dizziness occurred more delayed emptying at baseline [37 ].
frequently than with placebo [35]. As this trial did
not require documented delayed gastric emptying,
it remains unclear how many of these patients truly Surgery and endoscopic therapeutic
had gastroparesis and how many had dyspeptic approaches
symptoms with normal emptying. Furthermore, as Surgery is often considered the last resort in severe,
metoclopramide crosses the blood–brain barrier, medically refractory, gastroparesis, and few out-
the nasal spray formulation does not eliminate come studies are available [38]. A consecutive
the risk of extrapyramidal and other central nervous series of 35 patients (86% women) who underwent
system adverse events. laparoscopic total or near-total gastrectomy for
gastroparesis symptoms failing to respond to proki-
netic and antiemetic therapies was reported [39].
Psychotropic agents The primary symptoms were reflux, followed by
Based on the assumption that visceral hypersensi- nausea and abdominal pain. Remarkably, 46%
tivity contributes to symptom generation, psycho- had previously undergone pyloromyotomy, 54%
tropics, especially tricyclic antidepressants, are fundoplication, and 23% gastric electrical stimu-
often used to treat gastroparesis, although convinc- lation treatment. Total gastrectomy with esophago-
ing evidence of their efficacy is lacking [1,2]. The jejunostomy was performed in six, and subtotal
issue was addressed in a placebo-controlled trial gastrectomy with gastrojejunostomy in the others.
with nortriptyline in idiopathic gastroparesis, in Surgical anastomotic leak, requiring reintervention,
which a total of 130 patients from nine tertiary care occurred in 17%. No questionnaires were used, but
centers were randomized to 15 weeks treatment at quantification based on clinical reporting with a
bedtime with placebo or nortriptyline in increasing median follow-up of 6 months, showed that surgery
dose every 3 weeks (10, 25, 50, and 75 mg in case of resulted in major improvement of nausea, bloating,
good tolerance). Symptom outcomes were not sig- and belching while no significant effect was
nificantly different between both treatment arms, obtained for pain [39]. Although significant weight

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Stomach and duodenum

loss was the rule after surgery (median BMI glycemic control in determining abnormal gastric
decreased from 32 to 26), all patients were able to motility in type 2 diabetes is less clear. In type 1
resume or maintain oral feeding. Although this diabetes, loss of ICCs, perhaps mediated through a
study shows that some patients may improve after lack of M2 macrophages, may be a key event at the
near-total gastrectomy, the patient group is unusual cellular level. Studies with the ghrelin agonist
with a high rate of previous surgical pyloromyoto- TRP-102 in diabetic gastroparesis and with tricyclic
mies and fundoplications. Moreover, the manu- antidepressants in idiopathic gastroparesis failed to
script lacks details on gastric emptying rate of show benefit. The role of dietary therapy is being
solids and liquids (may be rapid after vagus lesions, explored, and case series of favorable outcome
e.g., with fundoplication or pyloromyotomy). Man- with surgical or endoscopic interventions have been
cini et al. [40] reported a retrospective analysis on published.
the outcome of pyloroplasty in 46 patients with
refractory gastroparesis. During follow-up of up to Acknowledgements
one year, both the GCSI and gastric emptying rate None.
were significantly improved compared with pre-
operative results. Financial support and sponsorship
These surgical studies report favorable out- This work is supported by Methusalem grant from
comes, but in an uncontrolled setting, with rela- Leuven University to Prof. Jan Tack.
tively short follow-up. Taking into account older
literature, the surgical option in gastroparesis Conflicts of interest
should be considered with caution, and temporary
J.T. institution has received lecture fees from Abbott,
nasointestinal tube feeding can be used to evaluate
Almirall, Aptelis, AstraZeneca, Janssen, Menarini,
tolerance of nutrients rapidly entering the small
Novartis, Shire, and Zeria; he is a consultant for Alfa-
bowel [38]. A number of case series of gastric elec-
Wasserman, AstraZeneca, Danone, Ironwood, Janssen,
trical stimulator insertion for refractory gastropare-
Menarini, Novartis, Rhythm, Shire, Sucampo, Takeda,
sis were also published, with response rates of up to
Theravance, Tsumura, Yuhan and Zeria. Dr Tack is also
60% [41–43]. However, these uncontrolled case
a board member of the Rome Foundation and has
series should be considered cautiously, as the two
received grant support from Novartis, Shire, Tsumura
most recent controlled trials with gastric electrical
and Zeria. F.C. and A.R. have no conflicts of interest.
stimulation failed to show significant differences in
the blinded periods with stimulator on or off
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